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Review of clinical trials: Update on oral insulin spray formulation
Abstract
Large clinical trials have shown that improving glycaemic control significantly reduces the risk of long-term microvascular complications in type 1 (T1DM) and type 2 (T2DM) diabetes. Achieving optimal glycaemic control often requires the use of multiple daily insulin injections. Current approaches to insulin administration are less than optimal; many T2DM patients view insulin therapy as inconvenient and uncomfortable and may delay starting insulin therapy because of this. A new oral insulin spray formulation and delivery system provides an alternative to injectable and inhaled insulin. The system allows a liquid oral spray insulin formulation to be delivered into the mouth via an aerosolized spray. The oral insulin spray is a tasteless liquid aerosol mist formulation that is administered to the buccal mucosa using a proprietary delivery system. The active pharmaceutical ingredient is recombinant human insulin; however, the formulation behaves in a fashion more similar to the synthetic fast-acting insulin analogues. In clinical studies of healthy subjects and subjects with T1DM and T2DM, investigators have shown that the oral insulin spray was absorbed in direct relation to the amount given and had a faster onset and a shorter duration of action when compared with regular insulin given subcutaneously. In all of the studies conducted, the oral insulin spray was generally well tolerated. Some healthy individuals and subjects with T1DM experienced transient (1-2 min) mild dizziness during dosing; these symptoms were mild and self-limited. No changes in vital signs, laboratory values or physical examination results were noted. The ease of use of the insulin spray formulation may increase patient acceptance and treatment compliance, thereby potentially reducing complications and improving quality of life for patients with insulin-dependent diabetes. This article provides an overview of the safety profile and proposed mechanism of action of this insulin formulation and presents findings from trials which studied its effects in subjects with T1DM and T2DM.
... It contains insulin and absorption enhancers which is delivered via the RapidMist™ hand-held device and sends small particles from an aqueous spray into the oral cavity. It prevents deposition in the lungs and allows for buccal absorption [33,40,41]. Oral-lyn™ showed a dose dependent absorption profile with a faster onset and shorter duration as compared to subcutaneous regular insulin [40]. ...
... It prevents deposition in the lungs and allows for buccal absorption [33,40,41]. Oral-lyn™ showed a dose dependent absorption profile with a faster onset and shorter duration as compared to subcutaneous regular insulin [40]. This oral insulin can be efficient in controlling postprandial glucose levels in patients with T1DM and T2DM [42,43]. ...
Diabetes mellitus, a metabolic disorder of glucose metabolism, is mainly associated with insulin resistance to the body cells, or impaired production of insulin by the pancreatic β-cells. Insulin is mainly required to regulate glucose metabolism in type 1 diabetes mellitus patients; however, many patients with type 2 diabetes mellitus also require insulin, especially when their condition cannot be controlled solely by oral hypoglycemic agents. Hence, major researches are ongoing attempting to improve the delivery of insulin in order to make it more convenient to patients who experience side effects from the conventional treatment procedure or non-adherence to insulin regimen due to multiple comorbid conditions. Conventionally, insulin is administered via subcutaneous route which is also one of the sole reasons of patient’s non-compliance due to the invasiveness of this method. Several attempts have been done to improve patient compliance, reduce side effects, improve delivery adherence, and to enhance pharmaceutical performance of the insulin therapy. Despite of facing substantial challenges in developing efficient delivery systems for insulin, vast researches have been carried out for the development of smart delivery systems to delivery insulin via ocular, buccal, pulmonary, oral, transdermal, as well as rectal routes. Therefore, the present review was aimed to overview the challenges encountered with the current insulin delivery systems and to summarize recent advancements in technology of various novel insulin delivery systems being discovered and introduced in the current market.
... Oral-lyn™ consists of a mixed micellar solution containing insulin and absorption enhancers. Each puff delivers 10U insulin, and with an absorption rate of 10%, results in 1 U of insulin absorbed [5,44,45,48]. Clinical trials involving individuals with T1DM, T2DM, as well as healthy subjects found that Oral-lyn™ showed a dosedependent absorption profile, with faster onset and shorter duration relative to SC regular insulin [5,45]. ...
... Each puff delivers 10U insulin, and with an absorption rate of 10%, results in 1 U of insulin absorbed [5,44,45,48]. Clinical trials involving individuals with T1DM, T2DM, as well as healthy subjects found that Oral-lyn™ showed a dosedependent absorption profile, with faster onset and shorter duration relative to SC regular insulin [5,45]. ...
Diabetes mellitus is a chronic disease affecting a great number
of the world’s population. Insulin therapy for diabetes is most
commonly delivered via subcutaneous injections, up to four times
a day. Long-term insulin therapy, compounded by the invasive
nature of its administration, has caused problems with patient
compliance, ultimately influencing patient outcomes. Extensive
research has been carried out to date, to explore possible
improvements to insulin therapy for diabetic patients, with some
new products already available and FDA-approved. This review
aims to highlight the new discoveries in novel insulin formulations,
such as novel injectable insulins, artificial pancreas systems,
oral insulins, transmucosal insulins including buccal insulins,
pulmonary/inhaled insulins, nasal insulins, ocular insulins, and
rectal insulins, as well as transdermal insulins, from preliminary
research data to market available insulin products, and finally
discuss potential future directions of insulin therapy.
... Inhaled insulin formulations have been under development for several years, and existing products are able to mimic both first-and second-phase insulin responses [107][108][109][110][111]. Pfizer's Exubera was available in the US market for approximately six months, but it was unsuccessful and was discontinued [112] due to large, difficult to titrate volumes that needed dispensation by a large device. Other formulations of inhaled insulin are in the works [107,[113][114][115][116], and their absorption and action profiles are excellent [107][108][109][110][111][113][114][115][116]. Limitations of inhaled insulin include difficulty titrating the exact dose needed, potential absorption issues through alveolar and/or buccal membranes, the size of the insulin delivery device itself, and the potential of repeated insulin dosing causing hypertrophy or other problems in the lungs [107,117,118]. ...
... Inhaled insulin formulations have been under development for several years, and existing products are able to mimic both first-and second-phase insulin responses [107][108][109][110][111]. Pfizer's Exubera was available in the US market for approximately six months, but it was unsuccessful and was discontinued [112] due to large, difficult to titrate volumes that needed dispensation by a large device. Other formulations of inhaled insulin are in the works [107,[113][114][115][116], and their absorption and action profiles are excellent [107][108][109][110][111][113][114][115][116]. Limitations of inhaled insulin include difficulty titrating the exact dose needed, potential absorption issues through alveolar and/or buccal membranes, the size of the insulin delivery device itself, and the potential of repeated insulin dosing causing hypertrophy or other problems in the lungs [107,117,118]. ...
This review summarizes the technologies in use and in the pipeline for the management of diabetes. The review focuses on glucose meters, continuous glucose monitoring devices, insulin pumps, and getting clinicians connected to technologies. All information presented can be found in the public domain, and was obtained from journal articles, websites, product review tables in patient publications, and professional conferences. The technology concerns, ongoing development and future trends in this area are also discussed.
... Each puff delivers 10 IU and with an absorption rate of 10%, resulting in 1 IU absorbed. 200 Sponges, highly porous and flexible materials, are ideal as they possess mucoadhesive properties. Portero et al. 201 prepared a sponge from a mucoadhesive chitosan layer containing insulin and an impermeable protective layer made of ethylcellulose. ...
Monitoring blood glucose levels for diabetic patients is critical to achieve tight glycaemic control. As none of the current antidiabetic treatments restore lost functional β-cell mass in diabetic patients, insulin injections and the use of insulin pumps are most widely used in the management of glycaemia. The use of advanced and intelligent chemical engineering, together with the incorporation of micro- and nanotechnological-based processes have lately revolutionized diabetic management. The start of this concept goes back to 1974 with the description of an electrode that repeatedly measures the level of blood glucose and triggers insulin release from an infusion pump to enter the blood stream from a small reservoir upon need. Next to the insulin pumps, other drug delivery routes, including nasal, transdermal and buccal, are currently investigated. These processes necessitate competences from chemists, engineers-alike and innovative views of pharmacologists and diabetologists. Engineered micro and nanostructures hold a unique potential when it comes to drug delivery applications required for the treatment of diabetic patients. As the technical aspects of chemistry, biology and informatics on medicine are expanding fast, time has come to step back and to evaluate the impact of technology-driven chemistry on diabetics and how the bridges from research laboratories to market products are established. In this review, the large variety of therapeutic approaches proposed in the last five years for diabetic patients are discussed in an applied context. A survey of the state of the art of closed-loop insulin delivery strategies in response to blood glucose level fluctuation is provided together with insights into the emerging key technologies for diagnosis and drug development. Chemical engineering strategies centered on preserving and regenerating functional pancreatic β-cell mass are evoked in addition as they represent a permanent solution for diabetic patients.
... Occasional mild, self-limiting dizziness is some of the side effects observed in some of the clinical studies. Insulin spray formulation may significantly impact treatment compliance [267]. However, more clinical studies are needed to inform glycemic durability, safety, and tolerability. ...
The Research Society for the Study of Diabetes in India (RSSDI) has regularly updated its Clinical Practice Guidelines on various aspects of diabetes. The pharmacotherapeutic management of diabetes involves a plethora of agents targeting different aetiopathogenic mechanisms administered orally or via injections as well as insulin. While most people with type 1 diabetes need complete insulin replacement therapy with multiple-daily subcutaneous injections of insulin or a continuous subcutaneous insulin infusion pump, patients with type 2 diabetes may also need insulin as and when needed, especially owing to the declining beta cell function due to the progressive nature of their diabetes. To date, various insulin regimens including basal-bolus, split-mixed, premix, and prandial therapy are available which can be individualized based on the patient profile though their prescription is often perceived as complex for management of diabetes, forming a major barrier in the acceptability of insulin. In order to provide physicians with a simple guidance on different aspects of insulin use including choosing the right insulin and regime to match the individual patient, the RSSDI for the first time has formulated this guideline on insulin therapy using simple algorithms for insulin initiation as well as titrations based on a systematic literature search of new clinical evidences on all aspects of insulin use. Insulin therapy is hereby proposed as easy to initiate and maintain, efficacious, and a safer option which when administered appropriately can almost mimic physiological insulin secretion in diabetic patients and help them achieve target glucose control and minimize complications while improving their quality of life.
... When oral insulin sprayed into the mouth, it gets into the bloodstream very quickly. 16,17 In all of the studies conducted with the oral insulin spray showed that it was generally well tolerated. Some healthy individuals and subjects with T1DM experienced transient (1-2 min) mild dizziness during dosing; these symptoms were mild and self-limited. ...
p>Abstract not available
Northern International Medical College Journal Vol.9(2) Jan 2018: 283-285</p
... This small study, together with another study (data shown in Table 3), suggests that buccal insulin is more reflective of a normal insulin response to meal intake in individuals without DM compared with s.c. injections, taking less time to reach peak activity and having a shorter duration of action [85,86]. Although there are some advantages of the Oral-lyn TM device and formulation, its low bioavailability could be a major drawback to the product obtaining approval worldwide. ...
At present, the main form of insulin administration is the invasive subcutaneous (s.c.) route and, for many patients, this means managing their glucose levels with multiple daily injections, which is both painful and difficult to administer chronically. To increase patient compliance, products are slowly reaching the market that are more patient friendly, such as the insulin patch-pump systems, including Omnipod and V-Go, but also the inhaled-insulin Afrezza® and the buccal insulin Oral-lyn™. In this review, we outline the history of insulin, the various options that are currently available in practice for insulin delivery, and the non-invasive delivery systems that have entered the different stages of clinical trials over the past decade.
... developed an insulin pill that is taken by mouth and works like an injection of quick-acting insulin. [51][52] Limitations of this preparation include that the pill must be taken on an empty stomach for proper absorption. Additionally, if the patient has a second helping of food, the second dose of the insulin pill is not effective because the food that is already in the stomach prevents is absorption. ...
... developed an insulin pill that is taken by mouth and works like an injection of quick-acting insulin. [51][52] Limitations of this preparation include that the pill must be taken on an empty stomach for proper absorption. Additionally, if the patient has a second helping of food, the second dose of the insulin pill is not effective because the food that is already in the stomach prevents is absorption. ...
... addition of nicotinamide [4], utilizing biochaperone technology [5] or the addition of EDTA or hyaluronic acid [1]. Delivery of short acting insulin via alternative routes such as inhaled [6], intradermal [7], or oral [8] have also been studied, with inhaled short-acting insulin currently available for clinical use. ...
... 4,5 Therefore, insulin administration has been designed and tested using other mucous membrane routes, such as the nasal cavity and the eyes, but the bioavailability is still as poor as in the oral route. 4,[6][7][8] Daily injection devices composed of an insulin pump and a subcutaneous catheter have been proven to achieve glucose control, but the equipment is inconvenient, and the catheter insertion may cause pain. 6,9,10 Besides, several new insulin analogs for pharmacodynamic purpose have also been developed, such as rapid-acting human insulin analogues (Linjeta, glulisine), long-acting insulin analogues (glargine, detemir), and the components accelerating the absorption. ...
Dissolving microneedles (MNs) display high efficiency in delivering poorly permeable drugs and vaccines. Here, two-layer dissolving polymeric microneedle patches composed of gelatin and sodium carboxymethyl cellulose (CMC) were fabricated with a two-step casting and centrifuging process to localize the insulin in the needle and achieve efficient transdermal delivery of insulin. In vitro skin insertion capability was determined by staining with tissue-marking dye after insertion, and the real-time penetration depth was monitored using optical coherence tomography. Confocal microscopy images revealed that the rhodamine 6G and fluorescein isothiocyanate-labeled insulin (insulin-FITC) can gradually diffuse from the puncture sites to deeper tissue. Ex vivo drug-release profiles showed that 50% of the insulin was released and penetrated across the skin after 1 hr, and the cumulative permeation reached 80% after 5 hrs. In vivo and pharmacodynamic studies were then conducted to estimate the feasibility of the administration of insulin-loaded dissolving MN patches on diabetic mice for glucose regulation. The total area above the glucose level versus time curve as an index of hypoglycemic effect was 128.4±28.3 (% hr) at 0.25 IU/kg. The relative pharmacologic availability and relative bioavailability of insulin from MN patches were 95.6% and 85.7%, respectively. This study verified that the use of gelatin/CMC MN patches for insulin delivery achieved a satisfactory relative bioavailability compared to traditional hypodermic injection and presented a promising device to deliver poorly permeable protein drugs for diabetic therapy. This article is protected by copyright. All rights reserved.
... Clinical trials on this type of administration are promising. 1 Research in the area of non-invasive types of insulin has been the subject of numerous investigations. In addition to the aforementioned respiratory and buccal routes, investigators have sought other ways for insulin delivery, including nasal, vaginal, rectal, and oral routes. ...
Oral Administration of an Insulin-Soybean Suspension in Streptozocin Rats: Effect of Aqueous Soybean Extract Vehicle. Drug Development & Delivery
... However, insulin as a protein has some problems if given orally. Undergoing significant degradations of the protein in the gastrointestinal tract and poor absorption are the main crucial limitations (5)(6)(7)(8)(9)(10). Development of an appropriate delivery system for insulin, hence, is mandatory (11). ...
Non-invasive administration of insulin is expected for better diabetes mellitus therapy. In this
report, we developed intraoral preparation for insulin. Insulin was encapsulated into nanocarrier using
self-assembly emulsification process. To increase lipophilicity of insulin, it was dispersed in phospholipid
resulted in insulin-phospholipid solid dispersion. The microemulsion formula was established from our
previous work which contained glyceryl monooleate (GMO), Tween 20, and polyethylene glycol (PEG
400) in a ratio of 1:8:1. To confirm the formation of insulin-phospholipid solid dispersion, PXRD, FTIR
spectroscopy, and Raman spectroscopy were performed. Then, the microemulsion was evaluated for
droplet size and distribution, zeta potential, entrapment efficiency, physical stability, and Raman spectroscopy.
In addition, microemulsion with expected characteristic was evaluated for in vitro release,
in vitro permeation, and in vivo activity. The droplets size of ∼100 nm with narrow distribution and
positive charge of +0.56 mV were formed. The insulin encapsulated in the oil droplet was accounted of
>90%. Water-soluble chitosan seems to be a promising film matrix polymer which also functioned as
insulin release controller. Oral administration of insulin microemulsion to healthy Swiss-Webster mice
showed hypoglycemic effect indicating the success of this protein against a harsh environment of the
gastrointestinal tract. This effectiveness significantly increased by fourfold as compared to free insulin.
Taken together, microemulsion seems to be a promising carrier for oral delivery of insulin.
... Although injection of exogenous insulin is a commonly used method to regulate blood glucose in the later stages of diabetes mellitus, the insulin injection is slowly absorbed and requires daily administration, leading to insufficient feedback regulation of blood glucose. Furthermore, the treatment effect is not satisfactory and is inconvenient to the patients [9][10] . Pancreas transplantation and islet transplantation have been applied for the treatment of diabetes mellitus (mainly type 1), but did not achieve satisfactory effects because of the shortage of transplant donors and transplant rejection [11] . ...
Previous studies have shown that sericin extracted from silk cocoon significantly reduces blood glucose levels and protects the nervous system against diabetes mellitus. In this study, a rat type 2 diabetes mellitus model was established by intraperitoneal injection of 25 mg/kg streptozotocin for 3 successive days, following which the rats were treated with sericin for 35 days. After treatment, the blood glucose levels of the diabetic rats decreased significantly, the growth hormone level in serum and its expression in the hippocampus decreased significantly, while the insulin-like growth factor-1 level in serum and insulin-like growth factor-1 and growth hormone receptor expression in the hippocampus increased significantly. The experimental findings indicate that sericin improves disorders of the growth hormone/insulin-like growth factor 1 axis to alleviate hippocampal damage in diabetic rats.
... In addition, issues related to the variability in absorption and interference from food must be addressed. Other delivery routes that are not discussed in this Review include the buccal, nasal, vaginal and ocular routes [139][140][141][142][143][144] . ...
The formulation and delivery of biopharmaceutical drugs, such as monoclonal antibodies and recombinant proteins, poses substantial challenges owing to their large size and susceptibility to degradation. In this Review we highlight recent advances in formulation and delivery strategies - such as the use of microsphere-based controlled-release technologies, protein modification methods that make use of polyethylene glycol and other polymers, and genetic manipulation of biopharmaceutical drugs - and discuss their advantages and limitations. We also highlight current and emerging delivery routes that provide an alternative to injection, including transdermal, oral and pulmonary delivery routes. In addition, the potential of targeted and intracellular protein delivery is discussed.
... It has been estimated that the cost of insulin is around US$100 per patient and per month in developed countries [162]. In addition, with the progress in other delivery technologies, including buccal spray, inhalable, and oral, insulin will soon be increasingly administered through non-injected means, which require between 5 to 7 times more insulin per dose than injectable insulin [163]. Therefore, there is a great need to increase insulin mass production as well as to reduce the economic burden of patients with diabetes by decreasing the cost of insulin. ...
Type 1 diabetes (T1D) is an autoimmune form of diabetes mellitus that accounts for about 10% of all diabetes cases and occurs predominantly during childhood or adolescence. The disease initiates when most of the insulinproducing β-cells in the pancreas are destroyed by autoimmune cells, including T-helper1 cells, cytotoxic lymphocytes and dendritic cells. The major autoantigens in T1D are insulin, glutamic acid decarboxylase, and insulinoma antigen. At-risk individuals with underlying islet inflammation can be identified by the presence of circulating autoantibodies to these specific islet antigens many years before the clinical onset of T1D, thus, providing a window for prevention strategies. Currently, there is no definitive cure for T1D; therefore, more effective therapeutic interventions for prevention of diabetes onset and progression are urgently needed. Vaccination with autoantigens to promote selfantigen-specific tolerance represents the most specific and safest means of preventing autoimmune diseases.Autoantigens administered by the mucosal route, which is “tolerogenic” by nature, is the most effective way to prevent or treat autoimmune diseases. However, the two major drawbacks of oral vaccination with autoantigens arethe large quantities required to induce significant tolerance, presumably because the protein is partially degraded in the stomach, and the high cost of producing recombinant autoantigens using the conventional cell culture-based
platforms. The expression of autoantigens in plants and the oral delivery of the plant tissue expressing the target antigen offer a potential solution for these two drawbacks. The goal of this review is to outline novel diabetes vaccinestrategies based on β-cell autoantigens with a focus on the advantages and potential of plant-produced islets self antigens and anti-inflammatory cytokines for the prevention and treatment of T1D
... In some of the cases, noncompliance may be caused by the specific characteristics of the prescribed drugs. The drugs which are prescribed with the causes like unpalatible formulations of the drug, administration of the drug through difficult routes, administration of unsuitable dosage forms (especially for the paediatric and the geriatric populations), the appearance of side effects at therapeutic doses and the designing of difficult medicine containers, can also be included among the drug related factors which lead to noncompliance to the treatment [26][27][28]. ...
Nepal is one of the developing countries having many limitations
in providing the quality health services to its population. In
many countries, improvement in patients’ adherence to the
pharmacotherapy had been one of major outcome of quality
pharmaceutical services. Till date, very less thing has been done
in this area in Nepal; so it seems mandatory to improve the patient
adherence to the treatment plans. Adherence to the medical therapy
can be explained by the extent of the behavioral coincidence to
the medication and non-medication regimen by a patient whereas
compliance and concordance are two different models of patient
adherence to the therapy. Compliance model suggests that
patients have been brought responsible for being unable to follow
‘doctor’s order and concordance tempts to measure the degree
of agreement between patient and his or her clinician about the
nature of illness and the best possible therapy for the welfare of
the patient. Non-adherence to the therapy may lead to different
problems as consequences of non-adherence in four different
level- individual, institutional, societal and national levels. Although
some programs like, “Direct Observation Treatment, Short-course
(DOTS) for tuberculosis, implementation of antiretroviral treatment
schedules for HIV patients and pediatric vaccination models,” are
the examples of attention towards the cases of noncompliance in
Nepal. It has long been faced its limitations in the forms of either
untrained manpower or lack of good documentation of patients’
adherence to therapy or high illiteracy rate or unaffordibility of
patients to their treatment or lack of pharmaceutical care services.
... Only side effects noted include mild, self-limited episodes of transient (1-2 min) mild dizziness during dosing in some healthy volunteers and subjects with type 1 DM. No changes in vital signs, laboratory values or physical examination results were said to have occurred [30] . The product is said to be on the market in a number of countries (e.g., Ecuador and India) [29] . ...
Insulin is a key player in the control of hyperglycemia for type 1 diabetes patients and selective individuals in patients of type 2 diabetes. Insulin delivery systems that are currently available for the administration of insulin include insulin syringes, insulin infusion pumps, jet injectors and pens. The traditional and most predictable method for the administration of insulin is by subcutaneous injections. The major drawback of current forms of insulin therapy is their invasive nature. To decrease the suffering, the use of supersonic injectors, infusion pumps, sharp needles and pens has been adopted. Such invasive and intensive techniques have spurred the search for alternative, more acceptable methods for administering insulin. Several non-invasive approaches for insulin delivery are being pursued. The newer methods explored include the artificial pancreas with closed-loop system, transdermal insulin, and buccal, oral and pulmonary routes. This review focuses on the new concepts that are being explored for use in future.
... Oral spray formulations of insulin with penetration enhancers, have been studied clinically in both volunteers and patients with type I and type 2 diabetes. (Pozzilli et al., 2010) 8 for delivery to the buccal mucosa: 10% of the administered insulin is said to be absorbed systemically. Performance was compared to standard subcutaneous insulin; it had a faster onset of action but a duration of action three times less than the sc insulin. ...
... Buccal spray insulin is absorbed by the mucosa of the mouth and has a faster onset than injectable insulin. Limitations of this approach include a shorter duration of action and a dosage requirement that is 5-7 times higher than injectable insulin as well as mild side effects such as dizziness (Pozzilli et al., 2010). Inhalable insulin faces similar challenges. ...
Current treatment for type I diabetes includes delivery of insulin via injection or pump, which is highly invasive and expensive. The production of chloroplast-derived proinsulin should reduce cost and facilitate oral delivery. Therefore, tobacco and lettuce chloroplasts were transformed with the cholera toxin B subunit fused with human proinsulin (A, B, C peptides) containing three furin cleavage sites (CTB-PFx3). Transplastomic lines were confirmed for site-specific integration of transgene and homoplasmy. Old tobacco leaves accumulated proinsulin up to 47% of total leaf protein (TLP). Old lettuce leaves accumulated proinsulin up to 53% TLP. Accumulation was so stable that up to ~40% proinsulin in TLP was observed even in senescent and dried lettuce leaves, facilitating their processing and storage in the field. Based on the yield of only monomers and dimers of proinsulin (3 mg/g leaf, a significant underestimation), with a 50% loss of protein during the purification process, one acre of tobacco could yield up to 20 million daily doses of insulin per year. Proinsulin from tobacco leaves was purified up to 98% using metal affinity chromatography without any His-tag. Furin protease cleaved insulin peptides in vitro. Oral delivery of unprocessed proinsulin bioencapsulated in plant cells or injectable delivery into mice showed reduction in blood glucose levels similar to processed commercial insulin. C-peptide should aid in long-term treatment of diabetic complications including stimulation of nerve and renal functions. Hyper-expression of functional proinsulin and exceptional stability in dehydrated leaves offer a low-cost platform for oral and injectable delivery of cleavable proinsulin.
Owing to their structural diversity, peptides are a unique source of innovative active ingredients. However, their development has been challenging because of their disadvantageous pharmacokinetic (PK) properties. Over the past decade, many attempts have been made to improve the oral bioavailability of peptide drugs. In this review, we highlight the most recent and promising techniques aimed at the improvement of the oral bioavailability of peptides. The most recent findings will influence future approaches of pharmaceutical companies in the development of new, more efficient, and safer orally delivered peptides.
Advances in insulin treatment options over recent decades have markedly improved the management of diabetes. Despite this, glycemic control remains suboptimal in many people with diabetes. Although postprandial glucose control has been improved with the development of subcutaneously injected rapid-acting insulin analogs, currently available insulins are not able to fully mimic the physiological time–action profile of endogenously secreted insulin after a meal. The delayed onset of metabolic action and prolonged period of effect induce the risk of postprandial hyperglycemia and late postprandial hypoglycemia. A number of alternative routes of insulin administration have been investigated over time in an attempt to overcome the limitations associated with subcutaneous administration and to provide an improved time–action insulin profile more closely simulating physiological prandial insulin release. Among these, pulmonary insulin delivery has shown the most promise. Technosphere® Inhaled Insulin (TI) is a rapid-acting inhaled human insulin recently approved by the FDA for prandial insulin therapy. In this article we discuss the pharmacokinetic and pharmacodynamic properties of TI, and, based on key studies performed during its clinical development, the implications for improved postprandial glucose control.
Endogenous insulin is the chief regulator of glucose homeostasis. It is formed in pancreatic beta cells and released into the portal vein in a pulsatile manner to act on the liver, muscle, other body organs, and on peripheral tissues. Insulin reduces hepatic glycogenolysis and gluconeogenesis, promotes glucose uptake and glycogenesis in liver and muscle, and triggers conversion of excess glucose to fatty acids for storage as triglycerides in adipose tissue (Hellman 2009; Zierler 1999).
SUMMARY Since its introduction, insulin therapy for diabetes has long been equated with pain, anxiety, lifestyle inconvenience and potential injection-site irritation and lipodystrophy. Efforts to develop noninvasive methods for insulin delivery have relied on molecular modifications, absorption enhancers and encapsulation techniques to resist degradation, promote drug penetration and achieve therapeutic plasma insulin levels. Product development attempts have targeted virtually every mucosal membrane in the body for potential drug delivery. Each administration route has unique physiologic constraints. Potential alternative insulin therapies are discussed with their respective technical challenges. An overview of new drug-delivery platforms currently in development is also provided.
The importance of insulin in the management of diabetes mellitus cannot be over emphasized. Newer formulations and delivery devices have improved the efficacy, safety and tolerability of insulin. All available insulins and insulin analogues, however, are administered by subcutaneous insulin. The subcutaneous route of administration is associated with a certain level of discomfort, which is not acceptable to some patients. This has led researchers to explore other methods of insulin delivery. Inhaled insulin, nasal insulin and oral insulin are some of the novel insulins which have been studied. This review highlights recent advances and patents related to oral insulin. It covers the limitations of subcutaneous insulin, the physiological rationale of administering oral insulin, and the barriers to these formulations. The review is based on a literature search, done by all authors, using the key words "oral insulin", from 1991 to 2010, using PubMed and Google Scholar. All four authors decided the relative importance of papers on various oral insulin formulations. Focus was kept on oral preparations which are still in active development, and stand a chance of reaching the commercial market. The review studies the methods of producing oral insulin such as encapsulation, protease inhibitor use, PEGylation, permeation enhancer use and liposomal administration. It highlights recent patents and studies for all these methods.
Diabetes Mellitus, a syndrome of disordered metabolism, characterised by abnormal elevation in blood glucose level, has become a life-threatening condition for many people. Current means of therapy for Diabetes Mellitus do not mimic the normal physiological pattern of insulin release. Oral delivery is the preferred route of administration due to its non-invasive nature. Oral delivery of insulin presents an overview of Diabetes Mellitus, and discusses the strategies and techniques adopted for oral delivery of insulin. This title begins with an introductory chapter on symptoms, complications and therapy for Diabetes Mellitus. Subsequent chapters cover the various routes for administering insulin; the challenges and strategies of oral delivery; experimental techniques in the development of an oral insulin carrier; lipids; inorganic nanoparticles and polymers in oral insulin delivery; and a summary and presentation of future perspectives on oral delivery of insulin. • Presents an overview of Diabetes Mellitus • Includes a discussion of various strategies and techniques adopted for oral delivery of insulin • Presents an update of research in the field.
The possibility of administering insulin orally instead of through painful subcutaneous route has been investigated over years in the arena of diabetes medicine. Nanoparticles, microparticles, hydrogel, capsule, tablet and film patch are dosage forms designed to deliver insulin orally. They are largely formulated with polymeric adhesive, protease inhibitor, insulin aggregation inhibitor and functional excipients to induce transcellular, paracellular, Peyers patches or receptor mediated transport of insulin in gastrointestinal tract. This review probes into pre-clinical and clinical performances of patenting and new oral insulin delivery systems formulated from polysaccharides, such as chitosan and alginate, in the form of nanoparticles. Their effectiveness at pre-clinical and clinical stages will be highlighted to provide an updated insight on the efforts devoted by researchers and industrialists.
Abstract An increasing number of medical conditions are chronically or acutely managed with some form of aerosolized therapy. Due to the benefit of directly administering medications to the intended site of action, there is great interest in evaluating treatments for aerosol use. One of the major challenges in selecting and testing new drug-device combinations in children is the uncertainty regarding the appropriate outcome measure to choose. In studies involving adult patients, typically exacerbations of disease or airflow obstruction are assessed as endpoints in drug trials or device assessment. However, in young children, choosing endpoints to assess efficacy is difficult due to the potential lack of sensitive, noninvasive endpoints that are easily performed across sites. In this review, we discuss the challenges and limitations of selecting clinical endpoints for drug-device trials in the youngest population, with a focus on novel emerging technologies. This article provides an overview of preschool and infant pulmonary function testing, multiple-breath washout, imaging techniques including computed tomography and magnetic resonance imaging, flexible bronchoscopy in children, mucociliary clearance scans, and exhaled breath condensate.
The development of Exubera(®) (inhaled insulin) has paved the way for consideration of future inhaled biotherapeutic products for systemic delivery. This route of drug delivery favors highly potent small peptides without self-association and large proteins resistant to enzymatic degradation for high bioavailability, while likely resulting in transient therapeutic effects. Improved therapeutic benefits with a needle-free delivery, such as inhaled insulin, are also rational pursuits. Molecules and their formulations must be carefully chosen and designed to optimize the rates of lung absorption and nonabsorptive loss. Novel molecular or formulation approaches, for example, Technosphere(®), Fc-/scFv-fusion protein, PEGylation, polymeric or lipid-based micro/nanoparticles and liposomes, offer opportunities to improve lung absorption and therapeutic duration of some biotherapeutics. Critical assessments are now essential as to their therapeutic benefits, safety, patient acceptance and market competition, as carried out for Exubera.
Aging is associated with alterations in insulin secretion and action. However, aging per se does not alter the pharmacokinetics of commercially available insulin and its analogues. Insulin therapy in older adults is complicated by psychosocial and physiological changes of aging. Several new insulin and insulin analogue preparations are now available for clinical use. Used as prandial (e.g. insulin lispro, insulin aspart or insulin glulisine) and basal insulin (e.g. insulin glargine, insulin detemir), these analogues simulate physiological insulin profiles more closely than the older conventional insulins.
The availability of multiple insulin products provides new opportunities to achieve control of diabetes mellitus. The choice of initial insulin therapy can be made based on blood glucose profiles. Overall, these profiles can be divided into three general patterns that include: (i) round-the-clock hyperglycaemia; (ii) fasting hyperglycaemia with daytime euglycaemia; and (iii) daytime hyperglycaemia with normal fasting blood glucose levels. The prescription of insulin is a dynamic process, and the insulin regimen should be adjusted based on individual response. The goal of diabetes care in older adults is to enhance quality of life without subjecting individuals to complicated treatment regimens that may interfere with their independence in carrying out daily activities.
The prevalence of diabetes mellitus increases with age and causes significant morbidity and poor quality of life in older adults. To review the current literature on the diagnosis and management of diabetes in the elderly, the relevant manuscripts were identified through a MEDLINE (2000-September 1, 2010) search of the English literature. The key phrase used was diabetes in older adults or diabetes in the elderly. The literature search was limited to core clinical journals that have accessible full texts. A total of 480 manuscripts were reviewed. Managing diabetes in older adults is a challenging task. Some features of the disease are unique to the older patient. Several new antidiabetic agents are now available for clinical use, and yet very few clinical trials have been carried out in this age group. For many older adults, maintaining independence is more important than adherence to published guidelines to prevent diabetes complications. The goals of diabetes care in older adults are to enhance quality of life without subjecting the residents to inappropriate interventions.
Background Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. Methods 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or. glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. in the conventional group, the aim was the best achievable FPG with diet atone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye,or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. Findings Over 10 years, haemoglobin A(1c) (HbA(1c)) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group-an 11% reduction. There was no difference in HbA(1c) among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). Interpretation Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes. None of the individual drugs had an adverse effect on cardiovascular outcomes. All intensive treatment increased the risk of hypoglycaemia.
Where adjustments of diet, physical activity, and dosage of insulin are well known to diabetologists and diabetic patients, present-day knowledge of factors of importance to the pharmacokinetics of insulin is frequently ignored. The pharmacokinetics of insulin comprise the absorption process, the distribution including binding to circulating insulin antibodies, if present, and to insulin receptors, and its ultimate degradation and excretion. The distribution and metabolism of absorbed insulin follow that of endogenous insulin. The distribution and metabolism cannot be actively changed, except in the case of circulating insulin antibodies, which in rare cases also may cause insulin resistance. The use of insulin preparation of low immunogeneity will avoid or reduce this course of variation in action. The absorption process, the detailed mechanisms of which are still unknown, is influenced by many variables where some can be controlled, thereby reducing the intrapatient variability in insulin absorption, which may reach 35%, causing a corresponding metabolic lability. Besides the known differences in timing among different preparations, the size of dose, the injected volume, and the insulin concentration are determinants of absorption role. Fortuitous injection technique contributes to variance, as do changes in blood flow of the injected tissue. This may be induced by changes in ambient temperature, exercise of injected limb, or local massage. Regional differences are also due to differences in blood flow. Serum insulin peaks may peak up to 1 h after injection of soluble insulin into the thigh versus into the abdominal wall. Local degradation of insulin seems of less importance but may, in rare cases, be the cause of high insulin "requirements." Available evidence is reviewed and the importance of implementing the consequences in the daily care of the insulin-treated patient is emphasized.
This paper describes systematic studies on the absorption kinetics of exogenous insulin from its subcutaneous tissue depot in 52 male nonobese volunteers (age 20-30 yr). Five experimental protocols were used: effect of changing injection site, effect of temperature change and local massage, effect of aprotinin and human serum, effect of mixing regular insulin with long-acting insulin preparations, and effect of temperature change, muscular exercise, and local massage on the absorption of long-acting insulin preparations. The fastest absorption of insulin occurred at the abdominal injection. Absorption after arm injection was faster than after thigh injection. A hot bath and local massage dramatically increased serum insulin levels in the first 90 min after injection; in contrast, a cold bath delayed absorption substantially. Both aprotinin and the subjects' own blood serum mixed with insulin caused a marked acceleration of the insulin absorption process. Absorption kinetics of two neutral regular insulins (Actrapid and Leo Regular) were virtually identical. Mixing Actrapid with Monotard caused higher serum insulin levels than the mixture of Leo Regular with NPH. A time lag of 5 min between the mixing of Actrapid and Monotard and the injection caused a delayed rise of serum insulin levels; in contrast, this delay could not be observed when Leo Regular and NPH were mixed. Volunteers performed bicycle exercise, applied a hot water bottle to the injection site, or rubbed the injection site 2 1/2 h after injection of long-acting insulin. Accelerated absorption of insulin was only observed after local massage of the injection site of Monotard, Leo NPH, and Mixtard. Local heat had no effect. Exercise caused only an increased absorption of insulin after the Mixtard injection but not after Monotard or NPH injection. These findings have clinical significance and should not be without potential benefit in the attempt to improve metabolic control in insulin-treated diabetic patients.
This study examines NIDDM patients' attitudes toward insulin injections, the basis of these attitudes, and how they may affect patients' willingness to take insulin.
Forty-four low-income Mexican American NIDDM patients were interviewed using open-ended in-depth interviewing techniques. Transcripts were analyzed using techniques of content analysis. Data classification was cross-checked in analysis conferences and through a second researcher coding 50% of the cases, comparing the results, then resolving any discrepancies.
Patients' positive attitudes toward insulin focus on its efficacy and efficiency, the avoidance of complications, and feeling better and more energetic. Negative attitudes were much more frequently discussed and include "technical concerns": anxiety about the pain, proper techniques, and general hassles of taking injections; about hypoglycemic symptoms; and about insulin causing serious health problems; and "experimental concerns": sensing that the disease has progressed into a serious phase, that past treatment efforts have failed, and that the patient has not taken proper care. Attitudes were based on personal experience, observation, what others say, and interactions with health care professionals.
Results from the few published reports on NIDDM patients' attitudes about insulin from various cultural settings were consistent with our findings, indicating that these themes may be generally applicable to a wider population. It is recommended that health care providers take care to avoid unwitting promotion of negative attitudes toward insulin and actively elicit and respond to patient attitudes to reduce reluctance to take the medication.
To evaluate the pharmacodynamic and pharmacokinetic properties and the dose-ranging effects of an oral insulin spray in comparison with subcutaneous regular insulin.
In this randomized, five-way, cross-over study, seven healthy volunteers were assessed under euglycemic clamp and received four different doses of oral spray and one dose of subcutaneous regular insulin.
The time to maximum insulin concentration was shorter for oral insulin than for subcutaneous insulin (25.9 +/- 9 vs. 145.7 +/- 49.5 min, P < 0.05). Maximum serum insulin levels (C(max)) were comparable between the subcutaneous and 20 puffs of oral insulin (39.1 +/- 19.6 vs. 34.0 +/- 7.4 microU/ml, NS). The Ins-AUC(0-120) (area under the curve from 0 to 120 min for serum insulin) (339.8 +/- 218, 681.3 +/- 407, and 1,586.7 +/- 8 microU/ml, P < 0.05) and C(max) (7.6 +/- 2.8, 16.4 +/- 9.3, and 39.1 +/- 19.6 microU/ml, P < 0.005) proved a dose-response relationship for the three doses of oral insulin (5, 10, and 20 puffs, respectively). Oral insulin had an earlier onset of action (31.7 +/- 12 vs. 77.8 +/- 3 min, P < 0.05), earlier peak (44.2 +/- 10 vs. 159.2 +/- 68 min, P < 0.05), and a shorter duration of action (85.1 +/- 25 vs. 319.2 +/- 45 min, P < 0.05) compared with subcutaneous insulin. The maximum metabolic effect (1.7 +/- 1.0, 3.09 +/- 1.7, and 4.6 +/- 1.5 mg . kg(-1) . min(-1), P < 0.05) and the GIR-AUC(0-120) (amount of glucose infused from 0 to 120 min) (106.7 +/- 74.3, 162.9 +/- 116.1, and 254 +/- 123 mg/kg) increased in a dose-dependent relationship for the three doses.
Oral insulin was absorbed in direct relation to the amount given and had a faster onset and a shorter duration of action compared with subcutaneous regular insulin. A dose-response relationship in the absorption and metabolic effect of the oral insulin was noted.
The aim of this study was to compare the glucose pharmacodynamics after oral spray insulin (Oral-lyn , Generex Biotechnology, Toronto, ON, Canada) and subcutaneous (sc) injection of regular insulin in 10 subjects with type 1 diabetes mellitus (T1DM).
Basal therapy was twice-daily insulin glargine. Preprandial (30 min) regular insulin was given for 3 days, followed by 9 days of Oral-lyn, eight to 12 puffs immediately pre- and postprandially. Adjustments for glycemia were made using standard snacks and additional regular insulin or Oral-lyn. Peripheral glucose measurements were self-monitored in duplicate. Serum concentrations of fructosamine and hemoglobin A1c (HbA1c) were determined at the start and the end of the study period.
Average glucose concentrations (in mmol/L) for the 3-day regular insulin and 9-day Oral-lyn periods, respectively, were: pre-breakfast (B), 5.06 and 3.89; 1-h post-B, 8.39 and 7.67; post-B, 6.00 and 6.33; pre-lunch (L), 5.50 and 4.72; 1-h post-L, 7.83 and 7.89; 2-h post-L, 5.89 and 6.33; pre-dinner (D), 5.61 and 5.17; 1-h post-D, 7.22 and 7.83; and 2-h post-D, 6.11 and 6.67. Areas under the curve for both treatments were not significantly different (P = 0.6875). Fructosamine (mean +/- SD, 338.7 +/- 77.4 micromol/L and 321.7 +/- 63.4 micromol/L), and HbA1c (mean +/- SD, 7.5 +/- 1.5% and 7.2 +/- 1.2%) did not change significantly.
Regular insulin and Oral-lyn had similar glucodynamic effects in subjects with T1DM receiving twice-daily insulin analogue as baseline therapy. Intensive monitoring and timely corrections with additional snacks, additional sc regular insulin, or Oral-lyn puffs resulted in appropriate glycemic control as assessed by individual daily glycemic responses and, especially, normal preprandial glycemia. Protein glycation decreased, but not significantly.
BACKGROUND
Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications.
METHODS
A total of 1441 patients with IDDM -- 726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly.
RESULTS
In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of ≥ 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of ≥ 300 mg per 24 hours) by 54 percent (95 percent confidence interval, 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia.
CONCLUSIONS
Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.
Inhalation of regular insulin for meal time glucose control has been found to be safe, efficacious and reliable in Type I and Type II diabetics. The administration of regular insulin through the human lungs by inhalation has been conducted in at least 14 short studies in both normal and diabetic subjects beginning as early as 1925. In all studies, significant insulin absorption and lowering of blood glucose was observed in the absence of penetration enhancers. Although a concern of variable dosing was raised in early studies, the development of new reproducible delivery systems has ensured that the variability of aerosol insulin can be as good, if not better, than subcutaneous (SC) injection. In the longest controlled studies in humans to date, both Type I and Type II insulin-dependent diabetics used a novel inhaled dry powder insulin delivery system for 3 months for meal time glucose control. The study results indicate that inhaled insulin provides equivalent glucose control, measured by hemoglobin A1c, when directly compared to SC injection. Interim results from an additional study with Type II diabetics who were failing oral hypoglycemic agents suggest that adjunctive therapy with inhaled insulin markedly improved glycemic control with a low risk of hypoglycemia. In all the 3 month studies the system was efficacious, well tolerated, well liked, and resulted in reproducible results. A potential advantage of aerosol insulin is that it is more rapidly absorbed (serum peak at 5–60 min) and cleared than SC injection (peak at 60–150 min), which provides a more relevant and convenient therapy for meal time glucose control. The relative efficiency of insulin delivery by aerosol, compared to SC injection, has been estimated from the dose measured at the exit point of the aerosol device, and found to range between 8 and 25% of SC, depending on the study.
The burgeoning number of people with diabetes mellitus is a global problem. Simple but effective treatment with minimal side effects will be required to reduce the risk for macro- and micro-vascular complications. A big part of this goal can be achieved by the ready administration of insulin with or without other medications.
The RapidMist drug delivery system places human recombinant insulin in a liquid formulation so as to be delivered to the buccal mucosa with an asthma-like device. As with nitroglycerin, the insulin PK-PD is very fast, thus affording flexibility.
Serial data show clinical efficacy in Type 1 and Type 2 diabetes with at least non-inferiority to regular insulin.
The present study was designed to determine, in a cross-sectional study, whether there was any relationship between levels of lactate dehydrogenase (LDH) and myeloperoxidase (MPO) in gingival crevicular fluid (GCF) and clinical periodontal status or microbial parameters. Another objective was to determine, in a longitudinal study, the effect of a single session of root planning on GCF levels of LDH and MPO and the relation to changes in clinical and microbial measurements. 15 and 12 test subjects with moderate to severe periodontal disease were seen in the cross-sectional and longitudinal study, respectively. 1 healthy and 2 diseased sites were evaluated in each subject. Higher LDH and MPO levels in GCF were closely associated with higher clinical and microbial signs of periodontal disease. Root planing was effective in reducing these enzymes in GCF, with an accompanying decrease in clinical and microbial signs associated with disease. The return of LDH to baseline levels at 3 months after instrumentation, without a corresponding return of clinical signs of disease, may serve as a marker for subclinical periodontal pathology.
Normal fasting subjects received regular insulin and mixtures of regular with NPH or lente to assess the effects of the combinations on serum insulin concentrations (SIC) and blood glucose responses (BGR). In addition, the influence of concentration, depth, and method and site of administration was investigated. In studies of mixtures of regular with NPH and with lente, it was observed that the regular: lente ratio needed to achieve peak SIC was higher than with the regular: NPH combination. Increased SIC, including either the peak and/or the time interval required to achieve the peak, were related to the depth and site (deltoid and abdominal greater than anterior thigh or buttocks). Assuming linear kinetics of absorption, significant quantities of insulin fail to reach the serum. Marked intra- and intersubject variations in SIC and BGR to regular, NPH, and lente insulins were observed.
Needle phobia in patients with Type 1 (insulin-dependent) diabetes mellitus is difficult to manage. We report a case of long-standing needle phobia in a patient with 33 years of Type 1 diabetes mellitus who has developed very few vascular complications. Further studies are required to identify the prevalence of needle phobia in Type 1 diabetes mellitus. Once these individuals have been identified, appropriate psychological and physical treatments should be implemented, in the hope of making such individuals less fearful of the treatment of their condition.
Conventional insulin therapy with subcutaneous injections of regular insulin at meal-times result in plasma insulin peaks that are lower and appear later than meal related insulin peaks in healthy individuals. The present study was designed in order to evaluate the resulting insulin concentrations in peripheral blood after inhalation of micro crystalline human insulin together with an absorption enhancer [dioctyl sodium sulphosuccinate (DOSS)] via a powder inhaler.
Ten insulin dependent middle-aged non-obese diabetic patients (mean diabetes duration 21 years) were included. Blood samples for glucose and insulin were taken immediately before and 13 times, up to 300 min, after insulin inhalation. The mass median aerodynamic diameter of the particles was 3.2 microm. The inhaled insulin dose was 39 U.
Within 5 min after the end of the 2 min inhalation procedure the mean increase of insulin was 7.0 microU ml-1, and the mean maximum concentration, 12.1 microU ml-1, was reached between 20 and 30 min. There was then a slow decline until base-line was reached after around 210 min and there were no adverse events.
Inhalation of a mixture of 39 U of insulin and enhancer resulted in a rapid plasma insulin peak with a slow decline, similar to the normal postprandial insulin profile.
Insulin therapy has proven benefits in Type 2 diabetes patients when combination therapy has failed. However, there is some reluctance by both patients and healthcare professionals to initiate insulin therapy. This reluctance has been termed 'psychological insulin resistance'. Barriers to the initiation of insulin therapy include patients' fear of disease progression and needle anxiety; mutual concerns about hypoglycaemia and weight gain; and health professionals' use of insulin as a threat to encourage compliance with earlier therapies. It is essential that these obstacles are identified and investigated as a means of overcoming these impediments to recommended levels of glycaemic control, an initiative being pursued by the DAWN study. Where concerns are tangible, such as fear of hypoglycaemia, therapeutic solutions can be pursued. Overcoming psychological barriers relies more on innovative management techniques. Improving insulin delivery to meet these needs, coupled with enhanced healthcare services, can address psychological insulin resistance and contribute to the maintenance of good metabolic control.
The aim of this study was to determine the metabolic effect and the safety of a novel oral insulin spray (Oralin) formulation at breakfast-time in subjects with type 2 diabetes with suboptimal glucose control and maintained on a combination therapy of oral hypoglycemic agents (OHAs). This was an open-label, crossover, randomized study design in subjects (n = 21) with type 2 diabetes (glycated hemoglobin A1c >8.0%). Subjects received each of the following treatments, in random order: metformin + glyburide and placebo puffs at time 0 min; or metformin + glyburide and Oralin spray (100 U) at time 0 min. Fifteen minutes later, subjects were given a standard breakfast containing 360 calories [Sustacal (Mead Johnson, Evansville, IN) liquid meal]. Blood samples were taken at regular intervals to measure serum glucose, insulin, and C-peptide. Time-averaged postprandial glucose increments (PPGIs) between 0 and 240 min were calculated for each treatment. Group mean PPGIs to OHAs versus Oralin in combination with OHAs were compared to determine the mean efficacy of the active treatment. The Oralin spray lowered the 2-h postprandial glucose rise significantly in comparison with the OHAs alone. The serum insulin levels were significantly higher with faster onset of action in the Oralin spray treatment when compared with the OHAs treatment. The reductions in C-peptides were also significantly greater in the Oralin arm than in the OHAs treatment. This study results demonstrated that Oralin could be used as meal insulin as an add-on therapy in combination with failing OHAs treatment in subjects with type 2 diabetes to regulate postprandial glucose levels.
Insulin therapy often relies on multiple daily injections of insulin. However this is a considerable burden to many people with diabetes and adherence to such an insulin regimen can be difficult to maintain, hence compromising optimal glycaemic control. Also, short acting injected insulin is absorbed more slowly than insulin released by the normal pancreas in response to a meal. Inhaled insulin has the potential to reduce the number of injections to perhaps one long-acting insulin per day, and provide a closer match to the natural state, by more rapid absorption from the lung.
To compare the efficacy, adverse effects and patient acceptability of inhaled versus injected insulin.
A sensitive search strategy for randomised controlled or cross-over trials was combined with key terms for inhaled insulins. Databases searched were: The Cochrane Library, MEDLINE, PubMed, EMBASE, Science Citation Index, BIOSIS, Web of Science Proceedings, National Research Register UK, Current Controlled Trials, ClinicalTrials.gov, Conference Papers Index, LexisNexis, and web sites of the ADA and EASD were searched for recent meeting abstracts. Reference lists and journals were handsearched. There were no language restrictions on searching. Manufacturers of inhaled insulin were also contacted. Date of last search October 2002.
Only randomised controlled trials with parallel groups or controlled cross-over trials, including type 1 or type 2 diabetic patients of any age treated with insulin, were considered eligible. The minimum trial duration considered was 10 weeks, as this is the time taken for glycated haemoglobin to reliably reflect changes in glycaemic control.
Trial selection and evaluation of study quality was performed independently by two reviewers. The quality of reporting of each trial was assessed according to a modification of the criteria outlined in Centre for Reviews and Dissemination (CRD) Report 4, Spitzer; and Jadad.
Six randomised controlled trials were found and the overall number of participants was 1191. Three trials included patients with type 1 diabetes and three with type 2 diabetes. Three trials had a duration of 24 weeks, and three of 12 weeks. All were open label. There was insufficient information to determine the study quality. Results for HbA1c were similar for all trials, in that all showed comparable glycaemic control for inhaled insulin compared to an entirely subcutaneous regimen. All trials that reported patient satisfaction and quality of life showed that these were significantly greater in the inhaled insulin group. Overall there was no difference in total hypoglycaemic episodes between the groups, but one trial showed a statistically significant increase in severe hypoglycaemic episodes for the inhaled insulin group. No adverse pulmonary effects were observed in any of the studies, but longer follow-up will be required to be sure that there are no adverse side-effects. Cavets include: few studies published in full (so quality could not be assessed), and only two studies used the same basal regimen in both the inhaled and injected groups.
Inhaled insulin taken before meals, in conjunction with an injected basal insulin, has been shown to maintain glycaemic control comparable to that of patients taking multiple daily injections. The key benefit appears to be that patient satisfaction and quality of life are significantly improved, presumably due to the reduced number of daily injections required. However, the patient satisfaction data is based on five trials, of which only two have been published in full; also the three trials containing quality of life data are all only published in abstract form at present. In addition, longer term pulmonary safety data are still needed. Also, the lower bioavailability, and hence higher doses of inhaled insulin required, may make it less cost-effective than injected insulin.
Proof-of-concept study of evaluation of metabolic effect of novel oral spray insulin (Oralin) formulation at breakfast time in subjects with type 2 diabetes on multiple daily injections.
This was an open-label, crossover, randomized study in (n = 23) subjects with type 2 diabetes on multiple daily injections. Subjects received each treatment, in random order, 3 to 7 days apart-a daily dose of SC injection (0.1 u/kg) on one occasion and Oralin spray (100 u) at time 0 min on another occasion. Subjects were given a standard breakfast containing 360 cal (Sustacal liquid meal) 10 min after the dose. Blood samples were taken at regular intervals to measure glucose, insulin, and C-peptide.
The 30- and 60-min postprandial glucose levels were significantly lowered with Oralin versus that with the injection treatment (146 +/- 5 mg/dL Oralin vs 184 +/- 7 mg/dL injection at 30 min and 192 +/- 6 mg/dL Oralin vs 236 +/- 9 mg/dL injection, p < 0.003 at 60 min). The rise in serum insulin levels was significantly higher (Cmax = 98 +/- 6 uU/mL for Oralin at 30 min vs 65 +/- 3 uU/ml injection, p < 0.001). The reduction in C-peptide was greater in Oralin during the first 60 min (1.38 +/- 0.21 ng/mL Oralin vs 1.75 +/- 0.38 ng/mL injection, p < 0.001).
This proof-of-concept study results demonstrated that Oralin could be used as meal insulin in place of mealtime-insulin injections in subjects with type 2 diabetes to regulate the postprandial glucose levels.
Oral insulin spray is a new, noninjectable method of insulin delivery. This system delivers an aerosol of uniform-sized droplets containing regular human insulin at a high velocity into the oropharyngeal cavity for local transmucosal absorption.
The purpose of this study was to compare the pharmacokinetic and pharmacodynamic properties of single-dose oral insulin spray and SC insulin injection in healthy subjects.
Healthy male volunteers aged 21 to 25 years participated in this open-label study conducted at the Diabetes Unit, Hadassah-Hebrew University Hospital, Jerusalem, Israel. Subjects presented at 2 visits separated by 7 to 14 days. At both visits, the euglycemic clamp technique was used to maintain a constant blood glucose level. At one visit, subjects received regular human insulin 0.1 U/kg by SC injection. At the other visit, subjects received 15 puffs (150 U) of oral insulin spray. The pharmacokinetic (insulin absorption) and pharmacodynamic (glucose uptake) properties of the drugs were evaluated using blood analyses over the subsequent 360 minutes.
Six volunteers were enrolled (mean [SD] age, 22.8 [1.2] years; mean [SD] body mass index, 23.2 [2.2] kg/m(2)). The mean (SD) baseline-corrected C(max) was significantly higher with oral insulin spray compared with SC insulin (54.0 [20.3] vs 30.8 [6.1] microU/mL; P = 0.028). Mean (SD) T(max) was significantly shorter with oral insulin spray compared with SC insulin (23.3 [5.2] vs 83.3 [42.2] minutes; P = 0.027). The mean (SD) time to maximal metabolic effect (maximum glucose infusion rate [GIR(max)]) (44.2 [8.6] vs 100.0 [35.6] minutes) and late time to half-maximal effect (101.0 [41.0] vs 257.2 [27.8] minutes) were shorter with oral insulin spray compared with SC insulin (both, P = 0.028). The baseline-corrected GIR(max) (6.8 [3.3] vs 6.2 [2.3] mg/kg . min) and glucose consumption (396.7 [178.0] vs 432.1 [226.0] mg/kg) during the 120 minutes after study drug administration were comparable between oral and SC insulin, respectively.
In this study in a small, selected population of healthy male subjects under euglycemic conditions, oral insulin spray was associated with a higher C(max), shorter T(max), and faster time to peak glucose uptake compared with SC insulin. The short T(max) and the 120-minute duration of effect of oral insulin spray suggest it may be a promising alternative for fulfilling meal-related insulin requirements in persons with diabetes.
To evaluate the metabolic effect of buccal spray insulin compared with subcutaneous regular insulin in patients with type 1 diabetes.
This study compared plasma glucose, insulin, and C-peptide levels in 18 patients with type 1 diabetes treated with subcutaneous regular or buccal spray insulin on 2 consecutive mornings. On day 1, patients were treated with their usual subcutaneous regular insulin regimens. On day 2, patients received buccal spray insulin. In the morning of both days 1 and 2, patients received a standard meal of 630 kJ. No intermediate or long-acting insulin was administered to patients on the morning of the test. Blood samples were collected for up to 4 hours for biokinetic analysis. In a subset of 3 patients, premeal buccal spray insulin was administered for 2 entire consecutive days. In these patients, glucose levels were monitored using the glucose sensor monitoring system.
Overall, there were no statistically significant differences in glucose, insulin, or C-peptide levels measured after administration of subcutaneous vs buccal spray insulin. However, at 90 and 120 minutes after subcutaneous regular insulin administration, significantly higher insulin levels and more prolonged hypoglycemic effect were detected compared with buccal spray insulin administration. In the 3 patients who received 1 day of regular and 2 entire days of buccal spray insulin, no significant differences were observed in glucose levels during the 3 days of glucose sensor monitoring.
Insulin administered via the buccal spray formulation is as effective as the subcutaneous route in lowering blood glucose levels.
This study evaluated the pharmacokinetic and pharmacodynamic properties and dose-response effects of an oral insulin spray formulation compared with those of subcutaneously injected regular insulin and placebo in patients with type 1 diabetes mellitus.
This was a single-center, randomized, single-blind, open-label, 5-way crossover study in which patients with type 1 diabetes received 5, 10, and 20 puffs of the oral insulin spray; regular insulin 0.1 U/kg SC; and placebo spray. The pharmacokinetic parameters of interest were the maximum serum insulin concentration (Ins-C(max)); the incremental insulin AUC from 0 to 120 minutes (Ins-AUC(0-120)), from 0 to 240 minutes, and from 0 to 360 minutes; and the time to maximum serum insulin concentration (Ins-T(max)). The pharmacodynamic parameters of interest were the maximum glucose infusion rate (GIR(max)); the incremental glucose AUC from 0 to 120 minutes (GIR-AUC(0-120)), from 0 to 240 minutes, and from 0 to 360 minutes; the time to maximum GIR (GIR-T(max)); the time to early half-maximal GIR (early T50%); and the time to late half-maximal GIR (late T50%). Pharmacokinetic and pharmacodynamic parameters were assessed using the euglycemic clamp technique.
The study enrolled 6 white men with type 1 diabetes (mean [SD] age, 37.5 [16.2] years, mean weight, 82.7 [17.0] kg). Ins-T(max) was shorter for 5, 10, and 20 puffs of oral insulin spray than for SC insulin (26.7 [13.7], 29.2 [7.4], 23.3 [5.2], and 142.5 [73.2] min, respectively; P < 0.05). There was no effect of dose on Ins-T(max). The Ins-AUC(0-120) for 5, 10, and 20 puffs of oral insulin spray (304.8 [277.9], 689.2 [353.0], and 1808.8 [1252.6] microU/mL per min, respectively; P < 0.05) and the corresponding Ins-Ca(max) (12.9 [8.7], 26.7 [14.5], and 47.6 [40.1] microU/mL; P < 0.05) suggested a dose-response relationship. Five, 10, and 20 puffs of oral insulin spray had an earlier onset of action than SC insulin (early T50%: 23.3 [15.1], 28.3 [12.3], 31.2 [111.8], and 87.0 [39.6] min, respectively; P < 0.05), an earlier maximal effect (GIR-T(max): 40.0 [23.7], 45.8 [22.7], 44.2 [5.8], and 145.0 [43.7] min; P < 0.05), and a shorter duration of action (late T50%: 56.5 [31.0], 70.2 [12.9], 75.5 [6.0], and 290.8 [84.0] min; P < 0.05). Dose-dependent increases in maximal metabolic effect were observed with 5, 10, and 20 puffs: the GIR(max) was 0.9 (0.5), 2.0 (1.3), and 3.9 (2.5) mg/kg per minute, respectively (P < 0.05), and the GIR-AUC(0-120) was 39.6 (34.9), 76.8 (67.4), and 189.1 (163.0) mg/kg per minute (P < 0.05).
In this study in patients with type 1 diabetes, oral insulin spray had a faster onset and shorter duration of action than subcutaneously injected regular insulin. A dose-response relationship was noted in the metabolic effect and absorption of oral insulin spray.
An estimated 246 million people worldwide have diabetes. Diabetes is a leading cause of death in most developed countries, and is reaching epidemic proportions in many developing and newly industrialized nations. Poorly controlled diabetes is associated with the development of renal failure, vision loss, macrovascular diseases and amputations. Large controlled clinical trials have demonstrated that intensive treatment of diabetes can significantly decrease the development and/or progression of microvascular complications of diabetes. There appears to be no glycaemic threshold for reduction of diabetes complications; the lower the glycated haemoglobin (HbA1c), the lower the risk. The progressive relationship between plasma glucose levels and cardiovascular risk extends well below the diabetic threshold. Until recently, the predominant focus of therapy has been on lowering HbA1c levels, with a strong emphasis on fasting plasma glucose. Although control of fasting hyperglycaemia is necessary, it is usually insufficient to obtain optimal glycaemic control. A growing body of evidence suggests that reducing postmeal plasma glucose excursions is as important, or perhaps more important for achieving HbA1c goals. This guideline reviews the evidence on the harmful effects of elevated postmeal glucose and makes recommendations on its treatment, assessment and targets.
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