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12.00 noon
/ Wednesday, May 6, 2015/Respiratory Drug Delivery Europe 2015


Re-thinking Inhaled Insulin’s Role in the Global Challenge to Treat Diabetes

John S Patton, Ph.D.,

Dance Biopharm, Brisbane, California, USA

Diabetes is a vast global health problem that is increasing in severity. Unfortunately, half of the people with diabetes do not know they have it, even as it works its destructive effects on the body.

Insulin has traditionally been used as a treatment of last resort in type 2 diabetes (that comprise more than 90 percent of patients worldwide) but treatment guidelines have recently been revised and now outline a more individualized approach to insulin treatment including recommendations to initiate insulin if diet, exercise, and oral agents do not control blood glucose within a few months of diagnosis, or if patients present signs of diabetes complications upon diagnosis.

Reluctance and refusal to take injected insulin is well documented, as is the strong patient preference for inhaled over injected insulin. Inhaled insulin has been studied in over 10,000 patients across more than 100 clinical trials, demonstrating safety and efficacy. After the premature demise of the first approved inhaled insulin product, Exubera®, inhaled insulin is commercially available once again in the US in the form of the ultra-rapid-acting dry powder product, Afrezza®. Dance Biopharm is developing an aqueous inhaled insulin product, Dance 501®, with unique characteristics which will provide patients with another option to obtain insulin non-invasively.

David Cipolla currently leads the preclinical R&D, pharmaceutical sciences and intellectual property efforts at Aradigm Corporation in Hayward, California. Aradigm is a specialty pharmaceutical company specializing in the development of inhalation treatments for severe respiratory disease. Aradigm’s lead product is an inhaled sustained release formulation of ciprofloxacin in phase 3 clinical development for non-cystic fibrosis bronchiectasis.

Prior to joining Aradigm, David worked at Genentech, Inc. in the Pharmaceutical Research and Development Group (1988-1996). His research investigated the development and characterization of the delivery of protein aerosols to the airways, culminating with the approval of Pulmozyme® rhDNase for the management of cystic fibrosis in 1993. David also made contributions to a number of marketed antibody products including Herceptin® Trastuzumab indicated for breast cancer and Xolair® Omalizumab for asthma.

David was elected to two terms (2011-2015) on the Board of the International Society of Aerosols in Medicine (ISAM). He was one of the organizers for the 2009 ISAM conference in Monterey, CA and served on the scientific advisory board for the 2011, 2013 and 2015 ISAM Congresses.

David chaired the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) in 2006-2008, which is addressing significant scientific and regulatory issues that affect development of respiratory products within the pharmaceutical industry; e.g., foreign particulates, cascade impaction methodology, delivered dose uniformity.

He is a pharmacist (University of Sydney, PhD) and chemical engineer by training (MIT, S.B.; University of California at Davis, M.S.)

Specialties: Drug Delivery, Inhalation, Biologics, Proteins and Antibodies, Formulation Development, Pharmaceutical Intellectual Property

The success of any pharmaceutic particle depends not only on its efficacy in treating a disease or condition, but also having superior pharmaceutic properties over other known therapeutics. Desirable pharmaceutic properties sought in a dry powder particle include improved aerodynamics, pharmacodynamics and stability. However, producing particles with such properties is an ongoing challenge in the art. One approach to achieving this aim in the art, lies in the methodology used to manufacture particles.

Thus, the present invention provides the novel and unexpected discovery that the pharmaceutic properties of the dry powder can be generally improved by using spray drying in preference to lyophilization to remove solvent from the particles.

Surprisingly, the density of the spray-dried particles was roughly twice that of freeze-dried particles. This can be advantageous in providing higher doses. Dry powder inhalers generally impose a limit on the volume of powder, and thus the dosage of active agent, that can be delivered in a single operation. A powder of higher density, but at least similar respirable fraction, allows larger doses to be administered in a single operation, rather than requiring more operations per dose, formulations with higher % loading of active agent, or alternate inhaler or inhaler cartridge designs to accommodate various volumes of powder.

Active agents contemplated for use in the compositions and methods described herein may include any polymer or large organic molecules, most preferably peptides and proteins. Examples include synthetic organic compounds, proteins and peptides, polysaccharides and other sugars, lipids, and nucleic acid sequences, having therapeutic, prophylactic, or diagnostic activities. Active agents may also include small molecules and vitamins. An active agent of the present invention may also be a vasoactive agent, a neuroactive agent, a hormone, an agent regulating metabolism, weight, or blood glucose levels, an anticoagulant, an immunomodulating agent, a cytotoxic agent, an antibiotic, an antiviral, an antisense molecule, or an antibody.

Latex allergy remains a significant problem, expecially among certain professional categories, and specific immunotherapy has been suggested as a suitable therapeutic option. The objective of the this article is to review the available literature on clinical trials of specific immunotherapy in latex allergy.

Data Sources 
Literature databases (PubMed, Embase, Google Scholar) were searched for latex immunotherapy clinical trials.

Study Selections
Clinical trials (either open or randomized controlled) using subcutaneous or sublingual immunotherapy with latex extracts were selected. Only articles published in English in peer-reviewed journals were considered. Case reports quoted in the clinical trials were also described, when pertinent.
Results
Eleven clinical trials (3 with subcutaneous and 8 with sublingual immunotherapy) were identified. Two of the 3 randomized trials of subcutaneous immunotherapy reported some benefit in adults but a remarkable occurrence of side effects. Concerning sublingual immunotherapy (SLIT), there were 6 randomized placebo-controlled (1 in children), 1 randomized open, and 1 open trials. All but 1 trial reported positive results, and the safety profile was overall superior to injection immunotherapy. The overall quality of the study was moderate, and the number of subjects studied was low.
Conclusion
Although guidelines do not consider allergy to latex as an accepted indication to desensitization, SLIT can be offered, in addition to symptomatic treatment, to selected patients, when avoidance measures are not feasible or effective. (But, this is rarely every performed!)

Anaphylaxis is common in children and has many differences across age groups. A systematic review of the literature from the past 5 years was conducted with the goal of updating the pediatrician. Food is the most common trigger in children, but insect venom and drugs are other typical causes. Clinical diagnostic criteria include dermatological, respiratory, cardiovascular, and gastrointestinal manifestations. A biphasic reaction is seen in some, with recurrence usually within 8 hours of the initial episode. Epinephrine is the drug of choice for acute reactions and the only medication shown to be lifesaving when administered promptly, but it is underutilized. Patients should have ready access to ≥2 doses of an epinephrine autoinjector, with thorough training regarding correct use of a given device and an emergency action plan. Management of anaphylaxis in schools presents distinct challenges. Pediatricians are in a unique position to assess and treat these patients chronically.

To: Hospital Administrators Latex Glove Manufacturers
Hospital Risk Managers Distributors/Importers
Hospital Procurement Managers

In the spring and summer of 1995, the spontaneous combustion of powder-free latex patient examination gloves caused four fires in different states. The fires all occurred in warehouses and involved large quantities of non-sterile, powder-free, chlorinated latex gloves stored on pallets. All of the gloves were labeled "Made in China" and manufacturers' serial numbers indicate they were manufactured between 1992 and 1994. We are concerned about the potential for future fires involving powder-free latex patient examination gloves and about glove quality. This Advisory offers recommendations which we believe will help reduce risks.

If you’re allergic to natural rubber latex, FDA has good news for you: in the future, you are less likely to be misinformed about the absence of this allergen in such products as medical devices. To avoid false assurances about this hazard to your health, FDA is recommending to manufacturers to stop using the labels “latex-free” or “does not contain latex”.

The reason for this recommendation is that the agency is not aware of any tests that can show a product contains no natural rubber latex proteins that can cause allergic reactions. Without a way to verify that a product is completely free of these proteins, a claim that it is "latex free" is scientifically inaccurate and may be misleading.

FDA’s final guidance document, issued on December 2, 2014, advises firms who want to indicate that natural rubber latex was not used in the manufacturing of their product, to state on the label that it was "not made with natural rubber latex."

Natural rubber latex is made from plant sources such as the sap of the Brazilian rubber tree. It is used in numerous medical products, including adhesive bandages, condoms, medical gloves, catheters, sanitary napkins, crutches and blood-pressure monitoring cuffs. Exposure can result in sensitivity to natural rubber latex proteins, with symptoms ranging from skin redness, rash, hives or itching to difficulty breathing and wheezing. Rarely, shock and even death can occur.

It is not possible to predict in advance just how much exposure to natural rubber latex might cause reaction in any specific person.

This article reviews information on the hazards of cornstarch powder on medical gloves. Dusting powders were first applied to latex gloves to facilitate donning. After 1980, manufacturers devised innovative techniques without dusting powder. It has been well documented that these powders on gloves present a health hazard to patients and health care workers by 5 different mechanisms.

First, the glove cornstarch has documented detrimental effects on wound closure techniques.

Second, this powder potentiates wound infection.

Third, cornstarch induces peritoneal adhesion formation and granulomatous peritonitis.

Finally, these powders serve as carriers as latex allergen and they precipitate a life-threatening allergic reaction in sensitized patients.

These well-documented hazards of glove powder have caused the United Kingdom and Germany to ban cornstarch powder on medical gloves over 10 years ago.

The Food and Drug Administration (FDA or Agency) has determined that Powdered Surgeon's Gloves, Powdered Patient Examination Gloves, and Absorbable Powder for Lubricating a Surgeon's Glove present an unreasonable and substantial risk of illness or injury and that the risk cannot be corrected or eliminated by labeling or a change in labeling. Consequently, FDA is proposing these devices be banned.

Submit either electronic or written comments by June 20, 2016.

DA has received several citizen petitions regarding the use of glove powder. In 1998, a citizen petition was submitted by Public Citizen requesting that FDA ban the use of cornstarch powder in the manufacture of latex surgeon's and patient examination gloves (see Docket No. FDA-2008-P-0531). While there was scientific evidence in 1998 that indicated that the use of glove powder was associated with negative health consequences (partly due to the ability of glove powder to facilitate sensitization of health care workers to NRL and partly due to adverse effects due only to contact with glove powder), as discussed previously, quality concerns, the lack of suitable alternatives, and costs weighed against FDA initiating the process to remove powdered gloves from the market. Moreover, the impact of reductions in the amount of NRL protein used in gloves and in the amount of powder added to gloves, which were being done as means to mitigate the risk of health care worker sensitization to NRL, had not yet been studied for a reasonable length of time. As a result of these considerations, we did not grant the 1998 petition to ban the use of glove powder.

Approximately a decade later, between 2008 and 2011, FDA received three petitions requesting, among other things, that the Agency ban the use of cornstarch powder on NRL and synthetic latex surgical and examination gloves (FDA-2008-P-0531-0001, FDA-2009-P-0117-0001, and FDA-2011-P-0331-0001). These petitions prompted us to evaluate new data on the risks of using powdered gloves, to consider new information regarding the current availability and costs of alternatives to glove powder for glove lubrication, and to reassess the frequency of use of powdered medical gloves.
As a result of these petitions, FDA published in 2011 in the Federal Register a document requesting comments related to the risks and benefits of powdered gloves (February 7, 2011, 76 FR 6684; FDA-2011-N-0027). In addition, although we believed that additional labeling would not correct or eliminate the risks associated with glove powder, we decided that it was important to inform consumers about the risks of powdered gloves while FDA assessed whether glove powder had benefits that might affect the determination of whether or not a ban on the devices was appropriate at this time. Accordingly, on February 7, 2011, FDA issued the draft guidance entitled “Draft Guidance for Industry and FDA Staff: Recommended Warning for Surgeon's Gloves and Patient Examination Gloves that Use Powder,” which proposed a general voluntary warning for powdered glove devices, regardless of whether the devices were surgeon's gloves or patient examination gloves (Ref. 7). As we reviewed the comments received on the benefits and risks of glove powder, we determined that a ban on powdered gloves is appropriate and determined not to finalize the draft guidance. This draft guidance was withdrawn on May 6, 2015 (80 FR 26059) as part of a mass withdrawal effort to remove draft guidance documents issued before 2014 that have not been finalized. When final, this rule will address the risks of powdered gloves that were addressed in the draft guidance.

Name: MANNKIND CORPORATION, RAYMOND URBANSKI
DBA: MANNKIND CORPORATION
Address: 1 CASPER ST LAB 208 DANBURY, CT 06810-6903
Credential: CSL.0001138
License Type: CONTROLLED SUBSTANCE LABORATORY
Effective Date: 02/22/2016
Expiration Date: 01/31/2017
Status: ACTIVE

Name: MANNKIND CORP
DBA: Address: 1 CASPER ST DANBURY, CT 06810-6903
Credential: CSM.0000766
License Type: MANUFACTURER OF DRUGS, COSMETICS & MEDICAL DEVICES
Effective Date: 07/01/2016
Expiration Date: 06/30/2017
Status: ACTIVE
www.elicense.ct.gov/Lookup/LicenseLookup.aspx
Read more: mnkd.proboards.com/thread/5928/having-trouble-understanding#ixzz4GZ2daYoa

Someone finally spotted it! Also, CT is a medical marijuana state and also a hemp state.

—CT has an active hemp industry or has authorized research. Hemp is a distinct variety of the plant species cannabis sativa L. that contains minimal (less than 1%) amounts of tetrahydrocannabinol (THC), the primary psychoactive ingredient in marijuana.
norml.org/laws/item/connecticut-penalties
Read more: mnkd.proboards.com/thread/5928/having-trouble-understanding#ixzz4GZ2daYoa

Post by cm5 on Jun 5, 2016 at 6:16pm

Andrea Leone-Bay on Linkedin
Chief Scientific Officer
Receptor Life Sciences
October 2015 – Present (9 months)
Receptor Life Sciences, Inc. is a pharmaceutical development company based in Seattle, Washington. Receptor is quietly laying the foundation for groundbreaking new products in the specialty pharmaceutical market.

6th Annual Targeting Pain with Novel Therapeutics ----Translating Success from Preclinical Assays to the Clinic June 14-17 2016 Boston

Read more: mnkd.proboards.com/thread/2667/mannkind-torrey-joint-patent-treating#ixzz4GZ3Wg8oY

Cara Therapeutics is an emerging biotechnology company focused on developing novel therapeutics to treat human diseases associated with pain, inflammation and pruritus. Cara possesses both near-term clinical development opportunities combined with proprietary approaches to developing first-in-class novel therapeutics.

Cara's most advanced compound, CR845, is currently undergoing clinical testing for acute pain and pruritus. This patented compound possesses analgesic, anti-inflammatory and anti-pruritic activities appropriate for multiple therapeutic applications. In addition, Cara aims to develop a future pipeline of first-in-class molecules at novel analgesic and anti-inflammatory targets using its proprietary drug screening technology.

The cannabinoid receptors are a class of receptors under the G-protein coupled receptor superfamily. Cannabinoid receptors work by inhibiting adenylate cyclase and thereby inhibit production of the second messenger molecule cyclic AMP. They are activated by cannabinoids, found naturally inside the body or introduced as a drug (which may be a synthetic compound or a herbal extract).

Centrally acting opiates are agents that bind to opioid receptors found principally in the central nervous system. There are four broad classes of opioids:
1--endogenous opioid peptides, produced in the body;
2--opium alkaloids, such as morphine (the prototypical opioid) and codeine;
3--semi-synthetic opioids such as heroin and oxycodone;
4--and fully synthetic opioids such as pethidine and methadone that have structures unrelated to the opium alkaloids.

The GPCR superfamily is the largest family of membrane proteins, members of which are involved in all types of stimulus-response pathways, from intercellular communication to physiological senses and consequently, pathological functions. GPCRs are the targets of 40 to 50% of modern medicinal drugs.

G-protein-coupled receptors are transmembrane receptors that transduce an extracellular signal (ligand binding) into an intracellular signal (via G protein activation). GPCRs represent the most successful and therapeutically useful drug targets in modern medicine.

Opiate analgesics can act through three different types of opioid receptors, called mu, delta, and kappa.

Morphine, the most widely used opiate analgesic, acts primarily via activation of the mu opioid receptor located in the central nervous system (CNS). This CNS action induces pain relief but is also associated with a wide array of CNS-mediated side effects including sedation, respiratory depression, and abuse liability.

As a way to avoid these undesirable CNS effects, there has been an effort to develop opioids which selectively activate (agonist) peripheral opioid receptors such as kappa receptors, present on sensory nerves, outside the central nervous system.

A kappa agonist (or kappa opioid agonist) is a substance that binds to a kappa opioid receptor and triggers a response in the cell. The receptors of the human body work by being stimulated or inhibited by natural (such as hormones and neurotransmitters) or synthetic (such as drugs) agonists and antagonists.

Methods and compositions for treating pain are disclosed. The compositions are based on dry powders comprising microparticles of diketopiperazines and an analgesic active agent. The analgesic in the compositions comprises one or more peptide analgesics or derivatives thereof, which are administered to a subject using a pulmonary inhalation drug delivery system comprising a dry powder inhaler and the analgesic composition. The present compositions produce fewer side effects associated with current opioid therapy.

Despite the progress that has occurred in recent years in the development of therapy, there is still a need  for effective and potent analgesics, especially for the treatment of chronic pain. One of the most important  analgesic drugs employed in clinical practice today continues to be the alkaloid morphine. In this  review, emphasis will be given to the important contribution and the history of Papaver somniferum,  Salix species, Capsicum species and Cannabis sativa in the development of new analgesics and their importance  in the understanding of the complex pathways related to electrophysiological and molecular  mechanisms associated with pain transmission. Recently discovered antinociceptive substances include  alkaloids, terpenoids and flavonoid. Plant-derived substances have, and will certainly continue to have, a relevant place in the process of drug discovery, particularly in the development of new analgesic drugs.

Copyright # 2000 John Wiley & Sons, Ltd.
Keywords: antinociceptive; Papaver somniferum; Cannabis sativa; Capsicum; alkaloids; terpenoids; flavonoids.

In  1842, O’Shaughnessy, an army physician in India,  published an extensive treatise on the use of cannabis in various medical conditions including as an analgesic. As a result, Cannabis was introduced into European  medicine and subsequently into other areas of Western 
medicine, including the United States.  Preparations such as tincture and extract of Cannabis were recognized for a  long time as official drugs and were listed in the US  Pharmacopoeia from 1850 until 1942. However, although C. sativa remained in the Pharmacopoeia until 1942, its  medical use was essentially abolished in 1937, when the  Marijuana Tax Act was introduced (Lemberger, 1980).
The Cannabis plant contains a complex mixture of substances that include at least 60 different cannabinoids,  many of which have been shown  present pharmacological activities (Burstein, 1997).

Peripheral antinociceptive effects of Cannabis have also recently been identified. Calignano et al., (1998) reported that CB1 and CB2 agonists attenuate nociception at the peripheral level in mice, suggesting that their  effects are distinct but synergistic (Fields and Meng, 1998) Recently, a CB1 receptor knockout mouse was  reported. In these animals, the spontaneous nociceptive
 threshold was not altered, but the THC effect was absent.(Ledent et al., 1999).

In an exemplary embodiment herewith, the method for treating pain comprises providing to a subject an inhalable pharmaceutical composition comprising a dry powder comprising one or more receptor agonist peptides. The receptor agonists can be, for example, alpha-MSH receptor agonists, or opioid receptor agonists, or the like

In a particular embodiment, the compositions comprise peptides or derivatives thereof that, for example, bind to cell receptors, or directly or indirectly affect cell receptor agonists. These cell receptors can include, for example, opioid receptors, alpha-MSH receptors, and the like. In embodiments the opioid receptors can include, for example, a μ opioid receptors, a δ opioid receptors, a κ opioid receptors, combinations of one or more of the receptors thereof, or all three receptors on cells in the central or peripheral nervous systems. In one embodiment, the peptide can be either δ (delta) opioid receptor agonists or μ opioid receptor agonists. In another embodiment, the peptide can bind nonspecifically to δ opioid, μ opioid or κ opioid receptors, or combinations thereof to bring about reduction or abolishment of the sensation of pain. In one particular embodiment, the composition for treating pain comprises a peptide or a peptide derivative which is substantially a κ opioid receptor-selective agonist. In certain embodiments herewith, the κ opioid receptor-selective agonist peptides and/or derivatives thereof can bind selectively to neurons in the peripheral nervous system

In a particular embodiment, a method of treating pain sensation comprises administering to a subject in need of said treatment a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable amount of μ opioid receptor agonist in a composition comprising 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine or 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine disodium salt. In certain embodiments, the pharmaceutical composition can comprise a pharmaceutically acceptable carrier or other inactive agents. In some embodiments, the μ opioid receptor agonist is a peptide that can cross the blood-brain barrier and can bind to the μ opioid receptor in brain cells. In another aspect of this embodiment, the pharmaceutical composition can comprise a δ opioid receptor agonist in the dry powder. In another aspect of this embodiment, the pharmaceutical composition can comprise a κ opioid receptor agonist in the dry powder. In other embodiments, the peptide can be primarily a κ opioid receptor agonist but also bind to either δ (delta) opioid receptors or μ opioid receptors as an agonist. In another embodiment, the peptide can bind nonspecifically to δ opioid, μ opioid or κ opioid receptors, or combinations thereof to bring about reduction or abolishment of pain sensation. In a particular embodiment, the opioid receptor agonist is a tetrapeptide.

But the new study found that over six months, patients had no better outcomes on liraglutide than on a placebo. Overall, about 38 percent were rehospitalized because their hearts were so weak, and 12 percent died. Indicators of heart failure such as breathlessness, difficulty walking, and a telltale blood protein did not improve in either group.



Almost 60 percent of these heart-failure patients also had diabetes. None had taken liraglutide before enrolling in the study. For the 91 who were put on liraglutide, outcomes including declining kidney function and rehospitalization were slightly worse than with a placebo, although it was not statistically significant, meaning it could be coincidental.



Lead author Kenneth B. Margulies, a heart-failure and transplant cardiologist at Penn, said diabetics with severe heart failure who are doing well on liraglutide should not quit the drug - but he wouldn't put them on it.