MannKind just got an oral insulin patent

[mnholdem]

patents.justia.com/patent/9259471

Example 11

Oral Administration of Disodium FDKP-Insulin

Capsules containing the FDKP salt and insulin are taken before a meal. The exact dosage is patient-specific, but generally on the order of 10-150 units of insulin is administered per dose.

This oral insulin formulation is used to replace pre-meal insulin injections in patients with diabetes. Additionally, insulin absorbed through the gastrointestinal tract mimics endogenous insulin secretion. Endogenous insulin is secreted by the pancreas into the portal circulation. Thus, the oral route of insulin administration delivers insulin to the site of action in the liver, offering the potential to control glucose levels while limiting systemic exposure to insulin.

Oral insulin delivery using a combination of insulin and the diacid form of FDKP is hindered by the poor solubility of the FDKP diacid in the low PH environment of the gastrointestinal tract. The FDKP salts, however, provide a local buffering effect that facilitates their dissolution in low PH.

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There is more, but this could be BIG NEWS to shareholders. Date of patent: February 16, 2016 Filed:January 8, 2014

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Note: Andrea Leone-Bay is listed as one of three inventors.

[BlueCat]

So - assume this is another prandial?

Yea. This is big. And also because it provides an alternative for those who can't (or don't ; ) - inhale

[mindovermatter]

I am sure the fudsers will just scream that it will cause stomach cancer.

[liane]

It still needs to survive the gastric acidity - that has been the Holy Grail of insulin delivery.

[jbe]

I wonder how long this will take to get FDA approval...

[rozale]

Kind of seems like this would canabalize their afrezza product, but I guess we would have to wait for details to truly determine that.

[tayl5]

Assuming units translate directly, that's a much higher amount of insulin per dose compared to Afrezza. I wonder if most of it doesn't survive the trip, and if the raw material cost relative to other formulations would be a serious disadvantage.

[alcc]

I never understand: why not sublingual?

[peppy]

patents.com/us-9259471.html

DETAILED DESCRIPTION OF THE INVENTION

These microparticles include microcapsules, which have an outer shell composed of either the heterocyclic compound alone or in combination with one or more drugs.

Example 11

Oral Administration of Disodium FDKP-Insulin

Capsules containing the FDKP salt and insulin are taken before a meal. The exact dosage is patient-specific, but generally on the order of approximately 10-150 units of insulin is administered per dose. The subsequent insulin absorption attenuates post-prandial blood glucose excursions. This oral insulin formulation is used to replace pre-meal insulin injections in patients with diabetes. Additionally, insulin absorbed through the gastrointestinal tract mimics endogenous insulin secretion. Endogenous insulin is secreted by the pancreas into the portal circulation. Insulin absorbed following oral administration also goes directly to the portal circulation. Thus, the oral route of insulin administration delivers insulin to its site of action in the liver, offering the potential to control glucose levels while limiting systemic exposure to insulin. Oral insulin delivery using a combination of insulin and the diacid form of FDKP is hindered by the poor solubility of the FDKP diacid in the low pH environment of the gastrointestinal tract. The FDKP salts, however, provide a local buffering effect that facilitates their dissolution in low pH.

SUMMARY OF THE INVENTION

The present invention provides improved drug delivery systems comprising carboxylate salts of heterocyclic compounds in combination with one or more drugs. In one embodiment of the present invention the heterocyclic compounds form microparticles that incorporate the drug or drugs to be delivered. These microparticles include microcapsules, which have an outer shell composed of either the heterocyclic compound alone or in combination with one or more drugs. The heterocyclic compounds of the present invention include, without limitation, diketopiperazines, diketomorpholines and diketodioxanes and their substitution analogs. The heterocyclic compositions of the present invention comprise rigid hexagonal rings with opposing heteroatoms and unbonded electron pairs.

(the woman is a genius.)

[peppy]

Feb 29, 2016 1:50:03 GMT -5 peppy said:

patents.com/us-9259471.html

DETAILED DESCRIPTION OF THE INVENTION

These microparticles include microcapsules, which have an outer shell composed of either the heterocyclic compound alone or in combination with one or more drugs.

Example 11

Oral Administration of Disodium FDKP-Insulin

Capsules containing the FDKP salt and insulin are taken before a meal. The exact dosage is patient-specific, but generally on the order of approximately 10-150 units of insulin is administered per dose. The subsequent insulin absorption attenuates post-prandial blood glucose excursions. This oral insulin formulation is used to replace pre-meal insulin injections in patients with diabetes. Additionally, insulin absorbed through the gastrointestinal tract mimics endogenous insulin secretion. Endogenous insulin is secreted by the pancreas into the portal circulation. Insulin absorbed following oral administration also goes directly to the portal circulation. Thus, the oral route of insulin administration delivers insulin to its site of action in the liver, offering the potential to control glucose levels while limiting systemic exposure to insulin. Oral insulin delivery using a combination of insulin and the diacid form of FDKP is hindered by the poor solubility of the FDKP diacid in the low pH environment of the gastrointestinal tract. The FDKP salts, however, provide a local buffering effect that facilitates their dissolution in low pH.

SUMMARY OF THE INVENTION

The present invention provides improved drug delivery systems comprising carboxylate salts of heterocyclic compounds in combination with one or more drugs. In one embodiment of the present invention the heterocyclic compounds form microparticles that incorporate the drug or drugs to be delivered. These microparticles include microcapsules, which have an outer shell composed of either the heterocyclic compound alone or in combination with one or more drugs. The heterocyclic compounds of the present invention include, without limitation, diketopiperazines, diketomorpholines and diketodioxanes and their substitution analogs. The heterocyclic compositions of the present invention comprise rigid hexagonal rings with opposing heteroatoms and unbonded electron pairs.

(the woman is a genius.)

quote: Insulin absorbed following oral administration also goes directly to the portal circulation. Thus, the oral route of insulin administration delivers insulin to its site of action in the liver, offering the potential to control glucose levels while limiting systemic exposure to insulin.

Phase 1? It is a big hit of insulin.

screencast.com/t/ZaphFSR2qYT

This has acquisition written all over it.

1. A microparticulate system for drug delivery comprising a composition comprising: microparticles of a pharmaceutically acceptable anion of a diketopiperazine compound comprising a carboxylate group, a divalent cation, and a biologically active agent, wherein the diketopiperazine compound is represented by the following general formula: ##STR00005## wherein E.sub.1 and E.sub.2 are NH, and R.sub.1 and R.sub.2 are independently selected from succinate-4-aminobutyl, glutarate-4-aminobutyl, maleate-4-aminobutyl, citraconate-4-aminobutyl, malonate-4-aminobutyl, oxalate-4-aminobutyl, and fumarate-4-aminobutyl.

2. The microparticulate system of claim 1 wherein said biologically active agent is a hormone, an anticoagulant, an immunomodulating agent, a cytotoxic agent, an antibiotic, an antiviral, an antisense, an antigen, an antibody or an active fragment or an analog thereof.

3. The microparticulate system of claim 1 wherein said biologically active agent is insulin, a cannabinoid, heparin, calcitonin, felbamate, parathyroid hormone or a fragment thereof, growth hormone, erythropoietin, glucagon-like peptide-1, somatotrophin-releasing hormone, follicle stimulating hormone, cromolyn, adiponectin, RNAse, ghrelin, zidovudine, didanosine, tetrahydrocannabinol, atropine, granulocyte colony stimulating factor, lamotrigine, chorionic gonadotropin releasing factor, luteinizing releasing hormone, .beta.-galactosidase, or Argatroban.

Holy chit what she can do with a charge.

A microparticulate system

microparticles of a pharmaceutically acceptable anion

a divalent cation

[seanismorris]

I like this one better...

In another embodiment, a composition comprising more than one active agent can be made using the present method. The method of making such composition comprises the steps as disclosed above for each individual active agent to form an active agent-FDKP suspension of each of the active agents to be incorporated into the composition. Then, the suspensions are combined and blended to form a mixture. Then the blended mixture is dispersed and spray-dried as described above to make the microcrystalline diketopiperazine particles comprising more than one active agent. In one exemplary study, insulin and GLP-1 combination powder was made.

Suspensions of FDKP crystallites prepared as in Example 1 were mixed with solutions of various active agents (e.g., ghrelin, low molecular heparin, oxyntomodulin) and spry dried to obtain particles similar in properties to those in Example 3.

A combination powder with two active agents (GLP-1 and insulin) was produced by first preparing a suspension of FDKP crystallites with insulin and a second suspension of crystallites with GLP-1. The two suspensions were then mixed and the combined suspension was spray-dried to obtain a dry powder containing both active agents. The crystallite suspensions were prepared as in Example 1; after the active agents were added, the suspension was adjusted to pH 4.5 to promote adsorption onto the crystallites. is a plot of data illustrating the particle size distribution of the spray-dried combination powder (1) and the crystallite suspension with the individual active agents, FDKP-insulin (2) and FDKP-GLP-1.

[peppy]

looks like she can make them all oral. rest in peace Al.

3. The microparticulate system of claim 1 wherein said biologically active agent is insulin, a cannabinoid, heparin, calcitonin, felbamate, parathyroid hormone or a fragment thereof, growth hormone, erythropoietin, glucagon-like peptide-1, somatotrophin-releasing hormone, follicle stimulating hormone, cromolyn, adiponectin, RNAse, ghrelin, zidovudine, didanosine, tetrahydrocannabinol, atropine, granulocyte colony stimulating factor, lamotrigine, chorionic gonadotropin releasing factor, luteinizing releasing hormone, .beta.-galactosidase, or Argatroban

a cannabinoid

I hope she is covering bases to bring the anti seizure cannabinoid to oral market.

14. The microparticulate system of claim 13 wherein said anion is 3,6-di(fumarate-4-aminobutyl)-2,5-diketopiperazine.

16. The microparticulate system of claim 6, wherein the divalent cation comprises Mg++ or Ca++.

These microparticles include microcapsules, which have an outer shell composed of either the heterocyclic compound alone or in combination with one or more drugs. The heterocyclic compounds of the present invention include, without limitation, diketopiperazines, diketomorpholines and diketodioxanes and their substitution analogs. The heterocyclic compositions of the present invention comprise rigid hexagonal rings with opposing heteroatoms and unbonded electron pairs.

[mnholdem]

Multiple routes of delivery

The microparticle formulations of the present invention can be administered as a liquid or solid form. These can include solutions, suspensions, dry powders, tablets, capsules, suppositories, patches for transdermal delivery, and the like.

Diketopiperazine salt formulations of biologically active agents may be administered orally. Microparticles, depending on the chemical nature and size, are absorbed through the epithelial lining of the gastrointestinal tract into the bloodstream or lymphatic system. Alternatively, the composition can be administered as a solution in which the DKP salt serves to facilitate the absorption of the drug. Additionally, the microparticles can be administered as a suspension or a solid dosage form that dissolves completely and is absorbed following dissolution.

For parenteral administration, microparticles of less than five microns readily pass through a needle for intravenous administration. Suitable pharmaceutical carriers, for example, phosphate buffered saline, are known and commercially available. Similarly, microparticles can be injected or implanted subcutaneously, intramuscularly, or intraperitoneally. Additionally, the microparticles can be placed in an implantable device to facilitate sustained and/or controlled delivery. NOTE: Medallion Therapeutics (another company formed by Alfred Mann) has a programmable implantable drug delivery pump scheduled to complete Phase III trial in June-2016. Source: clinicaltrials.gov/ct2/show/record/NCT01185470?term=medallion+therapeutics&rank=1

For topical or transdermal administration, microparticles can be suspended in a suitable pharmaceutical carrier for administration using methods appropriate for the carrier and site of administration. For example, microparticles are administered to the eye in a buffered saline solution, at a pH of approximately 7.4, or in an ointment such as mineral oil. The dosage will be dependent on the compound to be released as well as the rate of release. The microparticles, or aggregations of microparticles into films, disks, or tablets, with incorporated compound can be administered to the skin in an ointment, cream, or patch. Suitable pharmaceutical carriers are known to those skilled in the art and commercially available. Mucosal administration, including buccal, vaginal, rectal, nasal administration is also contemplated.

Pulmonary delivery can be very effectively accomplished using dry powders comprising the microparticles of the invention and can lead to rapid absorption into the circulation (bloodstream). Dry powder inhalers are known in the art and particularly suitable inhaler systems are described in U.S. patent application Ser. Nos. 09/621,092 and 10/655,153, both entitled “Unit Dose Capsules and Dry Powder Inhaler”, which are hereby incorporated by reference in their entirety.

[mnholdem]

Combination drugs are possible.

Dikeopiperazine salt counter cations may be selected to produce salts having varying solubilities. These varying solubilities can be the result of differences in dissolution rate and/or intrinsic solubility. By controlling the rate of DKP salt dissolution, the rate of drug absorption from the DKP salt/drug combination can also be controlled to provide formulations having immediate and/or sustained release profiles. For example, sodium salts of organic compounds are characteristically highly soluble in biological systems, while calcium salts are characteristically only slightly soluble in biological systems. Thus, a formulation comprised of a DKP sodium salt/drug combination would provide immediate drug absorption, while a formulation comprised of a DKP calcium salt/drug combination would provide slower drug absorption. A formulation containing a combination of both of the latter formulations could be used to provide immediate drug absorption followed by a period of sustained absorption.

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I can think of any number of drugs that would benefit by a dual-release action.

[kbrion77]

I guess I'm confused, a patent revolving around capsules when our entire company focus is inhalation?