WO2010118516A1 - Compositions for sublingual drug delivery and methods of use thereof - Google Patents

Compositions for sublingual drug delivery and methods of use thereof Download PDF

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Publication number
WO2010118516A1
WO2010118516A1 PCT/CA2010/000553 CA2010000553W WO2010118516A1 WO 2010118516 A1 WO2010118516 A1 WO 2010118516A1 CA 2010000553 W CA2010000553 W CA 2010000553W WO 2010118516 A1 WO2010118516 A1 WO 2010118516A1
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WIPO (PCT)
Prior art keywords
chitosan
composition
therapeutic agent
agent
insulin
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PCT/CA2010/000553
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French (fr)
Inventor
Julian Salari
Hassan Salari
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Globe Laboratories Inc.
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Publication of WO2010118516A1 publication Critical patent/WO2010118516A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2264—Obesity-gene products, e.g. leptin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin

Definitions

  • compositions for sublingual drug delivery and methods of use thereof
  • the present technology relates to the use of chitosan in formulations for sublingual delivery. More specifically, the present technology relates to compositions comprising chitosan, and methods and uses of those compositions in patients in need thereof.
  • Chitosans are linear cationic polysaccharides which are prepared by partial N-deacetylation of chitin, an abundant structural polysaccharide in crab and shrimp shells.
  • Chitosan consist of (l-4)-linked 2-acetamido-2-deoxy-D-glucopyranose (GIcNAc) and 2-amino-D-glucopyranose units. Both the number of GIcNAc units (degree of acetylation) and the molecular weight of chitosan have been shown to influence the physical and biological properties of the polymer (Ref: 1, 2).
  • Chitosans are potent absorption enhancers for poorly absorbed hydrophilic drugs.
  • Chitosan has been studied as a potential enhancer of intestinal mucosal drug absorption since 1990 (Ref: 3, 4, 5). They are tested to improve the uptake of drugs such as calcitonin, insulin and buserlin across nasal and intestinal epithelia (Ref: 6, 7). Chitosans have been shown to enhance the absorption of hydrophilic and hydrophobic molecules across the human epithelial cell line Caco-2 in a paracellular transport pathway, a process mediated through electrostatic binding of cationic chitosans with the negatively charged epithelium (Ref: 8).
  • the sublingual region of the mouth has a very thin tissue structure.
  • the blood vessels under the tongue are in close proximity to the epithelial cells or mucosal cells.
  • Absorption of drugs across mucosal tissue of the tongue involves trans or paracellular route though the several epithelial layers. Paracellular transport through epithelium is limited by the molecular size, hydrophobicity, and capability to penetrate tight junctions between the epithelial cells.
  • the transcellular route is highly restricted to movement of drugs that are in the native form or specially formulated.
  • An example of a drug that can be transported through the mucosal layers of the tongue transcellularly without the need for a special formulation is nitroglycerin.
  • Nitroglycerin is a small molecule with a physicochemical structure that allows for absorption into the epithelial cells and migration through the various cell layers to reach blood capillaries.
  • compositions containing chitosan, chitosan derivatives or chitosan salts in drug formulations for sublingual delivery.
  • the presence of chitosan, its derivatives or salts enhances absorption of the active ingredients and transport to the blood stream.
  • Small molecules, peptides and proteins can be administered in many forms, including gels, pills, and capsules. Placement of these under the tongue obviates the need for injections in some cases and reduces gastrointestinal distress in others.
  • the technology provides compositions and methods for administration of small molecule drugs, as well as peptides and proteins to humans via the mucosal surface of the tongue (sublingual).
  • Chitosan, chitosan derivatives or salts of chitosan are included.
  • chitosan derivatives it is meant ester, ether or other derivatives formed by bonding of acyl and/or alkyl groups with OH groups.
  • chitosan While any chitosan may be used, it is preferred that selected chitosan preferably has a molecular weight of at least 4,000 Daltons. Most preferable molecular weight of chitosan to be around 25,000 to about 2,000,000 Daltons, and most preferably about 50,000 to 300,000 Daltons. Chitosan of varying chitosanase or by the addition of nitrous acid. Both procedures are well known to those skilled in the art and are described in recent publications (Ref: 9).
  • the chitosan selected for use in the compositions and the methods of the technology is water-soluble. It may be produced from chitin by deacetylation to a degree of greater than about 40%, preferably between about 50% and about 98%, and more preferably between about 70% and about 90%.
  • Suitable chitosan containing formulations which can be used in the methods and compositions of the technology include, for example, those set forth in the U.S. Patent Nos. 6,207,197; 6,342,251; 6,391,318; 6,432,440; 6,465,626; and 6,534,065, the contents of which are incorporated herein by reference.
  • chitosan sold under the trade name PROTASANTM, available from NovaMatrix, FMC Biopolymer, Drammen, Norway. Additionally, other low and medium viscosity chitosan may be obtained from other sources. Suitable chitosan derivatives for use in the composition in the methods of the technology include those that are disclosed in Roberts, Chitin Chemistry, MacMillan Press Ltd., London (1992), the disclosure of which is incorporated herein.
  • the amount of the bioactive drug present in the composition will vary depending on various factors, including the disease or disorder for which the composition is intended to treat, the chemical nature of the selected drug and/or of the overall composition, the gender and other characteristics of the patient the intended dosage regime, etc. However, it is generally preferred that the amount of drug be present in the composition in a concentration of 5 mg, 10 mg, 40 mg, and 50 mg, of which the amount of chitosan is 10% (i.e. 0.5 mg, 1 mg, 4 mg, and 5 mg). In certain circumstances the amount of chitosan can be 20% of the weight of the drug.
  • the drug i.e.
  • small molecules such as sildenafil or peptides such as insulin, or proteins such as leptin
  • the ratio of chitosan to drug may be about 1:10, about 1 :5 or about 1:2.
  • the composition may be formulated in oral administration vehicles.
  • the sublingual administration vehicle maybe any that is pharmaceutically acceptable for such purpose, and may take any suitable form, including, but not limited to a hard pill, a soft pill, or a capsule. These are placed under the tongue where they dissolve.
  • the formulation preferably includes a sweetener such as sucralose and a rapid dissolution agent such as PharmaburstTM and other ingredients such as mint flavor, silicone oxide, magnesium stearate, and microcrystalline cellulose and/or carboxymethyl cellulose. Additionally, the formulation may contain a preservative.
  • sildenafil administered orally versus sublingually was compared.
  • Two volunteers first took a pill of sildenafil (ViagraTM) orally. Samples of 5cc of blood were collected at times 0, 15, 30, 60, 120, 180, and 240 minutes. The blood samples were tested for the presence of the drug (sildenafil) by phase high performance liquid chromatography (HPLC). The same volunteers returned for the next study four days later.
  • the drug was administered sublingually as a formulation comprising sildenafil plus chitosan.
  • Oral Admin 2 0 0 0 16 28 17 6 0
  • Insulin from Nova Nordisk (Denmark) was used. The bioavailability of insulin administered orally versus sublingually was determined. Two volunteers first took a pill of insulin orally.
  • Oral Admin 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  • Leptin from Globe Laboratories was used. The bioavailability of leptin administered orally versus sublingually was determined. Two volunteers first took a pill of leptin orally. Samples of 5cc of blood were collected at times 0, 15, 30, 60, 120, 180, and 240 minutes. The blood samples were tested for the presence of the drag (leptin) by ELISA bioassay technique. The same volunteers returned for next study four days later. In the second round of study the leptin was administered sublingually as a formulation comprising leptin plus chitosan.
  • Oral Admin 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
  • chitosan can open the tight junctions between the epithelial cells in the tongue. Additionally, chitosan appears to serve as an adhesive for the drugs to enable them to attach to the epithelium. Chitosan is useful for delivering drugs to blood vessels via mucosal layers of the tongue.
  • bioadhesives may be employed in the compositions, for example, but not limited to Polycarbophil, Carbopol/carbomer, Sodium carboxymethyl cellulose, Hydroxypropylcellulose, Hydroxypropylmethyl Cellulose, Hydroxyethyl Cellulose, Xanthan gum, Guar gum, Hydroxypropyl Guar, Carrageenan, Sodium Alginate, Poly (hydoxy butyrate), poly (e-caprolactone and copolymers, Poly (ortho esters), Poly (cyano acrylates), Polyphosphazenes, Poly (vinyl alcohol), poly (ethylene oxide), Poly (hydroxytheyl methacrylate), and Poly (ethylene oxide-beta propylene oxide).
  • Pharmaburst® may be employed including, but not limited to Pharmaburst® 100. It is expected that inclusion of at least one bioadhesive will assist in the compositions in adhering to the epithelium.
  • the therapeutic agent can be any small molecule, peptide or protein including for example, but not limited to leuprolide, luteinizing hormone and therapeutic agents for the treatment of one of cardiovascular diseases, addiction, neurological disorders, autoimmune diseases, endocrine diseases, cancer, endometriosis, obesity and diabetes.

Abstract

The present technology provides a composition comprising chitosan for the sublingual administration of pharmaceutical products. Pharmaceuticals such as sildenafil, insulin and leptin rapidly enter the bloodstream following sublingual administration of the composition. A use of the composition in the treatment of patients in need thereof is also provided. Further, a method of treating a patient in need thereof is provided.

Description

Compositions for sublingual drug delivery and methods of use thereof
Technical Field
The present technology relates to the use of chitosan in formulations for sublingual delivery. More specifically, the present technology relates to compositions comprising chitosan, and methods and uses of those compositions in patients in need thereof.
Background Art
Chitosans are linear cationic polysaccharides which are prepared by partial N-deacetylation of chitin, an abundant structural polysaccharide in crab and shrimp shells. Chitosan consist of (l-4)-linked 2-acetamido-2-deoxy-D-glucopyranose (GIcNAc) and 2-amino-D-glucopyranose units. Both the number of GIcNAc units (degree of acetylation) and the molecular weight of chitosan have been shown to influence the physical and biological properties of the polymer (Ref: 1, 2). Chitosans are potent absorption enhancers for poorly absorbed hydrophilic drugs. Chitosan has been studied as a potential enhancer of intestinal mucosal drug absorption since 1990 (Ref: 3, 4, 5). They are tested to improve the uptake of drugs such as calcitonin, insulin and buserlin across nasal and intestinal epithelia (Ref: 6, 7). Chitosans have been shown to enhance the absorption of hydrophilic and hydrophobic molecules across the human epithelial cell line Caco-2 in a paracellular transport pathway, a process mediated through electrostatic binding of cationic chitosans with the negatively charged epithelium (Ref: 8).
Anatomically, the sublingual region of the mouth has a very thin tissue structure. The blood vessels under the tongue are in close proximity to the epithelial cells or mucosal cells. Absorption of drugs across mucosal tissue of the tongue involves trans or paracellular route though the several epithelial layers. Paracellular transport through epithelium is limited by the molecular size, hydrophobicity, and capability to penetrate tight junctions between the epithelial cells.
The transcellular route is highly restricted to movement of drugs that are in the native form or specially formulated. An example of a drug that can be transported through the mucosal layers of the tongue transcellularly without the need for a special formulation is nitroglycerin. Nitroglycerin is a small molecule with a physicochemical structure that allows for absorption into the epithelial cells and migration through the various cell layers to reach blood capillaries.
References
1- Nordveit RJ., Varum K.M., Smidsrad O. 1994. Degradation of fully water-soluble partially N-acetylated chitosan withlysozyme. Carbohydrate. Polymer.23, 253-260
2- Kristiansen A., Varum, KM, Grasdalen H. 1998. The interactions between highly de-N-acetylated chitosan and lysozyme from chicken egg white studied by H-I-NMR spectroscopy. Eur. J. Biochem. 251, 335-342
3- Artursson , P. 1990. Epithelial transport of drugs in cell culture. I: A model for studying the passive diffusion of drugs over intestinal absorptive (Caco-2) cells. J. Pharm. Sci. 79, 476-482.
4- Anthonsen, M.W., Varum, K.M., Smidsrod, O. 1993. Solution properties of chitosan: conformation and chain stiffness of chitosan with different degrees of N-deacetylation. Carbohydrate. Polymer. 22, 193-201.
5- Artursson P. 1991. Cell cultures as models for drug absorption across the intestinal mucosa. Crit. Drug Carrier Syst. 8, 305-330.
6- Ilium L, Farraj NF, Davis SS. 1994. Chitosan as a novel nasal delivery system for peptide drugs. Pharm. Res. 11, 1186-1189.
7- Lussen HL, DeLeeuw BJ, Langemeijir, MWE, DeBoer, AG, Verhoef, J, Junginger HE. 1996. Mucoadhesive polymers in peroral peptide drug delivery. VI. Carbomer and chitosan improve the intestinal absorption of the peptide drug buserlin in vivo. Pharm. Res. 13, 1668-1672. 8- Schipper NGM, Olsson S, Hoogstraate AJ, DeBoer AG, Varum KM, Artursson P. 1997. Chitosan as absorption enhancers for poorly absorbable drug 2. Mechanism of absorption enhancement. Pharm Res. 14, 923-929.
9- Allan and Peyron. 1995. Carbohydrate Res. 277, 257-272.
Disclosure of Invention
The present technology is directed to the use of compositions containing chitosan, chitosan derivatives or chitosan salts in drug formulations for sublingual delivery. The presence of chitosan, its derivatives or salts, enhances absorption of the active ingredients and transport to the blood stream. Small molecules, peptides and proteins can be administered in many forms, including gels, pills, and capsules. Placement of these under the tongue obviates the need for injections in some cases and reduces gastrointestinal distress in others.
Detailed Description
The technology provides compositions and methods for administration of small molecule drugs, as well as peptides and proteins to humans via the mucosal surface of the tongue (sublingual). Chitosan, chitosan derivatives or salts of chitosan (such as, but not limited to, nitrate, phosphate, sulphate hydrochloride, glutamate, lactate, or acetate salts) are included. By "chitosan derivatives" it is meant ester, ether or other derivatives formed by bonding of acyl and/or alkyl groups with OH groups. Examples of chitosan derivatives for use in the technology include, without limitation, o-alkyl ethers of chitosan and o-acyl esters of chitosan. Modified chitosans, particularly those conjugated to polyethylene glycol, are also included as chitosan for use in the technology. Further, poly-N-acetyl-D-glucosamine, including all polyglucosamine and oligomers of glucosamine materials of different molecular weights in which a proportion of the N-acetyl group have been removed through hydrolysis (i.e. deacetylated chitins) are included.
While any chitosan may be used, it is preferred that selected chitosan preferably has a molecular weight of at least 4,000 Daltons. Most preferable molecular weight of chitosan to be around 25,000 to about 2,000,000 Daltons, and most preferably about 50,000 to 300,000 Daltons. Chitosan of varying chitosanase or by the addition of nitrous acid. Both procedures are well known to those skilled in the art and are described in recent publications (Ref: 9).
Preferably, the chitosan selected for use in the compositions and the methods of the technology is water-soluble. It may be produced from chitin by deacetylation to a degree of greater than about 40%, preferably between about 50% and about 98%, and more preferably between about 70% and about 90%. Suitable chitosan containing formulations which can be used in the methods and compositions of the technology include, for example, those set forth in the U.S. Patent Nos. 6,207,197; 6,342,251; 6,391,318; 6,432,440; 6,465,626; and 6,534,065, the contents of which are incorporated herein by reference.
Preferred is a chitosan sold under the trade name PROTASAN™, available from NovaMatrix, FMC Biopolymer, Drammen, Norway. Additionally, other low and medium viscosity chitosan may be obtained from other sources. Suitable chitosan derivatives for use in the composition in the methods of the technology include those that are disclosed in Roberts, Chitin Chemistry, MacMillan Press Ltd., London (1992), the disclosure of which is incorporated herein.
When preparing the composition, the amount of the bioactive drug present in the composition will vary depending on various factors, including the disease or disorder for which the composition is intended to treat, the chemical nature of the selected drug and/or of the overall composition, the gender and other characteristics of the patient the intended dosage regime, etc. However, it is generally preferred that the amount of drug be present in the composition in a concentration of 5 mg, 10 mg, 40 mg, and 50 mg, of which the amount of chitosan is 10% (i.e. 0.5 mg, 1 mg, 4 mg, and 5 mg). In certain circumstances the amount of chitosan can be 20% of the weight of the drug. The drug (i.e. small molecules such as sildenafil or peptides such as insulin, or proteins such as leptin) containing the composition to any mucosal surface (epithelial cells) of a mammal (i.e. human), preferably. The ratio of chitosan to drug may be about 1:10, about 1 :5 or about 1:2.
The composition may be formulated in oral administration vehicles. The sublingual administration vehicle maybe any that is pharmaceutically acceptable for such purpose, and may take any suitable form, including, but not limited to a hard pill, a soft pill, or a capsule. These are placed under the tongue where they dissolve. The formulation preferably includes a sweetener such as sucralose and a rapid dissolution agent such as Pharmaburst™ and other ingredients such as mint flavor, silicone oxide, magnesium stearate, and microcrystalline cellulose and/or carboxymethyl cellulose. Additionally, the formulation may contain a preservative.
While the technology is useful and applicable to a vast number of products, we have used three different compounds, one representing small molecules, one representing peptides, and one representing proteins as follows:
Example 1
Small molecule representation
S i ldenafil ( l - [ 4 - etho xy- 3 - ( 6 , 7 - dihydro - l - , ethyl - 7 - oxo - 3 -propyl - l - H-pyrazolo[4,3-d]pyrimidin-5-yl)phenylsulphonyl] -4-methyl piperazine, CAS 139755-83-2) (also known as Viagra™) was used to demonstrate the enhancement ability of chitosan.
The bioavailability of sildenafil administered orally versus sublingually was compared. Two volunteers first took a pill of sildenafil (Viagra™) orally. Samples of 5cc of blood were collected at times 0, 15, 30, 60, 120, 180, and 240 minutes. The blood samples were tested for the presence of the drug (sildenafil) by phase high performance liquid chromatography (HPLC). The same volunteers returned for the next study four days later. In the second round of study the drug was administered sublingually as a formulation comprising sildenafil plus chitosan.
The following chart is an example of ingredients were used to prepare our sildenafil pills:
Ingredients Dose (mg/tablet) %
Sildenafile citrate 25 11.9
Chitosan 30 14.3
Carboxymethyl cellulose 0.1 0.1
Pharmaburst 500™ 125 59.2
Microcrystalline cellulose 10 4.8
Mint flavor 5 2.4
Sucralose 10 4.8
Dye (white) 1 0.2 Magnesium stearate 2 1.0
Silicone dioxide 2 1.0
Results of the Study
Subject Sildenafil present in Blood After Various Times (minutes)
0 15 30 45 60 120 180 240
ng
Oral Admin 1 0 0 11 19 33 20 8 2
Oral Admin 2 0 0 0 16 28 17 6 0
Sublingual 1 0 31 40 28 15 8 2 0
Sublingual 2 0 45 47 31 22 13 6 0
The study showed that sublingually administered sildenafil reached the circulatory system much faster than the oral route of administration. The method therefore should apply to other small molecule drugs.
Example 2
Peptide representation
Insulin from Nova Nordisk (Denmark) was used. The bioavailability of insulin administered orally versus sublingually was determined. Two volunteers first took a pill of insulin orally.
Samples of 5cc of blood were collected at times 0, 15, 30, 60, 120, 180, and 240 minutes. The blood samples were tested for the presence of the insulin by biomarker assay and mass spectrometry. The same volunteers returned for the next study four days later. In the second round of study the insulin was administered sublingually as a formulation comprising insulin plus chitosan.
Ingredients Dose (mg/tablet) %
Insulin 25 11.9
Chitosan 30 14.3
Carboxymethyl cellulose 0.1 0.1
Pharmaburst 500™ 125 59.2
Microcrystalline cellulose 10 4.8
Mint flavor 5 2.4
Sucralose 10 4.8
Dye (white) 1 0.2
Magnesium stearate 2 1.0
Silicone dioxide 2 1.0
Results of the Study
Subject Insulin present in Blood After Various Times (minutes)
0 15 30 45 60 120 180 240
Pg
Oral Admin 1 0 0 0 0 0 0 0 0
Oral Admin 2 0 0 0 0 0 0 0 0
Sublingual 1 0 210 80 75 20 0 0 0
Sublingua 0 312 190 167 30 10 0 0 The study showed that sublingually administered insulin reached the circulatory system whereas the oral route of administration was ineffective in delivering the insulin to the circulatory system. The method should therefore apply to other peptide drugs.
Example 3
Protein representation
Leptin from Globe Laboratories was used. The bioavailability of leptin administered orally versus sublingually was determined. Two volunteers first took a pill of leptin orally. Samples of 5cc of blood were collected at times 0, 15, 30, 60, 120, 180, and 240 minutes. The blood samples were tested for the presence of the drag (leptin) by ELISA bioassay technique. The same volunteers returned for next study four days later. In the second round of study the leptin was administered sublingually as a formulation comprising leptin plus chitosan.
Ingredients Dose (mg/tablet) %
Leptin 25 11.9
Chitosan 30 14.3
Carboxymethyl cellulose 0.1 0.1
Pharmaburst 500™ 125 59.2
Microcrystalline cellulose 10 4.8
Mint flavor 5 2.4
Sucralose 10 4.8
Dye (white) 1 0.2
Magnesium stearate 2 1.0
Silicone dioxide 2 1.0
Results of the Study
Subject Leptin present in Blood After Various Times (minutes)
0 15 30 45 60 120 180 240
ng
Oral Admin 1 0 0 0 0 0 0 0 0
Oral Admin 2 0 0 0 0 0 0 0 0
Sublingual 1 0 120 100 115 90 35 0 0
Sublingual 2 0 45 67 11 15 8 0 0
The study showed that sublingually administered leptin reached the circulatory system whereas the oral route of administration was ineffective in delivering leptin to the circulatory system. The method should therefore apply to other proteins.
The results suggest that chitosan can open the tight junctions between the epithelial cells in the tongue. Additionally, chitosan appears to serve as an adhesive for the drugs to enable them to attach to the epithelium. Chitosan is useful for delivering drugs to blood vessels via mucosal layers of the tongue.
One or more bioadhesives may be employed in the compositions, for example, but not limited to Polycarbophil, Carbopol/carbomer, Sodium carboxymethyl cellulose, Hydroxypropylcellulose, Hydroxypropylmethyl Cellulose, Hydroxyethyl Cellulose, Xanthan gum, Guar gum, Hydroxypropyl Guar, Carrageenan, Sodium Alginate, Poly (hydoxy butyrate), poly (e-caprolactone and copolymers, Poly (ortho esters), Poly (cyano acrylates), Polyphosphazenes, Poly (vinyl alcohol), poly (ethylene oxide), Poly (hydroxytheyl methacrylate), and Poly (ethylene oxide-beta propylene oxide). In addition, different sizes of Pharmaburst® may be employed including, but not limited to Pharmaburst® 100. It is expected that inclusion of at least one bioadhesive will assist in the compositions in adhering to the epithelium.
The foregoing is a description of embodiments of the technology. As would be known to one skilled in the art, variations that do not alter the scope of the technology are contemplated. For example, the therapeutic agent can be any small molecule, peptide or protein including for example, but not limited to leuprolide, luteinizing hormone and therapeutic agents for the treatment of one of cardiovascular diseases, addiction, neurological disorders, autoimmune diseases, endocrine diseases, cancer, endometriosis, obesity and diabetes.

Claims

Claims
1. Use of a composition comprising a therapeutic agent, and chitosan or chitosan derivatives or chitosan salts, for sublingual administration of the therapeutic agent to a patient in need thereof.
2. The use of claim 1 wherein the therapeutic agent is a protein.
3. The use of claim 2 wherein the peptide is leptin.
4. The use of claim 1 wherein the therapeutic agent is a peptide.
5. The use of claim 4 wherein the protein is insulin.
6. The use of claim 1 wherein the therapeutic agent is a drug for the treatment of erectile dysfunction.
7. The use of claim 6 wherein the therapeutic agent is sildenafil.
8. The use of claim 1 , wherein the therapeutic agent is for the treatment of one of cardiovascular diseases, addiction, neurological disorders, autoimmune diseases, endocrine diseases, cancer, endometriosis, obesity, and diabetes.
9. The use of claim 1 wherein the therapeutic agent is leuprolide or luteinizing hormone.
10. The use of any one of claims 1 to 9 wherein the chitosan molecular weight is at least 4,000 Daltons.
11. The use of claim 10, wherein the composition further comprises sucralose and a rapid dissolution agent.
12. The use of claim 11, wherein the composition further comprises magnesium stearate, silicone dioxide and microcrystalline cellulose.
13. A composition for sublingual administration, the composition comprising a therapeutic agent; chitosan or chitosan derivatives or chitosan salts; and a rapid dissolution agent.
14. The composition of claim 13 wherein the chitosan is chitosan glutamate or chitosan acetate.
15. The composition of claim 14 wherein the therapeutic agent is sildenafil, insulin or leptin.
16. The composition of claim 15, wherein the ratio of chitosan to therapeutic agent is at least about 1 :10.
17. The composition of claim 16 wherein the ratio of chitosan to therapeutic agent is at least about 1:5.
18. The composition of claim 17 wherein the chitosan to therapeutic agent ratio is at least about 1 :2.
19. The composition of claim 15, wherein the composition comprises about 25 mg sildenafile citrate, about 30 mg chitosan, about 125 mg rapid dissolution agent and about 10 mg sucralose.
20. The composition of claim 19 further comprising at least one bioadhesive.
21. The composition of claim 20 further comprising a preservative.
22. A method of treating a mammalian subject in need thereof comprising sublingually administering a composition, wherein the composition comprises chitosan or chitosan derivatives or chitosan salts; and a therapeutic agent selected for treatment of the mammalian subject.
23. The method of claim 22, wherein the chitosan is chitosan glutamate and the therapeutic agent is one of leptin, insulin and sildenafil.
24. The method of claim 23 wherein the composition comprises about 25 mg sildenafϊle citrate, about 30 mg chitosan, about 125 mg rapid dissolution agent and about 10 mg sucralose.
25. A composition for sublingual administration, the composition comprising: a therapeutic agent; at least one bioadhesive; and a rapid dissolution agent.
26. The composition of claim 25 further comprising sucralose.
PCT/CA2010/000553 2009-04-14 2010-04-14 Compositions for sublingual drug delivery and methods of use thereof WO2010118516A1 (en)

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
WO2015132660A1 (en) * 2014-03-04 2015-09-11 Eastgate Pharmaceuticals Inc. Pharmaceutical composition for transmucosal delivery and methods for treating diabetes in a subject in need thereof
US10568936B2 (en) 2014-03-04 2020-02-25 Eastgate Pharmaceuticals Inc. Pharmaceutical composition for transmucosal delivery and methods for treating diabetes in a subject in need thereof
WO2019174995A1 (en) 2018-03-13 2019-09-19 Fulton Medicinali S.P.A. Sublingual tablet comprising sildenafil citrate

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