WO2014024193A1 - Compositions et procédés d'administration rapide, à travers les muqueuses, d'ingrédients pharmaceutiques - Google Patents
Compositions et procédés d'administration rapide, à travers les muqueuses, d'ingrédients pharmaceutiques Download PDFInfo
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- WO2014024193A1 WO2014024193A1 PCT/IL2013/050672 IL2013050672W WO2014024193A1 WO 2014024193 A1 WO2014024193 A1 WO 2014024193A1 IL 2013050672 W IL2013050672 W IL 2013050672W WO 2014024193 A1 WO2014024193 A1 WO 2014024193A1
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- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 claims abstract description 77
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- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims description 13
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- MRBDMNSDAVCSSF-UHFFFAOYSA-N phentolamine Chemical compound C1=CC(C)=CC=C1N(C=1C=C(O)C=CC=1)CC1=NCCN1 MRBDMNSDAVCSSF-UHFFFAOYSA-N 0.000 claims description 7
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- LJRDOKAZOAKLDU-UDXJMMFXSA-N (2s,3s,4r,5r,6r)-5-amino-2-(aminomethyl)-6-[(2r,3s,4r,5s)-5-[(1r,2r,3s,5r,6s)-3,5-diamino-2-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-hydroxycyclohexyl]oxy-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]oxyoxane-3,4-diol;sulfuric ac Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO LJRDOKAZOAKLDU-UDXJMMFXSA-N 0.000 claims description 6
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
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- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
Definitions
- the present invention relates to compositions and method for rapid delivery of a pharmaceutical ingredient across the oral mucosa by administering a liquid composition comprising a pharmaceutical ingredient, methylsulfonylmethane (MSM) and a carrier to oral mucous membranes of a subject in need thereof.
- a liquid composition comprising a pharmaceutical ingredient, methylsulfonylmethane (MSM) and a carrier to oral mucous membranes of a subject in need thereof.
- MSM methylsulfonylmethane
- the pharmaceutical industry is actively seeking to develop new and improved modes of drug delivery to enhance the effectiveness of particular drugs, including, targeting the drug to the intended site, reducing dosage, decreasing toxicity, and the like.
- Transmucosal drug delivery has been explored intensively during the last decade to overcome the disadvantages of oral drug delivery via the gastrointestinal (GI) tract.
- Advantages of the former include the bypass of first-pass metabolism and the avoidance of pre-systemic elimination within the GI tract.
- substances which are delivered by the traditional oral route i.e., swallowing
- an environment that includes hydrochloric acid, enzymes such as pepsin in the stomach, bile acids and bile juices, pancreatic enzymes, the alkaline pH of the small intestine, and the bacterial content of the large intestine.
- the avoidance of the first pass effect provides rationale for the use of mucous formulations.
- Mucous membranes are the moist linings of the orifices and internal parts of the body that are in continuity with the external surface. They cover, protect, and provide secretory and absorptive functions in the channels and extended pockets of the outside world that are incorporated in the body.
- the mucous membranes function as a barrier essential in preventing viruses and bacteria from entering into tissues.
- drug delivery via the mucous membranes in the oral cavity seems to be the most easily tolerated by patients.
- the mucous membranes of the oral cavity can be divided into five main regions: the floor of the mouth (sublingual), the cheeks (buccal), the gums (gingival), the roof of the mouth (palatal), and the lining of the lips. These regions differ from each other with respect to their anatomy, drug permeability, and physiological response to drugs. Sublingual delivery gives rapid absorption and good bioavailability for some small permeants, although this site is not well suited to sustained-delivery systems. The buccal mucosa, by comparison, is considerably less permeable, but is probably better suited to the development of sustained- delivery systems.
- the extent of drug delivery is also affected by the properties of the drug to be delivered.
- the ability of a molecule to pass through any mucous membrane is dependent upon its size, its lipid solubility, and the extent to which it is ionized, among other factors.
- the relatively small surface area of the oral mucosa and the significant loss of drug due to uncontrolled swallowing and salivary flow are the main limitations of this route.
- US Patent No. 6,676,959 discloses nicotine containing pharmaceutical compositions for transmucosal absorption of nicotine.
- compositions for the treatment of sexual disorders discloses pharmaceutical composition for the treatment of sexual disorders.
- the compositions may be administered by buccal or sublingual routes.
- U.S. Patent No. 4,572,832 discloses a soft buccal dosage form containing a medicament to be absorbed through the oral mucosa, a water-soluble protein, a polyhydric alcohol, and a fatty acid ester or/and a carboxyvinyl polymer, which can be used for administration to the mucous membranes of the mouth.
- U.S. Patent No. 4,764,378 discloses buccal dosage forms for transmucosal administration of drugs comprising a pharmaceutical compound dispersed in an erodible matrix comprising a low molecular weight polyethylene glycol component, a medium or high molecular weight polyethylene glycol component, and as an auxiliary a high molecular weight polymer.
- U.S. Patent No. 5,346,701 discloses a system for mucosal administration of a macromolecular drug, comprising an inner drug/enhancer/polymer layer having one surface adapted to contact the mucosal tissue of the oral cavity and adhere thereto, said inner layer containing a bile salt enhancer, a hydrophilic polymer and a macromolecular drug having a molecular weight of at least 500 daltons inter alia calcitonin or heparin.
- U.S. Patent No. 4,713,243 discloses a thin film capable of adhering to a wet mucous surface which comprises a bioadhesive layer consisting of hydroxypropyl cellulose, polyethylene oxide, a plasticizer, a medicament, and optionally a water-insoluble polymer.
- the film is useful for controlled release of a medicament such as anesthetics, antiinflammatories, antihistamines, antibiotics, and antibacterials.
- U.S. Patent Nos. 5,948,430, 6,177,096, 6,284,264, 6,592,887, and 6,709,671 disclose mucoadhesive films capable of rapidly dissolving and adhering to the oral cavity comprising a water-soluble polymer and a pharmaceutically or cosmetically active ingredient and methods of use thereof.
- Methylsulfonylmethane also known as dimethyl sulfone or organic sulfur, is a naturally occurring sulfur-containing compound found in a variety of fruits, vegetables, grains, mammal's milk and animals including humans. MSM is the primary oxidative metabolite product of dimethyl sulfoxide in humans.
- MSM is sold as a dietary supplement and is commonly used (often in combination with glucosamine and/or chondroitin) for treatment or prevention of osteoarthritis.
- U.S. Patent No. 4,568,547 discloses use of methylsulfonylmethane as a tableting and granulating excipient for pharmaceutical ingredients which are unstable in the presence of moisture.
- U.S. Patent Application Publication No. 2005/0181048 discloses compositions and methods for producing timed or retarded release neutraceutical formulations, inter alia those containing methylsulfonylmethane as the active substance.
- U.S. Patent No. 6,444,234 discloses a liquid carrier composition effective for the transdermal delivery of a medicament having a given polarity, the composition comprising methylsulfonylmethane as a solvent modifier.
- U.S. Patent No. 6,416,772 discloses a composition applied transdermally for relief of pain comprising alcohol, glycerin, an analgesic agent, the analgesic agent comprising a derivative of salicylic acid, methylsulfonylmethane, and emu oil.
- U.S. Patent Application Publication No. 2004/0247669 discloses long lasting flavored dosage forms for sustained release of beneficial agents within the mouth.
- the composition potentially comprises MSM.
- compositions and methods for enhancing protein anabolism and detoxification comprises MSM as a source of sulfur.
- the present invention provides compositions, methods and a dosage form that achieve rapid onset of a beneficial agent by delivery across the oral mucous membranes.
- the methods comprise administering a liquid composition comprising a beneficial agent, methylsulfonylmethane (MSM) and a carrier to the oral mucosa.
- MSM methylsulfonylmethane
- the methods achieve rapid and/or enhanced penetration of the beneficial agent into the blood circulation and allow lower therapeutic dosages of administration.
- a prominent advantage of an oral mucosal delivery system is the bypass of the first- pass metabolism and the avoidance of the pre-systemic elimination within the GI tract.
- the inventor of the present invention has found that the presence of MSM in a liquid composition provides an unexpected rapid absorption and enhanced penetration into the blood circulation of pharmaceutical agents. Oral absorption and penetration of a pharmaceutical ingredient into the blood circulation according to the present invention occurs within a few minutes (e.g., 5-15 minutes or less). Furthermore, in some embodiments, the invention provides lower amounts of administration of an active ingredient in order to achieve a therapeutic effect.
- oral mucosal delivery by the composition of the present invention wherein the active ingredient is the erectile dysfunction medicament, sildenafil citrate, facilitates a faster absorption and shorter time to maximal activity with a lower dose requirement when compared to oral delivery by swallowing of a tablet of sildenafil citrate.
- oral mucosal delivery by the composition of the present invention, wherein the active ingredient is the non-steroid anti-inflammatory drug ibuprofen results with higher levels of ibuprofen in the blood circulation, as compared to oral swallowing of ibuprofen.
- the amount of MSM that was found to induce a rapid and efficient delivery of a pharmaceutical ingredient does not exceed 10% w/w.
- This upper limit of MSM is of significant advantage in compositions for oral mucosal applications as this amount is devoid of the unpleasant smell and taste associated with compositions comprising amounts of above 10% w/w MSM which are thus less tolerable to patients.
- the present invention provides a pharmaceutical composition suitable for application to the oral mucosa, the composition comprising a pharmaceutical ingredient, methylsulfonylmethane and a carrier, wherein the composition is in the form of a liquid and wherein the methylsulfonylmethane is in an amount sufficient to induce rapid delivery of the pharmaceutical ingredient across the oral mucosa.
- the present invention provides a method for rapid delivery of a pharmaceutical ingredient across the oral mucosa, the method comprising administering to the oral mucosa of a subject in need thereof a liquid composition comprising a pharmaceutical ingredient, methylsulfonylmethane and a carrier, wherein the methylsulfonylmethane is in an amount sufficient to induce rapid delivery of the pharmaceutical ingredient across the oral mucosa.
- rapid delivery of the pharmaceutical ingredient is delivery that occurs within 5 to 15 minutes or less from administration of the pharmaceutical ingredient.
- the liquid composition utilized in the present invention is in the form selected from the group consisting of: a solution, a suspension and an emulsion.
- the emulsion is an oil-in-water emulsion or a water-in-oil emulsion.
- the emulsion is an oil-in-water emulsion.
- compositions utilized in the present invention comprise a carrier.
- the carrier comprises an edible oil, purified water, and lecithin.
- the edible oil is a vegetable oil.
- the vegetable oil is selected from the group consisting of: cottonseed oil, peanut oil, poppy seed oil, sunflower oil, sesame oil, soybean oil, corn oil, olive oil, canola oil, and combinations thereof. Each possibility represents a separate embodiment of the invention.
- compositions utilized in the present invention further comprise at least one excipient selected from the group consisting of: a sweetening agent, a flavoring agent, a plasticizer, an elastomeric solvent, a filler material, a preservative, a lubricating agent, a wetting agent, an emulsifying agent, solubilizing agent, a suspending agent, a coloring agent, a disintegrating agent and combinations thereof.
- a sweetening agent a sweetening agent
- a flavoring agent a plasticizer
- an elastomeric solvent e.glymerizing agent
- a filler material e.glymer of e., a lubricating agent, a wetting agent, an emulsifying agent, solubilizing agent, a suspending agent, a coloring agent, a disintegrating agent and combinations thereof.
- compositions utilized in the present invention comprise a pharmaceutical ingredient in an amount of between 0.1 % to 15% w/w, methylsulfonylmethane in an amount that does not exceed 10 % w/w, a vegetable oil in an amount of between 1 % to 20% w/w, purified water in an amount of between 50% to 85% w/w, sucrose in an amount sufficient to serve as a sweetener, and lecithin in an amount of between 1 % to 20% w/w.
- the compositions utilized in the present invention comprise a pharmaceutical ingredient in an amount of between 0.1 % to 15% w/w, methylsulfonylmethane in an amount that does not exceed 10 % w/w, a vegetable oil in an amount of between 1 % to 20% w/w, purified water in an amount of between 50% to 85% w/w, sucrose in an amount sufficient to serve as a sweetener, lecithin in an amount of between 1 % to 20% w/w, polysorbate 80 in an amount of between 1 % to 15% w/w, glycine in an amount of between 1% to 15% w/w, at least one flavoring agent in an amount of between 1 % to 10% w/w, at least one tocopherol in an amount of between 1% to 10% w/w, and sodium benzoate in an amount of between 1 % to 10% w/w.
- the compositions may further comprise glycerin in an amount of between 1 % to 10% w/w.
- the pharmaceutical ingredient to be administered within the composition utilized in the present invention is selected from the group consisting of: an erectile dysfunction medication, a non-steroid anti- inflammatory drug (NSAID), a phytochemical agent, an analgesic, a migraine medication, a menopause medication, a sleep disorder medication, an erectile dysfunction medication, and an appetite suppressant.
- NSAID non-steroid anti-inflammatory drug
- the pharmaceutical ingredient is selected from the group consisting of: a non-steroid antiinflammatory drug (NSAID), and.
- NSAID non-steroid antiinflammatory drug
- the pharmaceutical ingredient has a molecular weight of at least about 100 Daltons (Da) and up to about 5000 Da. In some embodiments, the pharmaceutical ingredient has a molecular weight of at least about 200 Daltons (Da) and up to about 5000 Da. In yet another embodiment, the pharmaceutical ingredient of the present invention is selected from the group consisting of: vitamin B12, an antibiotic, a peptide, calcitonin, vasopressin and oxytocin. In a particular embodiment, the pharmaceutical ingredinet is vitamin B 12.
- the NSAID is selected from the group consisting of ibuprofen (2- (isobutylphenyl)-propionic acid); methotrexate (N-[4-(2, 4 diamino 6-pteridinyl- methyl]methylamino]benzoyl)-L-glutamic acid); aspirin (acetylsalicylic acid); salicylic acid; diphenhydramine (2-(diphenylmethoxy)-NN-dimethylethylamine hydrochloride); naproxen (2-naphthaleneacetic acid, 6-methoxy-9-methyl-, sodium salt, (-)); phenylbutazone (4-butyl- l,2-diphenyl-3,5-pyrazolidinedione); sulindac (2)-5-fuoro-2-methyl-l-[[p-
- the analgesic is selected from the group consisting of: acetaminophen and dipyrone (4-methylamino-l,5- dimethyl-2-phenyl-3-pyrazolone sodium methanesulfonate).
- acetaminophen and dipyrone (4-methylamino-l,5- dimethyl-2-phenyl-3-pyrazolone sodium methanesulfonate).
- the phytochemical agent is selected from the group consisting of: parthenolide, theanine, resveratrol, elagic acid.
- the migraine medication is selected from the group consisting of: a triptan, sumatriptan (3-(2-(dimethylamino)ethyl)-N-methyl-lH-indole-5- methanesulfonamide), almotriptan ( 1 -(((3-(2(dimethylamino)ethyl)indol-5- yl)methyl)sulfonyl)pyrrolidine), and amitriptyline (3-(10,l l-dihydro-5H-dibenzo (a,d)cyclohepten- 5-ylidene)-N,N-dimethyl-l-propanamine).
- a triptan sumatriptan (3-(2-(dimethylamino)ethyl)-N-methyl-lH-indole-5- methanesulfonamide)
- almotriptan 1 -(((3-(2(dimethylamino)ethy
- the menopause medication is selected from the group consisting of: venlafaxine, paroxetine, a phytoestrogen; and a plant extract.
- the plant extract is derived from a plant selected from the group consisting of black cohosh and maca. Each possibility represents a separate embodiment of the invention.
- the sleep disorder medication is selected from the group consisting of diphenhydramine (2-(benzhydryloxy)-N,N-dimethylethylamine), valerian and melatonin (5-methoxy-N-acetyltryptamine).
- diphenhydramine (2-(benzhydryloxy)-N,N-dimethylethylamine)
- valerian valerian
- melatonin (5-methoxy-N-acetyltryptamine).
- the erectile dysfunction medication is selected from the group consisting of: sildenafil citrate, a prostaglandin, a testosterone, yohimbine, pentoxifylline, trazodone, apomorphine, minoxidil, misoprostol, papaverine, nitroglycerin, phentolamine, moxisylyte, linsidomine, and a pyridylguanidine compound.
- the erectile dysfunction medication is sildenafil citrate.
- the appetite suppressant is selected from the group consisting of: D-phenylalanine, L-phenylalanine and combination thereof.
- the liquid composition utilized in the present invention may be in any dosage form known in the art.
- the liquid composition is in the form of a spray.
- the composition is administered onto the oral cavity or surfaces by spraying the composition onto the oral cavity or surfaces.
- the composition is administered in a container in the form of a dropper.
- the composition is administered onto the oral cavity or surfaces by dripping a few drops of the composition onto the oral cavity or surfaces.
- the composition may be contained in a bottle and the composition may be administered by absorbing the composition onto a swab, a sponge, a cotton wool and the like.
- the oral mucosa is selected from the group consisting of the sublingual mucosa, the buccal mucosa, gingival mucosa, palatal mucosa and a combination thereof.
- the present invention provides a method for treating erectile dysfunction in a subject in need thereof, the method comprising, administering to the oral mucosa of a subject in need thereof a liquid composition comprising a therapeutic effective amount of an erectile dysfunction medication, methylsulfonylmethane, and a carrier, wherein said methylsulfonylmethane is in an amount sufficient to induce rapid delivery of said erectile dysfunction medication across the oral mucosa.
- the present invention provides a pharmaceutical composition for use in treating erectile dysfunction in a subject in need thereof, the composition comprising a therapeutic effective amount of an erectile dysfunction medication, methylsulfonylmethane, and a carrier, wherein said composition is in the form of a liquid and wherein said methylsulfonylmethane is in an amount sufficient to induce rapid delivery of said erectile dysfunction medication across the oral mucosa.
- the erectile dysfunction medication is selected from the group consisting of: sildenafil citrate, a prostaglandin, a testosterone, yohimbine, pentoxifylline, trazodone, apomorphine, tadalafil, minoxidil, misoprostol, papaverine, nitroglycerin, phentolamine, moxisylyte, linsidomine, and a pyridylguanidine compound flibanserin.
- the erectile dysfunction medication is sildenafil citrate.
- the sildenafil citrate is in an amount of between 1% to 3% w/w.
- the present invention provides a method for treating a condition that would benefit from administration of an NSAID in a subject in need thereof, the method comprising administering to the oral mucosa of a subject in need thereof a liquid composition comprising a therapeutic effective amount of an NSAID, methylsulfonylmethane, and a carrier, wherein said methylsulfonylmethane is in an amount sufficient to induce rapid delivery of said NSAID across the oral mucosa.
- the present invention provides a pharmaceutical composition for use in treating a condition that would benefit from administration of an NSAID in a subject in need thereof, the composition comprising a therapeutic effective amount of an NSAID, methylsulfonylmethane, and a carrier, wherein said composition is in the form of a liquid and wherein said methylsulfonylmethane is in an amount sufficient to induce rapid delivery of said erectile dysfunction medication across the oral mucosa.
- the NSAID is selected from the group consisting of: ibuprofen (2-(isobutylphenyl)-propionic acid); methotrexate (N-[4-(2, 4 diamino 6-pteridinyl- methyl]methylamino]benzoyl)-L-glutamic acid); aspirin (acetylsalicylic acid); salicylic acid; diphenhydramine (2-(diphenylmethoxy)-NN-dimethylethylamine hydrochloride); naproxen (2-naphthaleneacetic acid, 6-methoxy-9-methyl-, sodium salt, (-)); phenylbutazone (4-butyl- 1 ,2-diphenyl-3,5-pyrazolidinedione); sulindac-(2)-5-fuoro-2 -methyl- 1 -[[p-ibuprofen (2-(isobutylphenyl)-propionic acid); methotrexate (N-[4
- the NSAID is ibuprofen (2-(isobutylphenyl)-propionic acid). In a particular embodiment, the ibuprofen is in an amount of between
- the condition that would benefit from administration of an NSAID is at least one condition selected from the group consisting of: inflammation, mild to moderate pain, fever and arterial thrombosis. In some embodiments, the condition is at least one condition selected from the group consisting of: headaches or migraines, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhea, and renal colic.
- Figure 1 is a plot demonstrating the pharmacokinetic profile of sildenafil citrate administered either by Trans Mucosal Oral Delivery (TMOD) or by oral delivery using gavage. Presented are the average plasma concentrations at the indicated time points of sildenafil citrate ⁇ SEM in rabbits administered with either 10 mg/kg sildenafil citrate by gavage or with 5 mg/kg sildenafil citrate by the TMOD.
- TMOD Trans Mucosal Oral Delivery
- Figure 2 is a plot demonstrating the accumulated concentrations of sildenafil citrate in the plasma of rabbits administered with either 10 mg/kg sildenafil citrate by oral delivery using gavage or with 5 mg/kg of sildenafil citrate by TMOD.
- Figure 3 is a plot demonstrating ibuprofen concentrations in swine plasma following TMOD and PO administration of the composition of the present invention comprising ibuprofen or commercially available ibuprofen solution (all pigs received a total of 8 mg/kg of ibuprofen).
- the present invention provides methods and compositions for accelerating transmucosal delivery of pharmaceutical ingredients, inter alia, Non-Steroid Anti- Inflammatory Drugs (NSAIDs), and erectile dysfunction medications.
- the composition of the invention is particularly suitable for transmucosal delivery of molecules having molecular weight of at least about 100 Daltons (Da) and up to about 5000 Da, and is advantageous over prior art transmucosal delivery formulations which are suitable only for smaller sized molecules, for example up to about 200 Da.
- the present invention further provides methods of treating an erectile dysfunction and conditions or symptoms which would benefit from administration of an NSAID. Accordingly, the methods of the present invention comprise administering liquid compositions comprising MSM and a carrier to the oral mucosa to effectively and rapidly treat an erectile dysfunction or conditions treated with NSAIDs.
- Medicaments taken by mouth and swallowed are absorbed first into the blood perfusing the gastrointestinal tract.
- the venous drainage from the GI tract is drained into the blood perfusing the liver.
- medicaments absorbed from the lumen of gastrointestinal tract are immediately presented to the liver, the major detoxifying organ of the body.
- the liver also metabolizes medicaments, which are treated in the same way.
- Blood from the liver then returns to the left side of the heart via the hepatic portal vein and reaches the rest of the systemic circulation. This first pass through the liver may result in the removal of a substantial proportion of an ingested medicament. The first pass effect is more pronounced for some drugs than others.
- Certain areas of the alimentary canal have a venous drainage, which does not involve a first pass through the liver. These areas (the mucous membrane of the buccal cavity, under the tongue and the nasopharynx, and also the distal rectum) drain directly into the left side of the heart.
- the avoidance of this first pass effect is the rationale for the use of buccal, and sublingual formations.
- Both sublingual and buccal formulations depend on the efficient transfer of medicament from a hydrophilic vehicle to the mucous membrane of the sublingual or buccal mucosa. Transfer of medicament through the interstices between or through epithelial cells is governed principally by the lipid solubility of the medicament. Where a drug is water insoluble this is a further barrier to absorption from the sublingual area.
- the present invention relates to formulations which are particularly suitable for use in administration of pharmaceutical ingredients or medicaments via a mucosal surface such as, for example, the sublingual mucosa or the buccal mucosa.
- the composition of the invention is particularly suitable for transmucosal delivery of macromolecules having molecular weight of up to about 5000 Da and is advantageous over prior art transmucosal delivery formulations which are suitable only for smaller sized molecules, for example up to about 200 Da.
- the liquid composition is effective for oral transmucosal delivery of high molecular weight active agents, especially medicaments and other active agents having molecular weights of at least about 200, 250, 350, 450, 550 or 650 Daltons (Da) and up to about 5000 Da.
- Da Daltons
- the present invention provides a method for rapid delivery of a pharmaceutical ingredient across the oral mucosa, the method comprises administering to the oral mucosa of a subject in need thereof a liquid composition comprising a pharmaceutical ingredient and methylsulfonylmethane (MSM) in a carrier, wherein the methylsulfonylmethane is in an amount sufficient to induce rapid delivery of said pharmaceutical ingredient across the oral mucosa.
- MSM methylsulfonylmethane
- methylsulfonylmethane improves and accelerates the oral mucosal absorption of a pharmaceutical ingredient such as sildenafil citrate and ibuprofen.
- a pharmaceutical ingredient such as sildenafil citrate and ibuprofen.
- the present invention discloses that the provision of methylsulfonylmethane in a liquid composition unexpectedly accelerates delivery of active ingredients across the oral mucosa. As a consequence, the active ingredient appears in the blood circulation within a few minutes from administration.
- the MSM is provided in an amount sufficient to induce rapid delivery of a pharmaceutical ingredient across the oral mucosa.
- the amount of MSM that is sufficient to induce a rapid delivery of the pharmaceutical ingredient is an amount that does not exceed 10% w/w.
- the amount of MSM does not exceed 9 % w/w, 8 % w/w, 7 % w/w, 6 % w/w, 5 % w/w, 4 % w/w, 3 % w/w, 2 % w/w, 1 % w/w, or 0.5 % w/w of the total weight of the composition.
- Each possibility represents a separate embodiment of the present invention.
- the amount of MSM is 5% w/w of the total weigh of the composition.
- the term "amount sufficient to induce rapid delivery” refers to an amount of methylsulfonylmethane which upon formulation with a pharmaceutical ingredient, and following transmucosal administration to a subject, substantially increases the rate of appearance of the pharmaceutical ingredient in the blood circulation of the subject, as compared to a formulation of the same pharmaceutical ingredient which lacks methylsulfonylmethane.
- delivery it is meant that the pharmaceutical ingredient is released from the composition in which it is formulated, absorbed onto the oral mucosal site and penetrates to the mucous membranes and thereafter to the blood circulation.
- delivery of drugs may be measured by conventional pharmacokinetics methods known in the art and utilized in the Examples section that follows.
- compositions utilized in the present invention are very rapidly absorbed onto the mucous membranes of the mouth.
- the compositions are absorbed onto the mucous membranes within a few to several seconds after application and with a high percentage of the active agent being transmigrated and made bio-available.
- the rapid delivery occurs immediately following administration of the compositions utilized in the present invention.
- the delivery occurs within 1 to 30, 1 to 25, 1 to 20, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 minutes from administration of the composition.
- the delivery occurs within 5 to 30, 5 to 25, 5 to 20, 5 to 15, or 5 to 10 minutes from administration of the composition.
- Each possibility represents a separate embodiment of the invention.
- the delivery occurs within 5 minutes from administration.
- compositions utilized in the present invention are liquid.
- Liquid dosage forms include aqueous or non-aqueous solutions, lotions or suspensions, or oil-in-water or water-in- oil emulsions. Solutions or suspensions may be syrups or elixirs.
- the transmucosal oral delivery system of this invention is in the form of an oil-in-water emulsion.
- the means for storing or containing the dosage form include, but are not limited to, a container suitable for long storage and blister packaging for pharmaceuticals, among others.
- the compositions are liquid aerosol formulations adapted as mouth-sprays or as droppers.
- Spray containers may comprise a pump and metered dosing device to assist correct dosing. In general, from about 0.05 to about 3 ml, for example, about 0.14 ml of the compositions utilized in the present invention are administered in each spraying.
- the container is a bottle.
- administering refers to administration of the composition of the present invention to the mucous membranes of the oral cavity (i.e., oral mucosa).
- suitable sites of administration within the oral mucosa include, without limitation, the mucous membranes of the floor of the mouth (sublingual mucosa), the cheeks (buccal mucosa), the gums (gingival mucosa), the roof of the mouth (palatal mucosa), the lining of the lips, and combinations thereof.
- MSM effectiveness of MSM is not limited by the type of carrier used and suitable excipients may be selected as is well known in the art to impart to the compositions the desired consistency and other characteristics.
- the present invention provides a composition for rapid delivery across the oral mucosa, the composition comprising a pharmaceutical ingredient, methylsulfonylmethane, an edible oil, purified water, and lecithin.
- the edible oil is a vegetable oil.
- vegetable oils include, but are not limited to cottonseed oil, peanut oil, poppyseed oil, sunflower oil, sesame oil, soybean oil, corn oil, olive oil, canola oil and combinations thereof.
- the composition may further comprise at least one excipient, such as a sweetening agent, a flavoring agent, a plasticizer, an elastomeric solvent, a filler material, a preservative, a lubricating agent, a wetting agent, an emulsifying agent, solubilizing agent, a suspending agent, a coloring agent, a disintegrating agent, or combinations thereof. It is to be understood that some excipients may fall within more than one class of the aforementioned excipients.
- excipient such as a sweetening agent, a flavoring agent, a plasticizer, an elastomeric solvent, a filler material, a preservative, a lubricating agent, a wetting agent, an emulsifying agent, solubilizing agent, a suspending agent, a coloring agent, a disintegrating agent, or combinations thereof. It is to be understood that some excipients may fall within more than one class of the aforementioned excipients.
- the composition comprises at least one excipient selected from the group consisting of: sucralose, sucrose, calcium salt, polysorbate 80, glycine, tocopherol, glycerin, sodium benzoate, and combinations thereof.
- a calcium salt is calcium carbonate.
- glycolin interchangeably refers to glycerine or glycerol.
- the glycerin used for the preparation of the compositions of the present invention is glycerin USP.
- compositions utilized in the present invention comprise: a pharmaceutical or nutraceutical ingredient in an amount that does not exceed about 5%, MSM in an amount that does not exceed about 10%, vegetable oil in an amount that does not exceed about 40%, sucrose in an amount that does not exceed about 20%, lecithin in an amount that does not exceed about 20%, and purified water in an amount of at least about 50%, wherein the percentages are weight per weight percent calculated as the weight of each substance divided by the total weight of the composition and multiplied by 100.
- compositions utilized in the present invention comprise a pharmaceutical ingredient in an amount of between 0.1 % to 15% w/w, methylsulfonylmethane in an amount that does not exceed 10 % w/w, a vegetable oil in an amount of between 1 % to 20% w/w, purified water in an amount of between 50% to 85% w/w, sucrose in an amount sufficient to serve as a sweetener, and lecithin in an amount of between 1 % to 20% w/w.
- compositions utilized in the present invention comprise a pharmaceutical ingredient in an amount of between 0.1 % to 15% w/w, methylsulfonylmethane in an amount that does not exceed 10 % w/w, a vegetable oil in an amount of between 1 % to 20% w/w, purified water in an amount of between 50% to 85% w/w, sucrose in an amount sufficient to serve as a sweetener, lecithin in an amount of between 1 % to 20% w/w, polysorbate 80 in an amount of between 1 % to 15% w/w, glycine in an amount of between 1% to 15% w/w, at least one flavoring agent in an amount of between 1 % to 10% w/w, at least one tocopherol in an amount of between 1 % to 10% w/w, and sodium benzoate in an amount of between 1 % to 10% w/w.
- the composition comprises a pharmaceutical ingredient in an amount of between 1% to 10% w/w, between 1 % to 5% w/w, or between 2% to 4% w/w of the total weight of the composition. In one embodiment, the pharmaceutical ingredient is in an amount of between 2% to 4% w/w of the total weight of the composition.
- the methylsulfonylmethane is in an amount that does not exceed 10% w/w of the total weight of the composition. In some embodiments, the methylsulfonylmethane is present in an amount of between 2% to 7% w/w of the total weight of the composition.
- the vegetable oil is in an amount of between 1 % to 20% w/w, between 1 % to 15% w/w, or between 1% to 10% w/w of the total weight of the composition.
- the vegetable oil is in an amount of between 1 % to 5 % w/w of the total weight of the composition.
- the purified water is in an amount of between 50% to 85% w/w, between 50% to 80% w/w, between 50% to 70% w/w, or between 50% to 60% w/w of the total weigh of the composition.
- the purified water is in an amount of between 50% to 60% w/w of the total weigh of the composition.
- the sucrose is in an amount of between 1 % to 20% w/w, between 1 % to 15% w/w, between 5% to 15% w/w, or between 5% to 10% w/w, of the total weigh of the composition.
- the sucrose is in an amount of between 5% to 10% w/w of the total weight composition.
- the polysorbate 80 is in an amount of between 1% to 15% w/w, between 1 % to 10% w/w, or between 1% to 5% w/w, of the total weigh of the composition.
- the polysorbate 80 is in an amount of between 1 % to 5% w/w of the total weight of the composition.
- the glycine is in an amount of between 1% to 15% w/w, between 1 % to 10% w/w, or between 1 % to 5% w/w, of the total weigh of the composition.
- the glycine is in an amount of between 1% to 5% w/w of the total weight of the composition.
- the at least one flavoring agent is in an amount of between 1 % to 10% w/w, between 1% to 5% w/w, or between 1% to 3% w/w of the total weigh of the composition.
- the at least one flavoring agent is in an amount of between 1 % to 3% w/w of the total weight of the composition.
- the at least one tocopherol is in an amount of between
- the tocopherol is in an amount of between 0.1 % to 3% w/w of the total weight of the composition.
- the sodium benzoate is in an amount of between 0.1 % to 10% w/w, between 0.1% to 5% w/w, between 0.1 % to 3% w/w, or between 0.1 % to 1 % w/w of the total weigh of the composition.
- the sodium benzoate is in an amount of between 0.1 % to 2% w/w of the total weight of the composition.
- compositions utilized in the present invention are devoid of a polymer. Particularly the compositions of the present invention are devoid of a lactic acid polymer. Production of the composition utilized in the present invention
- compositions utilized in the present invention are in a liquid form.
- Exemplary liquid forms for oral mucosal (e.g. sublingual and buccal) administration include, but are not limited to a solution or a suspension in an aqueous liquid or non-aqueous liquid, or in the form of an oil-in-water emulsion or a water-in-oil emulsion.
- Solution or a suspension form may be of syrups or elixirs.
- Liquid dosage forms include droppers or sprayers useful for dispersion in the oral cavity.
- These liquid compositions can include pharmaceutically acceptable inert ingredients such as diluents (e.g.
- the composition utilized in the present invention can be produced by various methods.
- the water, methylsulfonylmethane, the pharmaceutical active ingredient, lecithin, and an edible oil are mixed at a temperature of between 40 °C to 70°C, the mixture is kneaded uniformly or homogenized, cooled, and inserted into a desirable container.
- Liposomes can be incorporated into the tablet by adding lecithin and vegetable oil in solution to form liposomes as the pharmaceutical solution, and then gently vortexing to prevent damage to the liposomes before introduction into molds where gelling occurs.
- the steps in these production processes may be combined in an adequate manner other than the manners mentioned above.
- the components are used in the amounts prescribed above.
- additives selected from among the various pharmaceutically acceptable additives available to those skilled in the art for the purpose of assisting in the development of characteristics of the composition of the present invention, by improving the processability, and quality of the preparation, and by enhancing the dispersability and stability of the composition.
- additives are other than those mentioned as the essential components and include the following substances.
- Flavors menthol, cherry flavor, saccharin sodium, glycyrrhizin, malt syrup, citric acid, tartaric acid, menthol, lemon oil, citrus flavor, common salt, etc.
- Stabilizers/preservatives parahydroxybenzoic acid alkyl esters, antioxidants, antifungal agents, etc.
- Colors water-soluble tar colors, natural colors, titanium oxide, etc.
- Excipients/disintegration adjusting agents magnesium silicate, light silicic acid anhydride, synthetic aluminum silicate, precipitated calcium carbonate, magnesium aluminum metasilicate, calcium hydrogen phosphate, etc.
- Water-soluble polymers other than water- soluble proteins naturally polymers, synthetic polymers, etc.
- Stearic acid and its salts talc, palmitic acid, and other substances known as emulsifiers, dispersants, binders, thickeners, etc.
- the present oral dosage form can be used to deliver any active or therapeutic agent where absorption across the oral mucosa is desired. While according to an exemplary embodiment, the present invention will hereinafter be discussed with reference to administration of sildenafil citrate or ibuprofen, it should be understood that other active agents, pharmaceutical ingredients, nutraceutical ingredients, medicaments, or drugs may be adjunctively or alternatively employed.
- Non-limiting examples include non-steroid anti-inflammatory drugs other then ibuprofen, analgesics, migraine medications, menopause medications, sleep disorder medications, erectile dysfunction medications other then sildenafil citrate, appetite suppressants, cough/cold/throat agents, vitamins, zinc, menthol, eucalyptus, hexyl resorcinol, caffeine, tooth whitening agents, anti-plaque agents, breath freshening agents, demulcents and the like.
- Pharmaceutical ingredients include non-steroid anti-inflammatory drugs other then ibuprofen, analgesics, migraine medications, menopause medications, sleep disorder medications, erectile dysfunction medications other then sildenafil citrate, appetite suppressants, cough/cold/throat agents, vitamins, zinc, menthol, eucalyptus, hexyl resorcinol, caffeine, tooth whitening agents, anti-plaque agents, breath freshening agents, demulcents and the like.
- NSAIDs which may be incorporated into the composition of the invention include ibuprofen (2-(isobutylphenyl)-propionic acid); methotrexate (N-[4-(2, 4 diamino 6-pteridinyl- methyl]methylamino]benzoyl)-L-glutamic acid); aspirin (acetylsalicylic acid); salicylic acid; diphenhydramine (2-(diphenylmethoxy)-NN-dimethylethylamine hydrochloride); naproxen (2-naphthaleneacetic acid, 6-methoxy-9-methyl-, sodium salt, (-)); phenylbutazone (4-butyl- 1 ,2-diphenyl-3,5-pyrazolidinedione); sulindac-(2)-5-fuoro-2 -methyl- 1 -[[p-ibuprofen (2-(isobutylphenyl)-propionic acid); methotrexate (N
- Analgesic compounds which may be incorporated into the composition of the invention include acetaminophen and dipyrone (4-methylamino-l ,5-dimethyl-2-phenyl-3- pyrazolone sodium methanesulfonate).
- Migraine medications which may be incorporated into the composition of the invention include triptans, such as sumatriptan ( 3-(2-(Dimethylamino)ethyl)-N-methyl-lH- indole-5-methanesulfonamide) and almotriptan l-(((3-(2(dimethylamino)ethyl)indol-5- yl)methyl)sulfonyl)pyrrolidine and amitriptyline 3-(10,l l-dihydro-5H-dibenzo (a,d)cyclohepten- 5 - ylidene) -N, N-dimethyl- 1 -propanamine .
- triptans such as sumatriptan ( 3-(2-(Dimethylamino)ethyl)-N-methyl-lH- indole-5-methanesulfonamide) and almotriptan l-(((3-(2(dimethyl
- Erectile dysfunction medications which may be incorporated into the composition of the invention include a steroid hormone such as testosterone, a peptide hormone, an amine hormone, and a hormone-like eicosanoid such as a prostaglandin, a leukotriene, flibanserin and a thromboxane.
- Phytochemical agents which may be incorporated into the composition of the invention include but are not limited to parthenolide, theanine, resveratrol, and elagic acid.
- phytochemical agent refers to chemical compounds that occur naturally in plants which have the potential to affect diseases.
- prostaglandin refers to a family of compounds originally discovered in seminal fluid and found to cause vasodilation, and contraction or relaxation of uterine smooth muscle.
- the prostaglandins, leukotrienes, and related compounds are called eicosanoids because they are synthesized by microsomal enzymes from 20-carbon essential fatty acids, e.g., arachidonic acid (Hardman, J. 1996, in Goodman and Gilmans's: The Pharmacological Basis of Therapeutics, Ch. 26, 9th ed., McGraw Hill).
- erectile dysfunction medications include testosterone, yohimbine, pentoxifylline, trazodone, apomorphine, phentolamine, tadalafil, sildenafil and other pyrozolopyrimidone derivatives.
- Other agents include minoxidil, misoprostol, papaverine, nitroglycerin, phentolamine, moxisylyte, linsidomine, linear or cyclic peptides, pyridylguanidine compounds, and renin- angiotensin system inhibitors. These agents may be incorporated into the transmucosal composition at an effective dose to correct erectile dysfunction.
- Menopause medications which may be incorporated into the composition of the invention include phytoestrogens, venlafaxine, paroxentine and plant extracts, such as those derived from black cohosh and maca.
- Sleep disorder medications which may be incorporated into the composition of the invention include diphenhydramine (2-(benzhydryloxy)-N,N-dimethylethylamine), valerian and melatonin (5-methoxy-N-acetyltryptamine).
- An appetite suppressant which may be incorporated into the composition of the invention is phenylalanine.
- the phenylalanine may be D-phenylalanine, L-phenylalanine or a mixture thereof.
- Macromolecules which may be incorporated into the composition of the invention include vitamin B12, antibiotics, peptides, polypeptides, calcitonin, vasopressin and oxytocin.
- the macromolecule is vitamin B12.
- the present invention provides a method for treating an erectile dysfunction in a subject in need thereof, the method comprising, administering to the oral mucosa of a subject in need thereof a liquid composition comprising a therapeutic effective amount of an erectile dysfunction medicament, methylsulfonylmethane, and a carrier, wherein said methylsulfonylmethane is in an amount sufficient to induce rapid delivery of said erectile dysfunction medicament across the oral mucosa.
- the erectile dysfunction medicament utilized in the present invention is sildenafil citrate.
- Sildenafile citrate sold as VIAGRA®, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension (PAH).
- PAH pulmonary arterial hypertension
- sildenafil is administered by oral swallowing of pills.
- compositions utilized in the present invention are preferably formulated as an orally administratable dosage form, such as a spray or a dropper, which thus enable convenient oral mucosal administration.
- the methylsulfonylmethane is present in the composition in an amount sufficient to enhance transmucosal delivery of the erectile dysfunction medicament (i.e., sildenafil citrate).
- the amount of methylsulfonylmethane in the composition is sufficient to rapidly induce or accelerate the appearance of an erectile dysfunction medicament in the blood of a subject following transmucosal administration thereto, and/or to enhance the appearance of the erectile dysfunction medicament in the blood, as compared to a formulation of the same pharmaceutical ingredient which lacks methylsulfonylmethane.
- transmucosal delivery of an erectile dysfunction medicament offers a rapid therapeutic effect.
- the subject to be treated is a mammal.
- the mammal is a human.
- NSAIDs non-steroid anti inflammatory drugs
- the present invention provides a method for treating symptoms that would benefit from administration of an NSAID in a subject in need thereof, the method comprises administering to the oral mucosa of a subject in need thereof a liquid composition comprising a therapeutic effective amount of an NSAID, methylsulfonylmethane, and a carrier, wherein said methylsulfonylmethane is in an amount sufficient to induce rapid delivery of said NSAID across the oral mucosa.
- NSAIDs are used primarily to treat inflammation, mild to moderate pain, and fever.
- the symptom or condition that would benefit from administration of an NSAID medicament is at least one symptom or condition selected from the group consisting of: inflammation, mild to moderate pain, and fever.
- the symptoms are caused by indications selected from the group consisting of: headaches and migraines, rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, such as ankylosing spondylitis, psoriatic arthritis, and reiter's syndrome, acute gout, sysmenorrhoea (menstrual pain), ileus, renal colic and arterial thrombosis.
- NSAIDs are associated with several side effects. The frequency of side effects varies among NSAIDs. The most common side effects are nausea, vomiting, diarrhea, constipation, decreased appetite, rash, dizziness, headache, and drowsiness. NSAIDs may also cause fluid retention, leading to edema. The most serious side effects are kidney failure, liver failure, ulcers and prolonged bleeding after an injury or surgery.
- the NSAID utilized in the present invention is ibuprofen.
- the NSAID ibuprofen sold under the trade names ADVIL ® , NUROFEN ® and others is a non-steroidal anti-inflammatory drug (NSAID) and a member of the World Health Organization "Essential Drugs List". Due to its mechanism of non-selective COX inhibition, when taken orally ibuprofen can result in gastric damages, such as ulcers.
- Example 1 Preparation of Trans Oral Mucosal Sildenafil citrate (TOMSIL) composition
- aqueous composition comprising sildenafil citrate was prepared as specified in table 1.
- the resulting composition is a light brown colored emulsion.
- the density of the emulsion for transmucosal administration is: lmg/ml.
- Table 1 Trans oral mucosal sildenafil citrate composition.
- Purified double distilled water (326.5 g) are poured into a 1000 ml beaker, stirred and heated to a temperature of 65°C - 70°C (for 1 hour).
- Example 2 An in-vivo pharmacokinetic study of the Trans Oral Mucosal Sildenafil Citrate composition (TOMSIL)
- the aim of the present study was to evaluate the pharmacokinetic and safety of transmucosal sildenafil citrate administration in liquid composition comprising methylsulfonylmethane (MSM) vs. oral administration of a commercial tablet of sildenafil.
- MSM methylsulfonylmethane
- An oil-in- water emulsion comprising sildenafil citrate (1.5% w/w), methylsulfonylmethane (MSM) (5% w/w), lecithin (7% w/w), and sunflower oil (5% w/w) was prepared for the TMOD administration.
- MSM methylsulfonylmethane
- a pharmacokinetic study was performed on male rabbits aged 11-12 weeks and weighing no less than 2 kg. Rabbits were administered with either 10 mg/kg in the form of a crushed tablet of sildenafil citrate by a gavage tube inserted directly into the stomach or with half dose (5 mg/kg) of sildenafil citrate oil-in-water emulsion by the TMOD administration by spraying the latter into the oral cavity.
- Figure 1 demonstrates the obtained results for oral delivery using gavage vs. transmucosal oral delivery of sildenafil citrate composition of the present invention.
- Table 2 The pharmacokinetic parameters for Oral delivery vs. TMOD of Sildenafil Citrate.
- the AUC (calculated according to the amount administered) achieved for sildenafil transmucosal formulation is substantially higher than the sildenafil AUC achieved following oral administration to rabbits, therefore the bioavailability of sildenafil citrate administered by the transmucosal administration is higher.
- Example 3 An in-vivo pharmacokinetic study of the Transmucosal oral delivery of Ibuprofen.
- TM trans-mucosal
- PO oral
- TMOD administration was performed using an injector inserting 2 ml (8 mg/kg) of the formulated composition directly onto the open mouth surfaces.
- Oral (PO) administration was performed using a 10 ml syringe by oral gavage inserting 5 ml (8 mg/kg) of commercial solution of ibuprofen directly into the esophagus. Blood Sampling
- Blood samples from each pig were collected prior and post dosing.
- Blood samples were prepared to measure Ibuprofen in swine plasma as follows: (i) add 200 ⁇ plasma into an Eppendorf tube containing 1000 ⁇ acetonitrile into; (ii) add ketoprofen as an internal standard solution (5 ppm concentration) and vortex for 20 s (ibuprofen standard solution of 18.4 ppm was used as a calibration); (iii) evaporate 800 ⁇ ; (iv) reconstitute the dry residue in 200 ⁇ 1 chromatographic mobile phase v; (v) inject a 2 ⁇ sample into the chromatographic system.
- Pigs were clinically observed before and during the study for any signs of vomiting, diarrhea, depression, pupil constriction, salivation, agitation, faeces present, a change in appetite or any other abnormal symptoms.
- each animal was observed with regard to their sensory function and behavior, body orifices and for their general health status. The local safety was evaluated as evaluation of erythema and oedema grades totaled separately for each individual following macroscopic observation on the oral cavity.
Abstract
La présente invention concerne des compositions et des procédés d'administration rapide d'un ingrédient pharmaceutique à travers la muqueuse buccale par l'administration d'une composition liquide comprenant un ingrédient pharmaceutique, du méthylsulfonylméthane (MSM) et un support sur des membranes muqueuses buccales d'un sujet qui en a besoin.
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994005293A1 (fr) * | 1992-09-04 | 1994-03-17 | Aws Shakir Mustafa Salim | Compositions destinees au traitement de la peau, contenant du dimethylsulfone et de l'allopurinol ou l'oxypurinol |
US20030104040A1 (en) * | 1998-07-07 | 2003-06-05 | Kirby Kenneth B. | Compositions for rapid and non-irritating transdermal delivery of pharmaceutically active agents and methods for formulating such compositions and delivery thereof |
US20040247669A1 (en) * | 2003-02-04 | 2004-12-09 | Gin Jerry B. | Long-lasting, flavored dosage forms for sustained release of beneficial agents within the mouth |
US20060263439A1 (en) * | 2003-04-11 | 2006-11-23 | Robert Fishman | Alcohol-free transdermal analgesic composition and processes for manufacture and use thereof |
WO2008099397A2 (fr) * | 2007-02-15 | 2008-08-21 | Derma-Young Ltd. | Compositions et méthodes permettant d'améliorer l'administration transmuqueuse |
-
2013
- 2013-08-07 WO PCT/IL2013/050672 patent/WO2014024193A1/fr active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994005293A1 (fr) * | 1992-09-04 | 1994-03-17 | Aws Shakir Mustafa Salim | Compositions destinees au traitement de la peau, contenant du dimethylsulfone et de l'allopurinol ou l'oxypurinol |
US20030104040A1 (en) * | 1998-07-07 | 2003-06-05 | Kirby Kenneth B. | Compositions for rapid and non-irritating transdermal delivery of pharmaceutically active agents and methods for formulating such compositions and delivery thereof |
US20040247669A1 (en) * | 2003-02-04 | 2004-12-09 | Gin Jerry B. | Long-lasting, flavored dosage forms for sustained release of beneficial agents within the mouth |
US20060263439A1 (en) * | 2003-04-11 | 2006-11-23 | Robert Fishman | Alcohol-free transdermal analgesic composition and processes for manufacture and use thereof |
WO2008099397A2 (fr) * | 2007-02-15 | 2008-08-21 | Derma-Young Ltd. | Compositions et méthodes permettant d'améliorer l'administration transmuqueuse |
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CN113336710A (zh) * | 2021-07-08 | 2021-09-03 | 山东理工大学 | 一种用于治疗脱发的米诺地尔-3-甲氧基苯甲酸盐晶型及其制备方法 |
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