HK1145630A - Compositions and methods for enhancing transmucosal delivery - Google Patents

Description

Compositions and methods for facilitating transmucosal delivery

Technical Field

The present invention relates to compositions and methods for transmucosal delivery of pharmaceutical agents, including macromolecular compounds, and nutrient (nutraceutical) components. The present invention includes the use of methylsulfonylmethane (methylsulfonylmethane) as a transmucosal delivery enhancer.

Background

Drug delivery via oral mucosa

Drugs taken orally and swallowed are first absorbed into the blood perfusing the Gastrointestinal (GI) tract. Venous drainage from the GI tract is first passed into the blood perfusing the liver. This means that the drug absorbed from the lumen of the gastrointestinal tract is immediately delivered to the liver, the major detoxifying organ in the body. In addition to protecting the organism from toxin uptake, the liver metabolizes the drug, making it inactivated by first pass metabolism in the liver. The liver blood 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 can result in the removal of a large portion of the ingested drug.

Thus, other routes of drug administration have been investigated, including those involving transport across the mucosa. Among the various mucous membranes (e.g. oral, rectal, vaginal, ocular, nasal), drug delivery via the mucous membranes in the oral cavity seems to be the most tolerated by patients. In addition to avoiding the problems of traditional oral administration, drug delivery via the oral mucosa has certain other advantages due to the nature of the oral mucosa itself. For example, the oral mucosa is highly vascularized and provides a sufficient site for lymphatic drainage.

Generally, the oral mucosa can be divided into five main areas: the bottom of the mouth (sublingual), the cheeks (cheeks), the gums (gingiva), the top of the mouth (palate), and the inner labial layer (lining). These regions differ from each other in terms of their anatomy, drug permeability, and physiological response to the drug. For example, in terms of relative permeability, the sublingual area is more permeable than the buccal area, and the buccal area is more permeable than the palatal area. This permeability is generally related to the relative thickness and degree of keratinization of these membranes, with the sublingual mucosa being relatively thin and non-keratinized, the buccal mucosa being thicker and non-keratinized, and the palatal mucosa being intermediate in thickness, but keratinized.

In addition to differences in permeability of various mucous membranes, the extent of drug delivery is also affected by the nature of the drug to be delivered. The ability of a molecule to pass through any mucosal membrane depends, among other factors, on its size, its lipid solubility, and the extent to which it ionizes.

Certain regions of the digestive tract have venous drainage, which does not include the first pass through the liver. These areas (buccal mucosa under the tongue and nasopharynx) drain directly into the left side of the heart. Avoidance of the first pass effect is the theoretical basis for the use of buccal and sublingual formulations. Delivery via the buccal mucosa allows for a smaller amount of the composition to take effect immediately.

However, sublingual and buccal administration of drugs is most beneficial for drugs that are extremely rapidly absorbed via the oral mucosa, such as nitroglycerin, because the continuous secretion of saliva quickly washes the dissolved drug out of the oral cavity. In order to maintain the drug in contact with the oral mucosa for a longer period of time, sustained release dosage forms have been developed which are particularly suitable for transmucosal administration of drugs. These dosage forms typically already contain the drug dispersed in a matrix, with slow release of the drug either by diffusion from the matrix or by slow dissolution or erosion of the matrix. In order to retain the dosage form in the mouth, it may be combined with an adhesive patch or the dosage form itself may be provided with an adhesive layer which adheres to the mucosa. Alternatively, the dosage form may itself adhere to the mucosa and slowly dissolve, releasing the drug contained therein.

U.S. patent No. 4,572,832 discloses a soft-buccal dosage form comprising (1) a drug to be absorbed via the oral mucosa, (2) a water-soluble protein, (3) a polyol, and (4) a fatty acid ester or/and a carboxyvinyl polymer, which is useful for administration to the oral mucosa.

U.S. patent No. 4,764,378 discloses buccal dosage forms for transmucosal administration of drugs comprising a drug compound dispersed in an erodible matrix comprising from about 20 to about 75 percent by weight of a low molecular weight polyethylene glycol component, from about 2 to about 65 percent by weight of a medium or high molecular weight polyethylene glycol component, from about 1% to about 40% percent by weight of a secondary high molecular weight polymer.

U.S. patent No. 5,346,701 discloses a system for mucosal administration of macromolecular drugs comprising an inner drug/enhancer/polymer layer having a surface adapted to contact and adhere to mucosal tissue of the oral cavity, said inner layer comprising a bile salt enhancer, a hydrophilic polymer and a macromolecular drug having a molecular weight of at least 500 daltons (especially calcitonin or heparin).

U.S. patent No. 4,713,243 to Schiraldi et al discloses a film capable of adhering to a wet, tacky surface, the film comprising a bioadhesive layer composed of hydroxypropyl cellulose, polyethylene oxide, a plasticizer, a drug, and optionally a water insoluble polymer. The membranes disclosed in U.S. patent No. 4,713,243 are useful for controlled release of drugs such as anesthetics, anti-inflammatory agents, antihistamines, antibiotics, and antibacterial agents.

U.S. Pat. Nos. 5,948,430, 6,177,096, 6,284,264, 6,592,887, and 6,709,671 to Zerbe et al disclose mucoadhesive films (which comprise a water-soluble polymer and a pharmaceutically or cosmetically active ingredient) that are rapidly dissolving and adhere to the oral cavity and methods of use thereof.

Vitamin B12

Vitamin B12 (also known as cobalamin) deficiency is caused by pernicious anemia, food-cobalamin malabsorption, vegetarian and other deficient states and is reported to have a prevalence of up to 29%. This condition can be corrected by intramuscular injection of vitamin B12, a method that has the disadvantage of causing pain to the patient and of being difficult to administer. Alternatively, it may be treated by oral administration of vitamin B12; however, this method is accompanied by the disadvantage that due to the poor absorption rate of the gastrointestinal tract, large doses (at least 500-1000. mu.g) are required in order to supply the daily requirement of 1. mu.g to 2.5. mu.g. Sublingual dosage forms of vitamin B12 are also commercially available, and although these dosage forms are said to provide increased bioavailability, it has been shown that treatment of subjects deficient in vitamin B12 with either conventional oral vitamin B12 or with sublingual vitamin B12 increases the serum concentration levels of the vitamin to the same extent (Sharabi et al (2003) Br J Clin Pharmacol 56: 635-638). Thus, there remains an unmet need for vitamin B12 dosage forms that provide increased bioavailability compared to prior art formulations.

Methylsulfonylmethane

Methylsulfonylmethane (MSM), also known as dimethylsulfone or organosulfur, is a naturally occurring sulfur-containing compound found in a variety of fruits, vegetables, grains, mammalian milk, and animals, including humans. MSM is the major oxidative metabolite of dimethyl sulfoxide in humans.

The toxicity of methylsulfonylmethane at a dose five to seven times greater than the maximum recommended dose in humans was evaluated in rats (Horvath et al, 2002, Food Chem Toxicol.40 (10): 1459-1462). MSM was well tolerated in rats at an acute dose of 2g/kg and at a subacute chronic dose of 1.5 g/kg.

MSM is sold as a dietary supplement sold under various requirements (diets) and is commonly used (often in combination with glucosamine and/or chondroitin) for the treatment or prevention of osteoarthritis. Kim et al (2006) disclose experimental studies showing MSM has the potential to alleviate knee Osteoarthritis (Kim et al (2006) Osteoarthritis Cartilage 14 (3): 286-94).

Published patents relating to the use of methylsulfonylmethane for the prevention, treatment or alleviation of various conditions include: U.S. patent nos. 6,440,391 and 5,569,679 (to control snoring); U.S. patent No. 4,973,605 (relief of pain and nocturnal cramps and reduction of stress-induced animal death); U.S. patent No. 4,559,329 (to alleviate gastric discomfort and allergic reactions); and U.S. patent No. 4,447,469 (as a topical formulation for softening skin, nails, and other tissues).

U.S. patent No. 4,568,547 discloses the use of methylsulfonylmethane as a tableting and granulation excipient for pharmaceutical ingredients that are unstable in the presence of moisture. In accordance with this disclosure, this invention relates to a solid pharmaceutical composition suitable for oral ingestion in the form of a tablet, granule, or free-flowing powder consisting essentially of an intimate physical mixture of an active agent that is storage unstable in the presence of moisture and a carrier consisting essentially of (i.e., at least 95%) methylsulfonylmethane, wherein the mixture is substantially anhydrous.

U.S. patent application publication No. 2005/0181048 discloses compositions and methods for preparing timed or delayed release nutrient formulations, particularly those containing methylsulfonylmethane as the active substance. According to this publication, a pellet (pellet) for timed or delayed release of MSM comprises MSM in an amount of about 60 to 95% by weight, saccharides in an amount of about 1.5 to 15% by weight, and specific percentages of additional components, in particular plasticizers, coagulants (agglutinatives) and lubricants.

U.S. patent No. 6,444,234 discloses liquid carrier compositions effective for transdermal delivery of drugs having known polarity, the formulation comprising (a) at least one non-aqueous non-toxic solvent; (b) limonene, lemon oil, or a mixture of limonene and lemon oil; (c) methylsulfonylmethane; (d) a skin stabilizer; (e) a solute modifier (solute modifier); and (f) Adenosine Triphosphate (ATP) or compounds that induce cyclic adenosine 3 '5' monophosphophosphate (cAMP) or cyclic guanosine monophosphate (cGMP) in situ.

U.S. patent No. 6,416,772 discloses a liquid composition for pain relief for transdermal application containing alcohol in an amount of about 57 to about 91 percent by weight; glycerin in an amount of about 1 to about 12 percent by weight; an analgesic agent in an amount of about 2 to about 28 percent by weight, the analgesic agent comprising a salicylic acid derivative; methylsulfonylmethane in an amount of about 0.02 to 5 percent by weight; and emu oil (emu oil) in an amount of about 0.01 to 3 percent by weight, the liquid composition penetrating the skin to relieve pain.

However, there is no background art disclosing or suggesting that methylsulfonylmethane facilitates transmucosal delivery.

Obesity and appetite suppression

Obesity is a chronic, essentially refractory metabolic disorder with an increasing prevalence for which no effective treatment is currently known. The rate of obesity is increasing worldwide and is currently considered to be the core epidemic in the western 21 st century world. More than 50% of the us population is considered overweight, and > 25% of the population is diagnosed as clinically obese. Statistical data show that obesity begins with a younger and younger age; 15% of children and adolescents suffer from overweight, at a rate 3 times higher than that reported 25 years ago.

Obesity is a recognized risk factor for the following diseases: type 2 diabetes, cardiovascular disease, hypertension, atherosclerosis, congestive heart failure, stroke, gallbladder disease, osteoarthritis, sleep apnea, reproductive disorders such as polycystic ovary syndrome, breast cancer, prostate cancer, and colon cancer, and increased incidence of general anesthesia complications (Reisin and Alpert, 2005, Am J Med sci.330, 6, 269-. It reduces life-span and carries a serious risk of co-morbidity (co-morbidity) as described above and complications including: infection, varicose veins, acanthosis nigricans, eczema, exercise intolerance, insulin resistance, hypertension, hypercholesterolemia, cholelithiasis, orthopedic injuries and thromboembolic disorders (Rissanen et al, BMJ 301: 835-7, 1990). Obesity is also a risk factor for a group of conditions known as insulin resistance syndrome or "syndrome X".

Therefore, there is a clear economic and medical theoretical basis for developing therapeutic strategies for the prevention and management of obesity.

Failure to control food intake in a normal manner has long been recognized as a major cause of obesity. Hunger cravings and extreme urge to eat are part of the binge eating cycle in obese and morbidly obese subjects. However, the lack of understanding of the control mechanisms that regulate food intake in normal animals or humans has hampered the effective clinical application of this concept.

Previously it was hypothesized that the mechanisms primarily responsible for physiological appetite control include increased blood glucose levels resulting from food intake and/or gastric distension. The theory behind this suggests that these controls are secondary, and that the primary mechanism for inducing satiety and suppressing feeding involves the release of peptide hormones in the small intestine upon food stimulation in pre-absorptive contact with mucosal gut receptors. Although many peptide hormones may be involved, the "satiety effect" (appetite suppression) of cholecystokinin (CCK) seems to be particularly effective (g.p. smith, biochemical pharmacology of Obesity, p. 407-. Clinical applications for appetite control include induction of endogenous release of intestinal peptides such as CCK.

DL-phenylalanine (DLPA) is an essential amino acid, which is a neurotransmitter. Some of the major functions of DLPA are reduced hunger, improved memory and mental alertness and reduced depression. DLPA also has the ability to convert to most of the other 14 important amino acids necessary to form proteins needed to translate cellular DNA.

It has been proposed to administer chemical stimulators to induce the release of the hormone of interest, including the use of L-phenylalanine as a pre-absorbed release agent for CCK. U.S. patent No. 4,833,128 discloses a dietary supplement formulated to suppress appetite comprising L-phenylalanine in combination with a limiting amount of protein, sugar, fat and dietary fiber.

U.S. patent No. 5,925,377 discloses a dietary supplement composition combining amino acids, minerals, vitamins, herbs and essential nutrients, and mild diuretics with digestive enzymes. According to this publication, DL-phenylalanine is combined with tyrosine to act as an appetite suppressant.

U.S. patent application publication No. 2005/0002927 discloses pharmaceutical compositions and methods for treating various diseases and disorders, including obesity, in mammalian subjects comprising at least one Y2 receptor-binding peptide, such as peptide YY (pyy), neuropeptide Y (npy), or Pancreatic Peptide (PP), and one or more mucosal delivery-promoting agents for promoting nasal mucosal delivery of peptide YY.

There is an unmet need for transmucosal formulations that facilitate convenient and rapid administration of drugs or nutrients via the oral mucosa. In particular, effective rapid delivery of analgesics, anti-inflammatory drugs, drugs for erectile dysfunction, for migraine or for menopausal symptoms; and there is an unmet need for the delivery of improved vitamins and active agents to be used for appetite suppression and for the treatment of obesity or eating disorders.

Summary of The Invention

The present invention provides transmucosal pharmaceutical compositions and methods for facilitating transmucosal delivery of pharmaceutical ingredients, including non-steroidal anti-inflammatory drugs, analgesics, migraine drugs, menopausal drugs, sleep disorder drugs, erectile dysfunction drugs, appetite suppressants, and macromolecules. The present invention further provides transmucosal nutrient compositions and methods for facilitating transmucosal delivery of nutrient ingredients, including vitamins, food supplements, and certain appetite suppressants. Advantageously, transmucosal delivery using the compositions and methods of the present invention provides rapid uptake and response to the administered agent.

The present invention discloses for the first time the discovery that methylsulfonylmethane (MSM) facilitates transmucosal oral delivery of a number of pharmaceutical and nutritional ingredients. According to various embodiments, the pharmaceutical ingredient is selected from the group consisting of: non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, migraine agents, menopausal medications, sleep disturbance medications, erectile dysfunction medications, appetite suppressants, and macromolecules. In other embodiments, the nutrient may be selected from vitamins, food supplements, and appetite suppressants. In exemplary embodiments, the appetite suppressant is DL-phenylalanine. Advantageously, transmucosal delivery of DL-phenylalanine responds rapidly to hunger cravings and impulses of appetite, which are part of the binge eating cycle in obese and morbidly obese subjects.

According to a first aspect, the present invention provides a pharmaceutical composition for facilitating delivery across the oral mucosa, the composition comprising a pharmaceutical ingredient and methylsulfonylmethane in a pharmaceutically acceptable carrier suitable for administration to the oral mucosa. In certain embodiments, the carrier comprises an edible oil; water and lecithin were purified.

Typically, the methylsulfonylmethane is present in a minimum amount suitable for use as a penetration enhancer and generally does not exceed 30% (w/w) of the total weight of the composition. According to certain embodiments, the methylsulfonylmethane is no more than 25% of the total weight of the composition; preferably it does not exceed 20%; more preferably it does not exceed 10%.

According to one embodiment, the edible oil is a vegetable oil. According to some embodiments, the vegetable oil is selected from the group consisting of: cottonseed oil, peanut oil, poppy seed oil, safflower oil, sesame oil, soybean oil, corn oil, olive oil, canola oil (canola oil), and combinations thereof.

According to other embodiments, the composition further comprises at least one excipient selected from the group consisting of: sweeteners, flavoring agents, protective agents, antioxidants, plasticizers, waxes, elastomeric solvents (elastomeric solvents), filler materials, preservatives, lubricants, wetting agents, emulsifiers, solubilizers, suspending agents, colorants, disintegrants and combinations thereof.

According to some embodiments, the composition comprises at least one excipient selected from the group consisting of: cocoa butter, sucralose (sucralose), calcium salts, and combinations thereof. According to one embodiment, the calcium salt is calcium carbonate.

According to some embodiments, the composition comprises:

a pharmaceutical ingredient in an amount of about 0.1% to 15%;

methylsulfonylmethane in an amount of about 1% to 30%;

a vegetable oil in an amount of about 5% to 40%;

purified water in an amount of about 5% to 30%;

cocoa butter in an amount of about 5% to 40%;

sucralose in an amount suitable for use as a sweetener;

calcium salt in an amount of about 1% to 20%; and

lecithin in an amount of about 1% to 20%; wherein the percentages are weight percentages based on the total weight of the composition and the total weight of the composition is equal to 100%.

According to one embodiment, the pharmaceutical ingredient is in an amount of about 1% to 5%;

the methylsulfonylmethane is in an amount of about 1% to 10%;

the vegetable oil is in an amount of about 20% to 40%;

the purified water is in an amount of about 10% to 30%;

the cocoa butter is in an amount of about 20% to 40%;

the sucralose is in an amount of about 0.05% to 0.2%;

the calcium salt is present in an amount of about 1% to 20%, and

the lecithin is in an amount of about 1% to 20%.

According to further embodiments, the pharmaceutical ingredient is in an amount of about 2% to 4%;

the methylsulfonylmethane is in an amount of about 2% to 5%;

the vegetable oil is in an amount of about 25% to 35%;

the purified water is in an amount of about 15% to 25%;

the cocoa butter is in an amount of about 25% to 35%;

the sucralose is in an amount of about 0.07% to 0.15%;

the calcium salt is present in an amount of about 5% to 15%, and

the lecithin is in an amount of about 5% to 15%.

According to some embodiments, the pharmaceutical ingredient is a non-steroidal anti-inflammatory drug (NSAID). According to some embodiments, the pharmaceutical ingredient is an analgesic. According to some embodiments, the pharmaceutical ingredient is a migraine drug. According to some embodiments, the pharmaceutical ingredient is a menopausal drug. According to some embodiments, the pharmaceutical ingredient is a sleep disorder drug. According to some embodiments, the pharmaceutical ingredient is an erectile dysfunction drug. According to some embodiments, the pharmaceutical ingredient is an appetite suppressant. According to some embodiments, the pharmaceutical ingredient is a macromolecule.

According to one embodiment, 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 ((-) 6-methoxy-9-methyl-2-naphthaleneacetic acid sodium salt); phenylbutazone (4-butyl-1, 2-diphenyl-3, 5-pyrazolidinedione); sulindac (2) -5-fluoro-2-methyl-1- [ [ p- (methylsulfinyl) phenyl ] methylene- ] -1-H-indene-3-acetic acid; diflunisal (2 ', 4', -difluoro-4-hydroxy-3-biphenylcarboxylic acid; piroxicam (4-hydroxy-2-methyl-N-2-pyridinyl-2H-1, 2-benzothiazine-2-carboxamide 1, 1-dioxide; meloxicam (4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1, 2-benzothiazine-3-carboxamide 1, 1-dioxide); another oxicam; indomethacin (1- (4-chlorobenzoyl) -5-methoxy-2-methyl-H-indole-3-acetic acid); meclofenamate sodium (N- (2, 6-dichloro-m-tolyl) anthranilic acid sodium salt monohydrate); nabumetone (4- (6-methoxy-2-naphthyl) -2-butanone); ketoprofen (2- (3-benzoylphenyl) -propionic acid; tolmetin sodium (1-methyl-5- (4-methylbenzoyl-1H-pyrrole-2-sodium acetate dihydrate), diclofenac sodium (2- [ (2, 6-dichlorophenyl) amino ] phenylacetic acid monosodium salt), hydroxychloroquine sulfate (2- { [4- [ (7-chloro-4-quinolyl) amino ] pentyl ] ethylamino } ethanol sulfate (1: 1), penicillamine (3-mercapto-D-valine), flurbiprofen ((±) 2-fluoro- α -methyl- [1, 1-biphenyl ] -4-acetic acid), etodolac (1-8-diethyl-13, 4,9, -tetrahydropyran- [3-4-13] indole-1-acetic acid; mefenamic acid (N- (2, 3-xylyl) anthranilic acid; and diphenhydramine hydrochloride (2-diphenylmethoxy-N, N-dimethylethylamine hydrochloride).

According to one embodiment, the analgesic is selected from the group consisting of: paracetamol and analgin (sodium 4-methylamino-1, 5-dimethyl-2-phenyl-3-pyrazolone mesylate).

According to one embodiment, the migraine medication is selected from the group consisting of: triptans; sumatriptan; (3- (2- (dimethylamino) ethyl) -N-methyl-1H-indole-5-methanesulfonamide); almotriptan (1- (((3- (2 (dimethylamino) ethyl) indol-5-yl) methyl) sulfonyl) pyrrolidine) and amitriptyline (3- (10, 11-dihydro-5H-dibenzo (a, d) cyclohepten-5-ylidene) -N, N-dimethyl-1-propylamine).

According to one embodiment, the menopausal medication is selected from the group consisting of: venlafaxine, paroxetine, phytoestrogen and botanical extracts. In one embodiment, the plant extract is derived from a plant selected from the group consisting of black cohosh (black cohosh) and maca (maca).

According to one embodiment, the sleep disorder drug is selected from the group consisting of: diphenhydramine (2- (benzhydryloxy) -N, N-dimethylethylamine), valerian (valerian), and melatonin (5-methoxy-N-acetyltryptamine).

According to one embodiment, the erectile dysfunction drug is selected from the group consisting of: prostaglandins, testosterone, yohimbine, pentoxifylline, trazodone, apomorphine, sildenafil, minoxidil, misoprostol, papaverine, nitroglycerin, phentolamine, moxiflorin, linsidomine, and pyridylguanidine compounds.

According to one embodiment, the appetite suppressant is DL-phenylalanine. According to one embodiment, the DL-phenylalanine is in an amount of from about 1% to about 5% by weight of the total weight of the composition. According to one embodiment, the DL-phenylalanine is in an amount of about 5% by weight of the total weight of the composition. According to certain embodiments, the DL-phenylalanine is selected from the group consisting of: d-phenylalanine, L-phenylalanine, and mixtures thereof.

According to one embodiment, the macromolecule is selected from the group consisting of: vitamin B12, antibiotics, peptides, calcitonin, vasopressin and oxytocin. In a specific embodiment, the macromolecule is vitamin B12. In a specific embodiment, the macromolecule has a molecular weight of up to about 5000 daltons.

According to certain embodiments, the compositions of the present invention are formulated in the form of lozenges, candies (candy) or dissolving tablets (dissolving tablets).

According to other embodiments, the oral mucosa is selected from the group consisting of: sublingual mucosa, buccal mucosa, gingival mucosa, palatal mucosa, and combinations thereof.

According to another embodiment, the present invention provides a method for facilitating the delivery of a pharmaceutical ingredient across the oral mucosa, said method comprising administering to a subject in need thereof an effective amount of a composition of the present invention. In one embodiment, the composition comprises a pharmaceutical ingredient, methylsulfonylmethane, an edible oil, purified water, and lecithin, wherein the methylsulfonylmethane is in an amount sufficient to facilitate transmucosal delivery of the pharmaceutical ingredient.

According to a further aspect, the present invention provides a method for suppressing the appetite of a mammal in need thereof, wherein said method comprises transmucosal administration of a composition comprising an appetite-suppressing amount of DL-phenylalanine, methylsulfonylmethane, an edible oil, purified water, and lecithin, thereby suppressing the appetite of said mammal in need thereof.

According to one embodiment, the transmucosal administration is via the oral mucosa. According to one embodiment, the methylsulfonylmethane is in an amount sufficient to facilitate transmucosal delivery of DL-phenylalanine. According to one embodiment, the mammal is a human. According to one embodiment, the mammal is obese. According to another embodiment, the mammal is morbidly obese.

According to a further aspect, the present invention provides the use of methylsulfonylmethane and an appetite-suppressing amount of DL-phenylalanine in the manufacture of a medicament for transmucosal oral delivery to suppress appetite in a mammal. According to one embodiment, the methylsulfonylmethane is used in an amount sufficient to facilitate transmucosal delivery of DL-phenylalanine.

These and other embodiments of the present invention will become apparent with reference to the following drawings, description and claims.

Brief Description of Drawings

Figure 1 shows the effect of methylsulfonylmethane (MSM) on transmucosal-buccal delivery of DL-phenylalanine. The change in blood concentration of DL-phenylalanine (nmol/ml) with time after buccal administration to humans is shown.

Detailed Description

The present invention provides compositions and methods for facilitating transmucosal delivery of a number of pharmaceutical ingredients, including those classified as non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, migraine agents, menopausal agents, sleep disorder agents, erectile dysfunction agents, and appetite suppressants. The compositions of the present invention are particularly suitable for transmucosal delivery of macromolecules having molecular weights up to about 5000 daltons, and have advantages over prior art transmucosal delivery formulations that are only suitable for molecules of smaller size, such as up to about 200 daltons. The invention further provides appetite suppressant compositions and methods. Thus, the disclosed appetite-suppressing compositions may be administered via the oral mucosa to effectively suppress, limit, reduce, or otherwise reduce the appetite of an individual. The appetite-suppressing compositions may be administered to an individual for weight management, or for the treatment of obesity or obesity-related disorders, including but not limited to type II diabetes, hypercholesterolemia, and metabolic syndrome.

The present invention discloses for the first time that methylsulfonylmethane is an effective enhancer for transmucosal delivery of active agents. It is particularly suitable for use in the delivery of drugs and nutrients via the oral mucosa.

The effectiveness of MSM is not limited by the type of carrier used, and suitable excipients can be selected as is well known in the art to impart the desired consistency and other characteristics to the composition. The composition may be liquid, semi-solid or solid. Conveniently, the composition may be in the form of a candy or confectionery (confection), or in the form of a film suitable for adhering to the oral mucosa.

According to certain typical embodiments, the composition comprises:

a pharmaceutical or nutraceutical ingredient in an amount of no more than about 5%;

methylsulfonylmethane in an amount of no more than about 10%;

a vegetable oil in an amount of no more than about 40%;

purified water in an amount of no more than about 30%;

cocoa butter in an amount of no more than about 40%;

sucralose in an amount of no more than about 0.2%;

calcium salt in an amount of no more than about 20%; and

lecithin in an amount of no more than about 20%; wherein the percentages are weight percentages based on the total weight of the composition and the total weight of the composition is equal to 100%.

Definition of

As used herein, the term "administering" refers to administering a composition of the present invention to the mucosa of the oral cavity (i.e., the oral mucosa). Examples of suitable sites of administration in the oral mucosa include, but are not limited to, mucosa at the bottom of the mouth (sublingual mucosa), mucosa at the cheek (buccal mucosa), mucosa at the gum (gingival mucosa), mucosa at the top of the mouth (palatal mucosa), mucosa at the inner layer of the lip, and combinations thereof.

As used herein, the term "D, L-phenylalanine (DLPA)" refers to D-phenylalanine (DPA), L-phenylalanine (LPA), or mixtures thereof.

The term "about" as used herein refers to +/-10% of the indicated amount.

As used herein, the term "macromolecule" refers to a chemical compound having a molecular weight in the range of about 500 to about 5000 daltons (Da).

As used herein, the term "appetite" refers to the instinctive desire necessary to sustain organic life; especially the desire to eat or the inherent craving to eat.

As used herein, the term "appetite suppressant" refers to a substance, such as a pharmaceutical ingredient, that is active in suppressing appetite.

As used herein, the term "appetite-suppressing amount" refers to an amount of a substance (e.g., a pharmaceutical ingredient) that substantially suppresses the appetite of a subject.

As used herein, the term "amount sufficient to facilitate transmucosal delivery" refers to an amount of methylsulfonylmethane that, after formulation with a pharmaceutical or nutraceutical agent and transmucosal administration to a subject, substantially increases the subject's blood level of the pharmaceutical or nutraceutical agent, and/or the incidence of the pharmaceutical agent in the blood, as compared to a formulation of the same pharmaceutical agent lacking methylsulfonylmethane.

As used herein, the term "hunger" refers to a feeling of uneasiness caused by lack of food.

As used herein, the term "hunger is suppressed" refers to a state in which hunger sensation is restrained, restricted or suppressed, or the intensity of hunger sensation is suppressed or suppressed to various degrees.

As used herein, the term "obesity" refers to a condition in which the adipose tissue reserve of a mammal (such as a human) is increased to a point associated with an adverse health condition and/or increased mortality. Obesity can be measured with objective conditions (objective term) such as according to Body Mass Index (BMI) equal to or greater than 30.0, or according to waist circumference of greater than 102cm for men and greater than 88cm for women.

As used herein, the term "safe and effective" refers to a state in which a subject produces or is able to produce a predictable, reproducible, desired response to the compositions and methods herein, and is not likely to produce adverse side effects and/or produces only minimal/mild side effects.

Administration via the oral mucosa

Drugs taken orally and swallowed are first absorbed into the blood perfusing the gastrointestinal tract. Venous drainage from the GI tract enters the blood perfusing the liver. This means that the drug absorbed from the lumen of the gastrointestinal tract is immediately delivered to the liver, the major detoxifying organ in the body. The liver, in addition to protecting the organism from the ingestion of toxins, also metabolizes drugs, which are treated in the same way. The liver blood 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 can result in the removal of a large portion of the ingested drug. The first-pass effect is more pronounced for some drugs than others.

Certain regions of the digestive tract have venous drainage, which does not include the first pass through the liver. These areas (buccal mucosa, under the tongue and nasopharynx, and also the rectal ends) drain directly into the left side of the heart. Avoidance of the first pass effect is the theoretical basis for the use of buccal and sublingual formulations.

Both sublingual and buccal formulations rely on the efficient transport of the drug from a hydrophilic vehicle to the sublingual or buccal mucosa. The transport of drugs through the interstices between epithelial cells or through epithelial cells is largely determined by the lipid solubility of the drug. When the drug is water insoluble, this is a further barrier to absorption from the sublingual area. Thus, there are physical and biological limitations to the therapeutic effectiveness of lipophilic drugs that are administered orally and swallowed. The present invention relates to formulations particularly suitable for administration of a pharmaceutical ingredient or drug via a mucosal surface such as, for example, a sublingual mucosal surface or a buccal mucosal surface.

According to the present invention, methylsulfonylmethane improves oral mucosal absorption of a pharmaceutical ingredient, such as DL-phenylalanine.

Pharmaceutical composition

NSAIDs that may be incorporated into the compositions of the present 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 ((-) 6-methoxy-9-methyl-2-naphthaleneacetic acid sodium salt); phenylbutazone (4-butyl-1, 2-diphenyl-3, 5-pyrazolidinedione); sulindac- (2) -5-fluoro-2-methyl-1- [ [ p- (methylsulfinyl) phenyl ] methylene- ] -1-H-indene-3-acetic acid; diflunisal (2 ', 4', -difluoro-4-hydroxy-3-biphenylcarboxylic acid; piroxicam (4-hydroxy-2-methyl-N-2-pyridinyl-2H-1, 2-benzothiazine-2-carboxamide 1, 1-dioxide; meloxicam (4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1, 2-benzothiazine-3-carboxamide 1, 1-dioxide); oxicams; indomethacin (1- (4-chlorobenzoyl) -5-methoxy-2-methyl-H-indole-3-acetic acid); meclofenamate sodium (N- (2, 6-dichloro-m-tolyl) anthranilic acid sodium salt monohydrate); nabumetone (4- (6-methoxy-2-naphthyl) -2-butanone); ketoprofen (2- (3-benzoylphenyl) -propionic acid; tolmetin sodium (1-methyl-5- (4-methylbenzoyl-1H-pyrrole-2-sodium acetate dihydrate), diclofenac sodium (2- [ (2, 6-dichlorophenyl) amino ] phenylacetic acid monosodium salt), hydroxychloroquine sulfate (2- { [4- [ (7-chloro-4-quinolyl) amino ] pentyl ] ethylamino } ethanol sulfate (1: 1), penicillamine (3-mercapto-D-valine), flurbiprofen ((±) 2-fluoro- α -methyl- [1, 1-biphenyl ] -4-acetic acid), etodolac (1-8-diethyl-13, 4,9, -tetrahydropyran- [3-4-13] indole-1-acetic acid; mefenamic acid (N- (2, 3-xylyl) anthranilic acid; and diphenhydramine hydrochloride (2-diphenylmethoxy-N, N-dimethylethylamine hydrochloride).

Analgesic compounds that may be incorporated into the compositions of the present invention include paracetamol and analgin (sodium 4-methylamino-1, 5-dimethyl-2-phenyl-3-pyrazolone methanesulfonate).

Migraine medications that can be incorporated into the compositions of the present invention include triptans, such as sumatriptan (3- (2- (dimethylamino) ethyl) -N-methyl-1H-indole-5-methanesulfonamide) and almotriptan (1- (((3- (2 (dimethylamino) ethyl) indol-5-yl) methyl) sulfonyl) pyrrolidine); and amitriptyline (3- (10, 11-dihydro-5H-dibenzo (a, d) cyclohepten-5-ylidene) -N, N-dimethyl-1-propylamine).

Erectile dysfunction medications that may be incorporated into the compositions of the present invention include steroid hormones such as testosterone, peptide hormones, amine hormones, and hormone-like eicosanoids such as prostaglandins, leukotrienes, and thromboxanes.

The term "prostaglandin" refers to a family of compounds that are initially found in seminal fluid and are believed to cause vasodilation and contraction or relaxation of uterine smooth muscle. Prostanoids, leukotrienes and related compounds are called eicosanoids because they are synthesized by 20-carbon essential fatty acids such as arachidonic acid by microsomal enzymes (Hardman, j.1996, Goodman and gilams: The pharmacological basis of Therapeutics, chapter 26, 9 th edition, McGraw Hill).

Other pharmaceutical ingredients useful as erectile dysfunction medications include testosterone, yohimbine, pentoxifylline, trazodone, apomorphine, phentolamine, tadalafil, sildenafil and other pyrazolopyrimidinone derivatives. Other agents include minoxidil, misoprostol, papaverine, nitroglycerin, phentolamine, moxiflorin, linsidomine, linear or cyclic peptides, pyridyl guanidine compounds, and renin-angiotensin system inhibitors. These agents may be incorporated into the transmucosal compositions of the present invention in an amount effective to correct erectile dysfunction.

Menopausal medications that may be incorporated into the compositions of the present invention include phytoestrogens, venlafaxine, paroxetine, and botanical extracts such as those derived from black cohosh and maca.

Sleep disorder medications that may be incorporated into the compositions of the present invention include diphenhydramine (2- (benzhydryloxy) -N, N-dimethylethylamine), valerian, and melatonin (5-methoxy-N-acetyltryptamine).

An appetite suppressant that may be incorporated in the present composition is DL-phenylalanine. The DL-phenylalanine may be D-phenylalanine, L-phenylalanine or a mixture thereof.

Macromolecules that may be incorporated into the compositions of the present invention include vitamin B12, antibiotics, peptides, polypeptides, calcitonin, vasopressin and oxytocin. In a specific embodiment, the macromolecule is vitamin B12.

Pharmaceutical composition

The present invention provides a composition for promoting delivery across the oral mucosa comprising a pharmaceutical ingredient, methylsulfonylmethane, an edible oil, purified water, and lecithin.

According to one embodiment, the edible oil is a vegetable oil. Exemplary vegetable oils include, but are not limited to, cottonseed oil, peanut oil, poppy seed oil, safflower 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 sweetener, flavoring agent, protective agent, plasticizer, wax, elastomeric solvent, filler material, preservative, lubricant, wetting agent, emulsifier, solubilizer, suspending agent, colorant, disintegrant, or a combination thereof. It is understood that certain excipients may belong to more than one of the aforementioned classes of excipients.

According to some embodiments, the composition comprises at least one excipient selected from the group consisting of: cocoa butter, sucralose, calcium salts, and combinations thereof. An example of a calcium salt is calcium carbonate.

According to one embodiment, the composition comprises a pharmaceutical ingredient in an amount of about 1% to 5% of the composition, wherein the percentage is a weight percentage based on the total weight of the composition and the total weight of the composition is equal to 100%. In one embodiment, the pharmaceutical ingredient is in an amount of about 5% of the composition. In certain embodiments, the pharmaceutical ingredient is in an amount of about 2% to 4% of the composition.

According to one embodiment, the methylsulfonylmethane is in an amount of about 1% to 10% of the composition, wherein the percentage is a weight percentage based on the total weight of the composition and the total weight of the composition is equal to 100%. In certain embodiments, the methylsulfonylmethane is present in an amount of about 2% to 5% of the composition.

According to another embodiment, the vegetable oil is in an amount of about 20% to 40% of the composition. In certain embodiments, the vegetable oil is in an amount of about 25% to 35% of the composition.

According to further embodiments, the purified water is in an amount of about 10% to 30% of the composition. In certain embodiments, the purified water is in an amount of about 15% to 25% of the composition.

According to yet another embodiment, the cocoa butter is in an amount of about 20% to 40% of the composition. In certain embodiments, the cocoa butter is in an amount of about 25% to 35% of the composition.

According to yet further embodiments, the sucralose is in an amount of about 0.05% to 0.2% of the composition. In certain embodiments, the sucralose is in an amount of about 0.07% to 0.15% of the composition.

According to yet another embodiment, the calcium salt is in an amount of about 1% to 20% of the composition. In certain embodiments, the calcium salt is in an amount of about 5% to 15% of the composition. In some embodiments, the calcium salt is calcium carbonate.

According to yet a further embodiment, lecithin is in an amount of about 1% to 20% of the composition. In certain embodiments, the lecithin is in an amount of about 5% to 15% of the composition.

The present invention relates to pharmaceutical formulations for the administration of pharmaceutical ingredients (such as DL-phenylalanine) via mucosal surfaces.

According to one embodiment, the composition of the invention is particularly directed to weight loss and comprises as a pharmaceutical ingredient the appetite suppressant DL-phenylalanine.

Preparation of the compositions of the invention

Exemplary solid forms for oromucosal (e.g., sublingual and buccal) administration include films, dispersible fluid or semi-solid compositions, and solid forms. Solid dosage forms intended for dispersion on or over the oral mucosa may conveniently be designed to take the form of a hard candy or a chewable confectionery. Other forms may include tablets, pills, capsules, powders and granular materials for dispersion in the oral cavity. These solid compositions may include pharmaceutically acceptable inert ingredients such as diluents (e.g., calcium carbonate, sodium chloride, lactose, calcium phosphate, sodium phosphate, and the like); granulating and disintegrating agents (e.g., potato starch, alginic acid, and similar granulating and disintegrating agents); binding agents (e.g., starch, gelatin, gum arabic, and the like); lubricants (e.g., magnesium stearate, stearic acid, talc, and similar lubricants). Other inert ingredients that may be used in the present invention include colorants, flavors, plasticizers, humectants, and the like. The solid compositions provided according to the present invention may be uncoated or they may be coated by various methods and with materials known in the art.

The compositions of the present invention may be prepared by a variety of methods. For example, manufacturing techniques applied to conventional tablets, chewing gum types or confectioneries may be used in the manufacture of the compositions of the present invention.

In a typical process for preparing the composition, water, methylsulfonylmethane, DL-phenylalanine, sucralose, lecithin, cocoa butter, vegetable oil, and calcium carbonate are mixed, the mixture is kneaded uniformly, compressed and spread while hot, and the resulting pieces are cut after cooling.

Liposomes can be incorporated into tablets by adding lecithin and vegetable oil to the solution to produce liposomes as a drug solution, and then vortexing gently to prevent disruption of the liposomes prior to introduction into the mold where gelation occurs.

In an alternative method, the above mixture is pulverized without the addition of water and then compression molded. In the third method, the above mixture is uniformly dispersed or dissolved in water, and thus it is molded by a wet process, and then dried. The steps in these production methods may be combined in an appropriate manner other than the above-mentioned manner. In preparing the compositions according to the invention, the components are used in the amounts suggested above.

In the step of molding or shape adjustment as described above, a composition having a desired shape (such as a plate-like, belt-like, disc-like, columnar, cylindrical or spindle-like form) can be obtained by adjusting a mold for compression molding to an appropriate shape or by pouring into a mold or extending a molding compound and then cutting the previously-produced molded article into pieces having an appropriate shape. This preparation method involves only simple and easy operations and steps, and is therefore an advantageous preparation method available on a commercial scale, by which compositions of various shapes suitable for each case purpose can be prepared according to the following procedures. When a dissolution or dispersion step is included, liquid or low melting point drugs that are difficult to incorporate into a solid formulation can be incorporated into the composition.

For the purpose of assisting in the development of the characteristics of the composition of the present invention by improving processability, moldability and formulation quality, and by increasing dispersibility and stability of the composition, other additives selected from various pharmaceutically acceptable additives available to those skilled in the art may be incorporated in addition to the above components. These additives are different from those mentioned as essential components and include the following.

Seasonings (saccharin sodium, glycyrrhizin, maltose syrup, citric acid, tartaric acid, menthol, lemon oil, citrus flavor, salt, etc.);

stabilizers/preservatives (alkyl parabens, antioxidants, antifungal agents, etc.);

coloring materials (water-soluble tar coloring materials, natural coloring materials, titanium oxide, etc.);

excipients/disintegration modifiers (magnesium silicate, light anhydrous silicic acid, synthetic aluminum silicate, precipitated calcium carbonate, magnesium aluminum metasilicate, calcium hydrogen phosphate, etc.);

water-soluble polymers other than water-soluble proteins (natural polymers, synthetic polymers, etc.), and

stearic acid and its salts, talc, palmitic acid and other substances known as emulsifiers, dispersants, binders, thickeners and the like.

According to certain preferred embodiments, the compositions of the present invention are preferably formulated in the form of lozenges, candies or dissolving tablets (e.g. slow dissolving or fast dissolving tablets) for transmucosal-buccal administration.

In certain embodiments, the tablet is a dissolving tablet, such as a slow dissolving tablet or a fast dissolving tablet, that is dissolved by the subject's saliva without chewing. For example, a dissolving tablet placed on the tongue of a subject may be used for buccal delivery of a therapeutic agent. Alternatively, a dissolving tablet placed under the tongue of a subject may be used to deliver the therapeutic agent sublingually. Such dosage forms may be particularly suitable for pediatric and geriatric patients, as children and elderly individuals often have difficulty chewing something. Typically, the dissolving tablet is formulated to dissolve within about 30 seconds to about 5 minutes, preferably within about 1 minute to about 3 minutes, after application. It will be appreciated by those skilled in the art that fast dissolving tablets dissolve more rapidly than slow dissolving tablets, which are typically dissolved gradually by the subject's saliva rather than rapidly.

In certain other embodiments, the tablet is a chewable tablet that is chewed by a subject and formulated to dissolve rapidly or gradually. For example, chewable tablets placed on the tongue of a subject may be used for buccal delivery of a therapeutic agent. During chewing, the chewable tablet may move around within the mouth and may sometimes reside between the gum and cheek or under the tongue. Thus, at least a portion of the therapeutic agent contained within the chewable tablet may also be delivered sublingually (i.e., across the sublingual mucosa). Typically, the chewable tablet is formulated to dissolve within about 30 seconds to about 5 minutes, preferably within about 1 minute to about 3 minutes, after administration.

The present oral dosage forms can be used to deliver any active or therapeutic agent when absorption across the oral mucosa is desired. While the present invention will be discussed below with respect to administration of the appetite suppressant, DL-phenylalanine, according to exemplary embodiments, it will be understood that other active agents may be used additionally or alternatively.

Non-limiting examples include non-steroidal anti-inflammatory drugs, analgesics, migraine medications, menopausal medications, sleep disorder medications, erectile dysfunction medications, appetite suppressants, cough/cold/throat agents, vitamins, zinc, menthol, eucalyptus oil (eutrophus), hexylresorcinol, caffeine, tooth whitening agents, anti-plaque agents, breath freshening agents, demulcents (demulcent), and the like.

The composition is orally dissolvable and can be in any form that is normally sucked, licked and/or chewed and eaten, such as a tablet, lozenge, stick (stick), rod (can), popping candy (pop), and the like. Tablets and lozenges are preferred forms. The tablets and lozenges of the present invention are buccal dosage forms intended to be held in the mouth and generally sucked. For example, they may be held in the buccal cavity or sublingually. The tablets or lozenges may be of various shapes, including flat, round, octagonal, and biconvex. According to a preferred embodiment, the tablet is a chocolate flavored tablet.

According to other embodiments, the oral dosage form may be a film designed to adhere to the oral mucosa. For example, U.S. Pat. No. 4,713,243 to Schiraldi et al discloses a film capable of adhering to a wet, tacky surface, the film including a bioadhesive layer composed of hydroxypropyl cellulose, polyethylene oxide, a plasticizer, a drug, and optionally a water-insoluble polymer. The membranes disclosed in U.S. patent No. 4,713,243 are useful for controlled release of drugs such as anesthetics, anti-inflammatory agents, antihistamines, antibiotics, and antibacterial agents.

U.S. Pat. Nos. 5,948,430, 6,177,096, 6,284,264, 6,592,887, and 6,709,671 to Zerbe et al disclose mucoadhesive films capable of rapid dissolution and adherence to the oral cavity comprising a water-soluble polymer and a pharmaceutically or cosmetically active ingredient and methods of use thereof.

Methods for appetite suppression

The present invention further provides a method for suppressing the appetite of a mammal in need thereof, wherein said method comprises transmucosal administration of a composition comprising an appetite-suppressing amount of DL-phenylalanine, methylsulfonylmethane, edible oil, purified water, and lecithin, thereby suppressing the appetite of said mammal in need thereof.

The composition is preferably formulated into a dosage form, such as a tablet, that can be administered orally and thus can be administered transmucosally via the oral mucosa. Methylsulfonylmethane is present in the composition in an amount sufficient to facilitate transmucosal delivery of DL-phenylalanine. That is, upon transmucosal administration of the composition to a subject, the amount of methylsulfonylmethane in the composition is sufficient to substantially increase the subject's blood level of DL-phenylalanine and/or the incidence of DL-phenylalanine in the blood as compared to a formulation of the same pharmaceutical ingredient lacking methylsulfonylmethane. As exemplified in example 2 herein, containing DL-phenylalanine according to the inventionTransmucosal oral compositions of an acid and methylsulfonylmethane provide an increase in C upon administration to a human subject, as compared to a similar composition lacking methylsulfonylmethane_maxAnd reduced T_max。

Advantageously, transmucosal delivery of the appetite suppressant DL-phenylalanine provides a rapid response to hunger cravings and appetite impulses, which are clearly part of the binge eating cycle in obese and morbidly obese subjects. Moreover, the provision of appetite suppressants in transmucosal-oral dosage forms addresses the need for oral satisfaction (oral diagnosis) that is prevalent in many obese subjects.

Thus, the compositions and methods of the present invention utilizing the appetite suppressant DL-phenylalanine and the transmucosal delivery promoter methylsulfonylmethane are useful in the planning of weight loss and weight control in overweight subjects, including those divided into obese and morbidly obese.

According to one embodiment, the mammal is a human. According to one embodiment, the mammal is obese. According to another embodiment, the mammal is morbidly obese.

Classification of a subject as obese or morbidly obese is within the ability of one of ordinary skill in the art and may include the use of objective parameters such as Body Mass Index (BMI), waist circumference measurements, and/or body fat measurements.

BMI according to formula BMI ═ kg/m²Where kg is the weight of the subject in kilograms and m is the height of the subject in meters.

The following guidelines (according to the World Health Organization technical report series 894, "Obesity: preventive and managing the global epidemic," Geneva: World Health Organization, 2000) can be used to determine Obesity:

BMI	definition of
		Less than 18.5	Overweight and underweight
18.5-24.9	Normal body weight
		25.0-29.9	Being overweight
30.0-39.9	Obesity
		40.0 or higher	Morbid obesity
35.0 or more in the presence of at least one other severe co-disease	Morbid obesity

In a clinical setting, physicians consider race (race), ethnicity (ethnicity), lean mass (muscle development), age, gender, and other factors that may affect the definition of BMI. BMI overestimates body fat in very strong populations, and it can underestimate body fat in people who have lost weight (e.g., many elderly people).

BMI does not account for the different ratios of fat to lean tissue nor does it distinguish between different forms of obesity, some of which may be more closely associated with cardiovascular risk. The growing understanding of the biology of different forms of adipose tissue has shown that visceral fat or central obesity (male or apple-type obesity) is particularly more strongly associated with cardiovascular disease than BMI alone.

Absolute waist circumference (men > 102cm and women > 88cm) or waist-to-hip ratio (men > 0.9 and women > 0.85) were used as measures of central obesity.

An alternative method of determining obesity is to assess the percent body fat. It is generally accepted that men with over 25% body fat and women with over 30% body fat are obese. The most publicly accepted method of accurately measuring body fat is to weigh a person underwater, a procedure limited to a laboratory with specialized equipment. Two simpler methods for measuring body fat are the skin fold test (skinfold test), in which a pinch of skin is accurately measured to determine the thickness of the subcutaneous fat layer; or bioelectrical impedance analysis. Other measurements of body fat include computed tomography (CT/CAT scan), magnetic resonance imaging (MRI/NMR), and dual energy X-ray absorptiometry (DXA).

According to a further aspect, the present invention provides the use of methylsulfonylmethane and an appetite-suppressing amount of DL-phenylalanine in the manufacture of a medicament for delivery across the oral mucosa to suppress appetite in a mammal.

While the present invention has now been generally described, it will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.

Examples

EXAMPLE 1 preparation of a composition containing DL-phenylalanine

A soft-buccal dosage formulation was prepared in the form of chocolate tablets weighing 3 grams each.

Each sheet comprising:

DL-phenylalanine 150mg

Methylsulfonylmethane (MSM)100mg

30 percent of vegetable oil

Cocoa butter 30%

0.1 percent of sucralose

Calcium carbonate 10%

Lecithin 10%, and

purified water was added to 100%.

The process for preparing the composition comprises the steps of:

step 1: 20ml of deionized water were poured into the homogenization system and heated to a temperature of 50 ℃.

Step 2: MSM was added to water and homogenized well.

And step 3: phenylalanine was added to water and homogenized well.

And 4, step 4: sucralose is added to water and homogenized well.

And 5: the ingredients were mixed thoroughly for 30 minutes to produce solution a.

Step 6: lecithin was added to solution a and mixed thoroughly for 60 minutes.

And 7: cocoa butter was added to the vegetable oil and mixed thoroughly for 30 minutes.

And 8: the cocoa butter and vegetable oil mixture was added to the solution and mixed thoroughly for 30 minutes.

And step 9: calcium carbonate was added to the solution and mixed thoroughly for 30 minutes.

Step 10: the solution was poured into a sterile container and left for 24 hours.

Example 2 comparison of bioavailability of formulations containing DL-phenylalanine in the Presence or absence of Methylsulfonylmethane (MSM)

Tablets prepared by the method described in example 1 were administered to three healthy adult male subjects between the gingiva and the cheek in the oral cavity at a dose of 450mg DL-phenylalanine per subject. (A) Formulation without MSM, 60 seconds retention time (in the oral cavity); (B) MSM containing formulation, 30 seconds retention time (in the oral cavity); and (C) MSM containing formulation, 60 seconds retention time (in the oral cavity). These subjects fasted from 12 hours prior to administration to the end of the trial.

Blood samples (3ml) were taken before administration and at 20, 40, 60 and 80 minutes after administration of the formulation. The measurement of DL-phenylalanine in blood was carried out according to the following analytical method.

After separation of the blood, the plasma was stored at-20 ℃ until chemical analysis was performed. Plasma to which internal standard had been added was deproteinized with 35% sulfosalicylic acid, centrifuged and filtered through a 0.2u filter. The filtrate was used for analysis. The instrument used was a Biochrom 20 plus a proprietary amino acid analyzer (Pharmacia Biotech Ltd. Cambridge, England). The separation of the amino acids is effected on an ion exchange column. The resin used was sulfonated polystyrene crosslinked with divinylbenzene.

The final separation was achieved by varying the column temperature, varying the pH of the buffer, and varying the time of injection of the buffer. After separation was achieved, the eluted amino acids were reacted with ninhydrin and the color read photometrically at 570nm and 440 nm. The digital signals corresponding to the colors are read by a computer, integrated and compared to known standards, and then each concentration is measured. The data processing software used to collect and process the data was EZCrome ELITE^TMCLIENT/SERVER chromatography Software (Scientific Software Inc, Pleasanton, Calif.).

Blood levels of DL-phenylalanine after buccal administration of the exemplary formulation are shown in figure 1.

As shown in fig. 1, the MSM is storedMaximum blood level of DL-phenylalanine (C) at lower_max) About 103nmol/ml, the time required to reach maximum blood level (T)_max) 40 min (subject C), and maximum blood level of DL-phenylalanine in the absence of MSM (C)_max) About 66nmol/ml, the time required to reach maximum blood level (T)_max) 60 minutes (subject A). Thus, the presence of MSM in the formulation increased buccal absorption of DL-phenylalanine.

Example 3 Effect of the compositions of the invention on weight loss

A 90-day double-blind retrospective study was conducted to investigate the effect of the composition described in example 2 on weight loss. The effect of the composition was compared to placebo tablets.

Test panels (test panels) of 40 individuals were selected, who averaged 60 pounds overweight. Individuals were divided into two groups. Group I consisted of 20 members receiving 6 placebo tablets per day. Group II consisted of 20 members and received 6 tablets of the composition per day. Both groups received 3 doses per day, 2 tablets each, taken 30 minutes prior to the meal. All patients were prepared with a diet schedule and asked to record daily food and liquid intake. Consultation is performed weekly between the patient and the doctor or other medical professional. Patients are encouraged to discuss their weight loss program, including success, difficulty, or topics of their interest. During each week of consultation, the patient was weighed and blood pressure, pulse rate and respiration were recorded by measurement. Patients were asked to report their energy level, motor activity, craving for sugars and carbohydrates, any change in appetite, and any possible side effects during treatment. Weight loss was measured and recorded in three ways: (1) total body weight loss from the patient's initial body weight; (2) reduction of excess body weight; and (3) the percentage of excess body weight that has been lost. To test whether the compositions of the present invention are effective in reducing hunger and thus overeating overweight individuals, data were obtained in a double-blind retrospective clinical study.

The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without undue experimentation and without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. While the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

It should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

Claims (56)

1. A pharmaceutical or nutraceutical composition for facilitating delivery through the oral mucosa, comprising a pharmaceutical or nutraceutical ingredient and methylsulfonylmethane in a carrier suitable for application to the oral mucosa.

2. The composition of claim 1, wherein the carrier comprises edible oil, water, and lecithin.

3. The composition of claim 2, wherein the edible oil is a vegetable oil.

4. The composition of claim 3, wherein the vegetable oil is selected from the group consisting of: cottonseed oil, peanut oil, poppy seed oil, safflower oil, sesame oil, soybean oil, corn oil, olive oil, canola oil, and combinations thereof.

5. The composition of claim 1, wherein the composition further comprises at least one excipient selected from the group consisting of: sweeteners, flavoring agents, protective agents, antioxidants, plasticizers, waxes, elastomeric solvents, fillers, preservatives, lubricants, wetting agents, emulsifiers, solubilizers, suspending agents, colorants, disintegrants, and combinations thereof.

6. The composition of claim 5, wherein the composition comprises at least one excipient selected from the group consisting of: cocoa butter, sucralose, calcium salts, and combinations thereof.

7. The composition of claim 6, wherein the calcium salt is calcium carbonate.

8. The composition of claim 7, wherein the composition comprises:

a pharmaceutical ingredient in an amount of about 0.1% to 15%;

methylsulfonylmethane in an amount of about 0.5-30%;

vegetable oil in an amount of about 5-40%;

purified water in an amount of about 5-30%;

cocoa butter in an amount of about 5-40%;

calcium salt in an amount of about 1-20%; and

lecithin in an amount of no more than about 1-20%; wherein the percentages are weight percentages based on the total weight of the composition and the total weight of the composition is equal to 100%.

9. The composition of claim 7, wherein the pharmaceutical ingredient is in an amount of about 1% to 5%;

the methylsulfonylmethane is in an amount of about 1% to 10%;

the vegetable oil is in an amount of about 20% to 40%;

the purified water is in an amount of about 10% to 30%;

the cocoa butter is in an amount of about 20% to 40%;

the calcium salt is present in an amount of about 1% to 20%, and

the lecithin is in an amount of about 1% to 20%.

10. The composition of claim 8, wherein the pharmaceutical ingredient is in an amount of about 2% to 4%;

the methylsulfonylmethane is in an amount of about 2% to 5%;

the vegetable oil is in an amount of about 25% to 35%;

the purified water is in an amount of about 15% to 25%;

the cocoa butter is in an amount of about 25% to 35%;

the calcium salt is present in an amount of about 5% to 15%, and

the lecithin is in an amount of about 5% to 15%.

11. The composition of claim 1, wherein the pharmaceutical ingredient is selected from the group consisting of: non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, migraine agents, menopausal medications, sleep disturbance medications, erectile dysfunction medications, appetite suppressants, and macromolecules.

12. The composition of claim 11, wherein 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 ((-) 6-methoxy-9-methyl-2-naphthaleneacetic acid sodium salt); phenylbutazone (4-butyl-1, 2-diphenyl-3, 5-pyrazolidinedione); sulindac- (2) -5-fluoro-2-methyl-1- [ [ p- (methylsulfinyl) phenyl ] methylene- ] -1-H-indene-3-acetic acid; diflunisal (2 ', 4', -difluoro-4-hydroxy-3-biphenylcarboxylic acid; piroxicam (4-hydroxy-2-methyl-N-2-pyridinyl-2H-1, 2-benzothiazine-2-carboxamide 1, 1-dioxide; meloxicam (4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1, 2-benzothiazine-3-carboxamide 1, 1-dioxide); oxicams; indomethacin (1- (4-chlorobenzoyl) -5-methoxy-2-methyl-H-indole-3-acetic acid); meclofenamate sodium (N- (2, 6-dichloro-m-tolyl) anthranilic acid sodium salt monohydrate); nabumetone (4- (6-methoxy-2-naphthyl) -2-butanone); ketoprofen (2- (3-benzoylphenyl) -propionic acid; tolmetin sodium (1-methyl-5- (4-methylbenzoyl-1H-pyrrole-2-sodium acetate dihydrate), diclofenac sodium (2- [ (2, 6-dichlorophenyl) amino ] phenylacetic acid monosodium salt), hydroxychloroquine sulfate (2- { [4- [ (7-chloro-4-quinolyl) amino ] pentyl ] ethylamino } ethanol sulfate (1: 1), penicillamine (3-mercapto-D-valine), flurbiprofen ((±) 2-fluoro- α -methyl- [1, 1-biphenyl ] -4-acetic acid), etodolac (1-8-diethyl-13, 4,9, -tetrahydropyran- [3-4-13] indole-1-acetic acid; mefenamic acid (N- (2, 3-xylyl) anthranilic acid; and diphenhydramine hydrochloride (2-diphenylmethoxy-N, N-dimethylethylamine hydrochloride).

13. The composition of claim 11, wherein the analgesic is selected from the group consisting of: paracetamol and analgin (sodium 4-methylamino-1, 5-dimethyl-2-phenyl-3-pyrazolone mesylate).

14. The composition of claim 11, wherein the migraine medication is selected from the group consisting of: triptans; sumatriptan (3- (2- (dimethylamino) ethyl) -N-methyl-1H-indole-5-methanesulfonamide); almotriptan (1- (((3- (2 (dimethylamino) ethyl) indol-5-yl) methyl) sulfonyl) pyrrolidine) and amitriptyline (3- (10, 11-dihydro-5H-dibenzo (a, d) cyclohepten-5-ylidene) -N, N-dimethyl-1-propylamine).

15. The composition of claim 11, wherein the menopausal medication is selected from the group consisting of: venlafaxine, paroxetine, phytoestrogen and botanical extracts.

16. The composition of claim 15, wherein the plant extract is derived from a plant selected from the group consisting of black cohosh and maca.

17. The composition of claim 11, wherein the sleep disorder drug is selected from the group consisting of: diphenhydramine (2- (benzhydryloxy) -N, N-dimethylethylamine), valerian and melatonin (5-methoxy-N-acetyltryptamine).

18. The composition of claim 11, wherein the erectile dysfunction drug is selected from the group consisting of: prostaglandin, testosterone, yohimbine, pentoxifylline, trazodone, apomorphine, sildenafil, tadalafil, minoxidil, misoprostol, papaverine, nitroglycerin, phentolamine, moxideril, linsidomine, and pyridylguanidine compounds.

19. The composition of claim 11, wherein the macromolecule is selected from the group consisting of: vitamin B12, antibiotics, peptides, calcitonin, vasopressin and oxytocin.

20. The composition of claim 19, wherein the macromolecule is vitamin B12.

21. The composition of claim 11, wherein the macromolecule has a molecular weight of up to about 5000 daltons.

22. The composition of claim 11, wherein the appetite suppressant is DL-phenylalanine.

23. The composition of claim 22, wherein the DL-phenylalanine is in an amount of about 1% to 5% by weight of the total weight of the composition.

24. The composition of claim 22, wherein the DL-phenylalanine is selected from the group consisting of: d-phenylalanine, L-phenylalanine, and mixtures thereof.

25. The composition according to any one of claims 8-10, wherein the pharmaceutical ingredient is DL-phenylalanine.

26. The composition of claim 1, wherein the composition is in a dosage form selected from the group consisting of: lozenges, chewing gums, chewable tablets, and dissolving tablets.

27. A method for facilitating the delivery of a pharmaceutical ingredient across the oral mucosa, the method comprising administering to a subject in need thereof a composition comprising a pharmaceutical ingredient and methylsulfonylmethane in a carrier suitable for application to the oral mucosa; wherein the methylsulfonylmethane is in an amount sufficient to facilitate transmucosal delivery of the pharmaceutical ingredient.

28. The method of claim 27, wherein the carrier comprises edible oil, purified water, and lecithin.

29. The method of claim 28, wherein the edible oil is a vegetable oil.

30. The method of claim 29, wherein the vegetable oil is selected from the group consisting of: cottonseed oil, peanut oil, poppy seed oil, safflower oil, sesame oil, soybean oil, corn oil, olive oil, canola oil, and combinations thereof.

31. The method of claim 27, wherein the composition further comprises at least one excipient selected from the group consisting of: cocoa butter, sucralose, calcium carbonate, and combinations thereof.

32. The method of claim 31, wherein the composition comprises the composition of claim 7, wherein the composition comprises:

a pharmaceutical ingredient in an amount of about 0.1% to 15%;

methylsulfonylmethane in an amount of about 0.5-30%;

vegetable oil in an amount of about 5-40%;

purified water in an amount of about 5-30%;

cocoa butter in an amount of about 5-40%;

sucralose in an amount sufficient to act as a sweetener,

calcium salt in an amount of about 1-20%; and

lecithin in an amount of no more than about 1-20%; wherein the percentages are weight percentages based on the total weight of the composition and the total weight of the composition is equal to 100%.

33. The method of claim 32, wherein the pharmaceutical ingredient is in an amount of about 1% to 5%;

the methylsulfonylmethane is in an amount of about 1% to 10%;

the vegetable oil is in an amount of about 20% to 40%;

the purified water is in an amount of about 10% to 30%;

the cocoa butter is in an amount of about 20% to 40%;

the sucralose is in an amount of about 0.05% to 0.2%;

the calcium carbonate is present in an amount of about 1% to 20%, and

the lecithin is in an amount of about 1% to 20%.

34. The method of claim 33, wherein the pharmaceutical ingredient is in an amount of about 2% to 4%;

the methylsulfonylmethane is in an amount of about 2% to 5%;

the vegetable oil is in an amount of about 25% to 35%;

the purified water is in an amount of about 15% to 25%;

the cocoa butter is in an amount of about 25% to 35%;

the sucralose is in an amount of about 0.07% to 0.15%;

the calcium carbonate is present in an amount of about 5% to 15%, and

the lecithin is in an amount of about 5% to 15%.

35. The method of claim 28, wherein the pharmaceutical ingredient is selected from the group consisting of: non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, migraine agents, menopausal medications, sleep disturbance medications, erectile dysfunction medications, appetite suppressants, and macromolecules.

36. The method of claim 35, wherein the appetite suppressant is DL-phenylalanine.

37. The method of claim 36, wherein the DL-phenylalanine is in an amount of about 1% to 5% by weight of the total weight of the composition.

38. The method of claim 36, wherein the DL-phenylalanine is selected from the group consisting of: d-phenylalanine, L-phenylalanine, and mixtures thereof.

39. The method of claim 28, wherein the composition is in a dosage form selected from the group consisting of: lozenges, chewing gums, chewable tablets, and dissolving tablets.

40. The method of claim 28, wherein the oral mucosa is selected from the group consisting of: sublingual mucosa, buccal mucosa, gingival mucosa, palatal mucosa, and combinations thereof.

41. A method for suppressing appetite in a mammal in need thereof, wherein the method comprises transmucosal administration of a composition comprising an appetite-suppressing amount of DL-phenylalanine, methylsulfonylmethane, an edible oil, purified water, and lecithin, thereby suppressing appetite in the mammal in need thereof.

42. The method of claim 41, wherein the edible oil is a vegetable oil.

43. The method of claim 43, wherein the vegetable oil is selected from the group consisting of: cottonseed oil, peanut oil, poppy seed oil, safflower oil, sesame oil, soybean oil, corn oil, olive oil, canola oil, and combinations thereof.

44. The method of claim 41, wherein the composition further comprises an excipient selected from the group consisting of: sweeteners, flavoring agents, protective agents, plasticizers, waxes, elastomeric solvents, filler materials, preservatives, lubricants, wetting agents, emulsifiers, solubilizers, suspending agents, colorants, disintegrants and combinations thereof.

45. The method of claim 44, wherein the composition comprises at least one excipient selected from the group consisting of: cocoa butter, sucralose, calcium carbonate, and combinations thereof.

46. The method of claim 45, wherein the composition comprises:

DL-phenylalanine in an amount of no more than about 5%;

methylsulfonylmethane in an amount of no more than about 10%;

a vegetable oil in an amount of no more than about 40%;

purified water in an amount of no more than about 30%;

cocoa butter in an amount of no more than about 40%;

sucralose in an amount of no more than about 0.2%;

calcium carbonate in an amount of no more than about 20%; and

lecithin in an amount of no more than about 20%; wherein the percentages are weight percentages based on the total weight of the composition and the total weight of the composition is equal to 100%.

47. The method of claim 45, wherein the DL-phenylalanine is in an amount of about 1% to 5%;

the methylsulfonylmethane is in an amount of about 1% to 10%;

the vegetable oil is in an amount of about 20% to 40%;

the purified water is in an amount of about 10% to 30%;

the cocoa butter is in an amount of about 20% to 40%;

the sucralose is in an amount of about 0.05% to 0.2%;

the calcium carbonate is present in an amount of about 1% to 20%, and

the lecithin is in an amount of about 1% to 20%.

48. The method of claim 47, wherein the DL-phenylalanine is in an amount of about 2% to 5%;

the methylsulfonylmethane is in an amount of about 1% to 5%;

the vegetable oil is in an amount of about 25% to 35%;

the purified water is in an amount of about 15% to 25%;

the cocoa butter is in an amount of about 25% to 35%;

the sucralose is in an amount of about 0.07% to 0.15%;

the calcium carbonate is present in an amount of about 5% to 15%, and

the lecithin is in an amount of about 5% to 15%.

49. The method of claim 41, wherein the DL-phenylalanine is selected from the group consisting of: d-phenylalanine, L-phenylalanine, and mixtures thereof.

50. The method of claim 41, wherein the composition is in a dosage form selected from the group consisting of: lozenges, chewing gums, chewable tablets, and dissolving tablets.

51. The method of claim 41, wherein the oral mucosa is selected from the group consisting of: sublingual mucosa, buccal mucosa, gingival mucosa, palatal mucosa, and combinations thereof.

52. The method of claim 41, wherein the mammal is a human.

53. The method of claim 41, wherein the mammal is obese.

54. The method of claim 53, wherein the mammal is morbidly obese.

55. The method of claim 41, wherein the methylsulfonylmethane is in an amount sufficient to facilitate transmucosal delivery of the DL-phenylalanine.

56. The method of claim 46, wherein the DL-phenylalanine is in an amount of about 5%.