Title of Invention

ORALLY DISINTEGRATING PHARMACEUTICAL COMPOSITION CONTAINING SILDENAFIL CITRATE

Abstract

The invention disclosed in this application relates to a pharmaceutical composition in the form of a tablet that disintegrates rapidly in the mouth, releases the active substance for absorption through sublingual mucosal layers in the oral cavity which comprises an inclusion complex of sildenafil or its salts or mixtures with cyclo dextrin and a matrix carrier consisting of pharmaceutical vehicles which enhance the solubility of the complex. The invention disclosed in this application also provides a process for preparing the pharmaceutical composition The composition can be used for the treatment of male erectile dysfunction.

Full Text

In the recent times numerous advances have taken place in the field of pharmacology and pharmaceutics with respect to the administration of drugs to treat various conditions. Despite the tremendous advancements in the field, however, drugs continue to be administered using substantially the same techniques that have been used for many decades. The vast majority of pharmaceutical agents continue to be administered either orally or by injection. Oral administration is probably the most prevalent method of administering pharmacological medicaments. The medicament is generally incorporated into a tablet, capsule, or a liquid base, and then swallowed. The oral administration modality is often preferred because of its convenience. In addition, oral administration is generally non-invasive, painless, and simple to accomplish for most patients. Nevertheless, oral administration of drugs suffers from several disadvantages. One disadvantage is that pediatric and geriatric patients frequently have difficulty swallowing pills and other solid dosage-forms, and such patients often reifies to cooperate in swallowing a liquid medication. In addition, for many medicaments, the act of swallowing the medicament often requires fluids that increase gastric volume and the likelihood of nausea and vomiting. A further problem with oral administration is that the rate of absorption of the drug substance into the bloodstream after swallowing varies from patient to patient. The absorption of the drug substance is dependent upon the movement of the drug substance from the stomach to the small and large intestines and the effects of secretions from these organs and on the resulting pH within the stomach and intestines as well as food. Anxiety and stress can dramatically reduce these movements and secretions, prevent or reduce the final effects of the drug substance, and delay onset of the drug's effects. Most significant is the fact that there is normally a substantial delay between the time of oral administration and the time that the therapeutic effect of the drug begins. As mentioned above, the drug must pass through the gastrointestinal system in order to enter the bloodstream; this typically takes 30 to 60 minutes or longer. Further, anxiety and stress often increase this delay. For many applications, such as pre-medication before surgery or where immediate relief from pain or a serious medical condition or immediate effectiveness of the drug is required, this delay is unacceptable. The other disadvantage of oral administration is that many drugs almost immediately experience metabolism or inactivation. The veins from the stomach and the small and large intestines pass directly through the liver. Thus, drugs entering the bloodstream must first pass through the liver before distribution into the general blood circulation. More than sixty percent of most drugs(and essentially one hundred percent of certain drugs) are removed from the patient's bloodstream during this "first pass" through the liver. The result is that oral administration is impractical for many drugs, particularly many central nervous system and cardiovascular'-acting drugs that are used for rapid onset in critical care situations, as a pre-medication prior to surgery, or for the induction of anesthesia. Further, additional stress is placed on the liver as it removes the excess drug from the bloodstream. This is particularly severe if the drug treatment has been occurring over an extended period of time. The liver may become overloaded with the drug's metabolite, which then must be excreted. As a result, there is an increased risk of hepatic or renal disorders. Some investigators have suggested that it may be possible to administer medication through the buccal mucus of the cheek pouch or by sublingual administration. See, U.S. Pat. No. 4,671,953 entitled "METHODS AND COMPOSITIONS FOR NONINVASIVE ADMINISTRATION OF SEDATIVES, ANALGESICS, AND ANESTHETICS". Such administration through the mussel tissues of the mouth, pharynx, and esophagus of therapeutic drugs possesses a distinct usefulness. Administration of drugs by this route does not expose the drug to the gastric and intestinal digestive fluids. In addition, the drugs largely bypass the liver on the first pass through the body, thereby avoiding additional metabolism and/or inactivation of the drug. Rapidly dissolving or disintegrating pharmaceutical dosage forms are available for human patients who have difficulty in swallowing conventional dosage forms such as tablets or capsules and for the sublingual and buccal administration of drug. Most of these dosage forms are prepared either by compression or molding. In US Patent 5 785 989 composition and methods of manufacture for producing a candy type flavored dissolvable matrix containing medicament capable of absorption through the mussel tissues of the mouth, pharynx and esophagus useful in administering lipophilic and non lipophilic drugs to which an appliance or holder is attached was disclosed. The solid dosage form is meant for use in the delivery of drug in a pharmacologically effective dose in which the drug being dispersed in a soluble matrix capable of being sucked on while held with in the mouth, with attached holder to permit convenient insertion and removal of the drug containing integral mass into and out of the mouth of the patient. The dissolvable matrix optionally contains permeation enhancers, pH buffering agents to increase the absorption of the drug through the mucosal tissue. In WO 9626714 a process for the preparation of a solid pharmaceutical dosage form comprising a carrier, elegizing hydrochloride as an active ingredient in the form of a fast dispersing dosage form designed to release the active ingredient in the oral cavity was disclosed. The pharmaceutical composition available in markets for oral administration for treating male erectile dysfunction contains sildenafil citrate (Manufactured by M/s Pfizer Inc.). Sildenafil citrate is soluble in dimethylformamide, sparingly soluble in acetic acid, slightly soluble in alcohol. About 3.5 mg is soluble in water. In JP 10298062 a pharmaceutical composition in the form of tablets that rapidly soluble in the oral cavity and manufacturing procedure has been disclosed. In WO 9830209 a rapidly releasing and taste masking pharmaceutical composition comprising a core containing sildenafil, an inner coating layer formed of a water soluble polymer and an outer coating layer formed on inner coating containing saliva insoluble polymer and a process for preparing such oral dosage form has been disclosed. In US patent, US 5,874,437 nitro sated and nitrosylated phosphodiestrase inhibitors having the formula NOn , where n = 1 or 2 and compositions comprising such compound in pharmaceutically acceptable carrier and a method for treating male impotence in humans by administering the compounds and compositions thereof has been disclosed. J As reported in Extra Pharmacopoeia, 32 edition, "Sildenafil is rapidly absorbed following administration by mouth, with a bioavailability of approximately 40%. Peak plasma concentrations are attained within 30 to 120 minutes. The rate of absorption is reduced when sildenafil is administered with food". It is commercially available as viagra tablets in 25mg, 50mg and lOOmg strength. The active ingredient in viagra namely , sildenafil citrate, is poorly soluble in water and becomes even less soluble when it reaches the small intestine where it is absorbed by the blood. Food in the stomach can delay the rate of absorption into the blood resulting in delays in the effect of the drug. Hence it is felt that an alternate dosage form overcoming the said limitations can be designed which can ensure the double advantage of faster absorption of the drug and to overcome the effect of food on the absorption of the drug, in order to reduce the time required for the drug to show it's action. One such popular and well accepted route of administration is the sublingual route. This refers to a method of administering substances via the mouth so that the substances are absorbed via the blood vessels under the tongue and in the mouth rather than via the digestive tract. The route of absorption via the highly vascularised buckle mucus allow the substances a more direct access to the bloodstream. Sublingual administration of substances to a human or animal body is generally more efficient than more conventional oral delivery methods since substances may be absorbed directly into the blood steam by the use of a sublingual delivery. In order to enhance the solubility of poorly soluble drugs and thus their absorption into the bloodstream, cyclodextrin are extensively reported in the literature to be useful in improving the drugs solubility besides helping in so many other ways. The book " Hand book of pharmaceutical excipients - 2^^ edition, published by the pharmaceutical press states as follows under. "Functional Category: Stabilising agent, solubilising agent. In shape, cyclodextrins are bucket like or cone - like torpid molecules. They thus have a rigid structure with a central cavity whose size varies according to the cyclodextrin type. Due to the arrangement of hydroxyl groups within the molecule the internal surface of the cavity is hydrophobic whilst the outside of the tours is hydrophilic. This arrangement permits the cyclodextrin to accommodate a guest molecule within the cavity so forming an inclusion complex. Cyclodextrins may thus be used to form inclusion complexes with a variety of drug molecules resulting primarily in improvements to dissolution and bio availability due to enhanced solubility and improved chemical and physical stability. Cyclodextrin inclusion complexes have also been used to mask the unpleasant taste of active materials and to convert a liquid substance to a solid material. Selected list of drugs with enhancement of solubility after inclusion complex formation with cyclodextrin are : Barbiturates, Biphenylacetic acid, chloramphenicol, diazepam, digoxin, astroidal, furosemide, hydrochlorthiazide, hydrocortesone, Ibruprofen, indomethacin, pancratestatin, phenytoin, prostaglandins, progesterone, sulfonamides, testosterone, tolbutamide. Improvement of Taste and odour - prostaglandins, spironolactone Enhancement of bioavailability: Aspirin, barbiturates, clofibrate, diazepam diltiazem, famotidine, ibuprofen, protamine, spironolactone Enhancement of stability: against dehydration - misogynic, prostaglandins. Against hydrolysis - aspirin, atropine, digoxin, procaine Against oxidation: aldehydes, epinephrine, phenothiazens Against photodecomposition: phenothiazines, ubiquinones Formation of solid inclusion complexes: clofibrate, essential oils, nitroglycerine, oil soluble vitamins. B-cyclodextrin is able to form inclusion complexes with a number of molecules of pharmaceutical interest. B-cyclodextrin is considered to be non-toxic when administered orally and has thus become primarily used in tablet and capsule formulations". US Patent no 6407079 lists a number of drugs with improved solubility due to cyclodextrin complexation: Accordingly the patent provides the following information. "Saturation solubility at 25°c of different drugs was determined using a 10% hydroxy propyl beta-cyclodextrin solution in phosphate buffer The above data shows that cyclodextrin improves solubility of some drugs due to complexation with poorly soluble drug substances. The main objective of present invention is to provide a pharmaceutical composition containing sildenafil, for application sublingually which can elicit rapid onset of action when compared to the oral dosage form available for treatment of male erectile dysfunction. Another objective of the present invention is to provide a fast-acting, tablet pharmaceutical composition for oral administration, capable of rapidly disintegrating in the mouth, carrying drug for the treatment of male erectile dysfunction due to organic, psychogenic and the associated symptoms, in the form of a free base or its pharmaceutically acceptable salt or ester, there by allowing the dissolution of the active substance in saliva and transmucosal absorption of the medicament for rapid onset of action. Yet another objective of the present invention is to provide a method for preparing the pharmaceutical composition containing sildenafil or its salt for sublingual administration. We have observed that an inclusion complex of sildenafil and cyclo dextrin prepared using a molecular ratio and when the inclusion complex is combined with other pharmaceutical vehicles enhances the solubility and absorption of the drug and hence the bioavailability of the drug sildenafil. The permeation of drug through mucosal membrane is further improved due to the presence of surface active agents. So far, no inclusion complex’s of Sildenafil or its salts with cyclodextrins are reported in the literature. Based on the literature detailing the capability of cyclodextrin in improving the solubility of certain drugs, we have conducted the solubility studies on Sildenafil citrate with / without p cyclodextrin and the results were encouraging. From the above data, it is clear that cyclodextrin enhances the solubility of Sildenafil citrate. Accordingly , the present invention provides a new pharmaceutical composition for the treatment of male erectile dysfunction that disintegrates rapidly in the mouth and releases the active substance for / absorption through sublingual mucosal layers in the oral cavity which / comprises an inclusion complex of sildenafil and cyclo dextrin and a matrix carrier consisting of pharmaceutical vehicles which enhance the solubility of the complex In a further embodiment of the present invention there is provided a process for the preparation of the new orally disintegrating pharmaceutical composition, useful for the treatment of male erectile dysfunction that disintegrates rapidly in the mouth and releases the active substance for absorption through sublingual mucosal layers in the oral cavity, which comprises (i) forming an intrusion complex of sildenafil or its salts or their mixtures with cyclo dextrin and (ii) mixing the resultant complex with a matrix carrier consisting of pharmaceutical vehicles which enhance the solubility of the complex In a preferred embodiment of the present invention the inclusion complex is prepared using sildenafil and cyclodextrin a molecular ratio of 1:1 . The amount of sildenafil or its salt equivalent to sildenafil may range from 3.0% to 30.0% w/w per tablet preferably 5.0% to 25.0% w/w per tablet In another embodiment of the present invention the cyclodextrin used is selected from a-cyclodextrin, p-cyclodextrin, x,-cyclodextrin, substituted cyclodextrin such as 2-hydroxypropyl - p-cyclodextrin and the like The amount of cyclodextrin used may range from 5.0% to 80.0% w/w more preferably 7.2% to 72% w/w per tablet The sildenafil used in the pharmaceutical composition may be present as a base or its salt form with organic acids such as citric acid, lactic acid, acetic acid and the like or inorganic acids such as sulphuric acid, diluted hydrochloric acid, nitric acid, orthophosphoric acid etc. The sildenafil used is present in the composition in a therapeutically effective amount that can be readily determined by one skilled in the art. In determining such amounts, the particular compound being administered, the bioavailability characteristics of the pharmaceutical, the dose regime, the age and weight of the patient and other factors must be considered. The pharmaceutical composition also contains matrix forming carriers including diluents, disintegrates, binders, lubricants. / The amount of diluent, disintegrant and binder used ranges from 5.0% to 80.0% w/w, 3.0% to 30.0% w/w, 2.0% to 15.0% w/w , more preferably from 10.0% to 60.0% w/w, 5.0% to 20.0% w/w and 3.0% to 10.0% w/w per tablet, respectively. The amount of lubricant present in the composition may range from 0.5% w/w to 5.0% w/w per tablet, more preferably from 1.0% w/w to 3.0% w/w per tablet. The carrier material used in the pharmaceutical composition of the invention may be any water-soluble or water-dispersible inert pharmaceutical excipients which are capable of forming a rapidly disintegratable tablet, preferably a water insoluble material since this results in most rapid disintegration of the matrix when the product is placed in mouth. These pharmaceutical vehicles ( Carrier) employed may be selected from Diluents, disintegrant, binders Organoleptic additives (flavors and colours). Surface- active agents buffering agents ,Lubricants , binders , sweeteners and their mixtures , The amount of flavor may range from 0.25% to 4.0% w/w more preferably from 0.5% to 3.0% w/w per tablet, the amount of sweeteners may range from 0.5% to 5% w/w per tablet, more preferably from 1.0% to 4.0% w/w. The pharmaceutical composition also contains ingredients other than the active substance and matrix forming carriers. These additional ingredients include completing agents, buffering agents, sweetening agents, flavoring agents, coloring agents and surface-active agents. It is highly essential to make the inclusion complex of Sildenafil citrate, due to its a molecular weight of 667 units, which may cause difficulty or may not cross the mucosal membrane due to its molecular size and other physicochemical characteristics such as degree of ionization, KPa, lipophihcity, melting point, etc. The making of inclusion complex of active substance with cyclo dextrin may eliminate the above said and facilitates the sildenafil molecule easily to cross the mucosal membrane. Further the release of drug in locally micro buffered area may thus lead to its un-ionized form which has a tendency to permeate at rapid rate than an ionized sildenafil. Buffering agents are incorporated in the composition to provide a favorable pH environment for passage across the mucosal tissues of the mouth, pharynx and esophagus. Buffering agents can be used to effect pH change in the saliva environment of the mouth in order to favor the existence of a unionized form of the active substance, which more rapidly moves through the mucosal tissues. Appropriate pH adjustment can aid in producing a more palatable product with active substances which are either severely acidic (and thus sour) or severely basic (and thus bitter). A buffer system such as carbonate, bicarbonate, phosphate and the like may be used. The sweetening agents are selected such as aspartame. Sodium saccharin, mono ammonium glycyrrhizin ate and their derivatives. The flavoring agents used in this formulation are selected from orange flavor, bitter mask, mixed fruit flavor, pineapple, chocolate, strawberry, raspberry, mango, peppermint and/ or the mixture thereof The coloring agents are incorporated to improve the austerity of the product. These include quinolines yellow, sunset yellow, yellow iron oxide, red iron oxide, terrain, cramoisy or mixtures thereof The amount of coloring agent used may range from 0.025% to 1.50 % w/w more preferably from 0.05% to 1.0% w/w per tablet. The surface active agents are included in the formulation to improve wettability and permeation. These are selected from materials such as polysorbate 80, polysorbate 60, polysorbate 40, polysorbate 20, sodium lauryl sulphate, dioctyl sodium sulphosuccinate and the mixtures thereof The amount of surfactants used ranges from 0.05% to 3.0% w/w per tablet, / more preferably from 0.10% to 2.0% w/w per tablet. The invention is described in detail in the examples given below which are provided by way of illustration only and therefore should not be constmed to limit the scope of the invention. EXAMPLE -1 Each tablet contains Sildenafil 25.0 mg Mannitol 120.0 mg Microcrystalline cellulose 35.0 mg p - Cyclo Dextrin 60.0 mg Plasdone XL 20.0 mg Colloidal Silicon dioxide 5.0 mg Potassium bicarbonate 30.0 mg Orange flavor 1.0 mg Bitter Mask 2.0 mg Peppermint Flavor 2.0 mg Sodium saccharin 5.0 mg Dicalcium phosphate 20.0 mg Sodium starch glycolate 5.0 mg Magnesium stearate 5.0 mg Quinoline Yellow Lake 1.0 mg Polysorbate 60 5.0 mg Preparation of complex: The inclusion complex of sildenafil and p - Cyclo dextrin (1:1) was prepared by dissolving the sildenafil in dimethyl formamide and p - Cyclo dextrin in water followed by addition of the sildenafil solution to the p -Cyclo dextrin solution with continuous stirring. It is followed by vaccum evaporation to remove the solvents. The dried mass was pulverised and sieved prior to admixing with the other inert pharmaceutical agents. Sifl the materials Sildenafil-P-Cyclodextrin complex prepared as explained above and the microcrystalline cellulose, mannitol, plasdone XL, colloidal silicon dioxide, potassium bicarbonate, dicalcium phosphate and sodium starch glycolate, quinoline yellow and polysorbate 60 using the amounts specified above and they are lubricated using magnesium stearate and compressed into slugs. The resulting slugs are milled and the granules produced are passed through 18# and mixed with plasdone XL, Bitter mask, peppermint flavor, orange flavor, sodium saccharin in the quantities mentioned above and lubricated with magnesium stearate. They are compressed into tablets on a rotary tablet compression machine. EXAMPLE - 2 Each tablet contains Sildenafil 50.0 mg Mannitol 120.0 mg Microcrystalline cellulose 80.0 mg p - Cyclo Dextrin 120.0 mg Plasdone XL 36.0 mg Colloidal Silicon dioxide 12.0 mg Sodium bicarbonate 40.0 mg Strawberry 3.0 mg Bitter Mask 5.0 mg Mango Flavor 3.0 mg Sodium saccharin 16.0 mg Dicalcium phosphate 40.0 mg Sodium starch glycolate 10.0 mg Magnesium stearate 10.0 mg Di octyl sodium sulphosuccinate 5.0 mg Yellow iron oxide 1.0 mg Preparation of complex: The inclusion complex of sildenafil and p - Cyclo dextrin (1:1) was prepared by dissolving sildenafil in dimethyl form amide and p - Cyclo dextrin in water followed by addition of sildenafil solution to the p -Cyclo dextrin solution with continuous stirring. It was followed by vacuum evaporation to remove the solvents. The dried mass was pulverized and sieved prior to admixing with the other inert pharmaceutical agents. Sift the materials sildenafil-P-Cyclo Dextrin complex as prepared above , microcrystalline cellulose, mannitol, plasdone XL, colloidal silicon dioxide, sodium bicarbonate, Dicalcium phosphate and sodium starch glycolate, dioctyl sulpho succinate, yellow iron oxide . They are lubricated with magnesium stearate and compressed into slugs. The slugs are milled , and the granules are passed through 18# and mixed with plasdone XL, bitter mask, straw berry flavor, mango flavor, sodium saccharine using the mounts mentioned above and lubricated with magnesium stearate. The lubricated granules are compressed into tablets on a rotary tablet compression machine. EXAMPLE - 3 Each tablet contains Sildenafil Citrate 70.0 mg Mannitol 70.0 mg Microcrystalline cellulose 40.0 mg 2-hydroxypropyl-P-CycloDextrin 140.0 n Plasdone XL 20.0 mg Sodium carbonate 40.0 mg Colloidal Silicon dioxide 12.0 mg Orange flavor 4.0 mg Bitter Mask 2.0 mg Mixed Fruit Flavor 3.0 mg Aspartame 10.0 mg Dicalcium phosphate 40.0 mg Sodium starch glycolate 10.0 mg Magnesium stearate 10.0 mg Polysorbate 80 5.0 mg Red iron oxide 1.0 mg Preparation of complex: The inclusion complex of sildenafil citrate and 2-hydroxypropyl - p-Cyclodextrin (1:1) was prepared by dissolving sildenafil citrate in dimethyl formamide and 2-hydroxypropyl - P-Cyclo dextrin in water followed by addition of sildenafil citrate solution to the 2-hydroxypropyl - p-Cyclo dextrin solution with continuous stirring. It was followed by vaccum evaporation to remove the solvents. The dried mass was pulverised and sieved prior to admixing with the other inert pharmaceutical agents. Sift the materials Sildenafil citrate - 2-hydroxypropyl p-CycloDextrin complex, prepared as explained above , microcrystalline cellulose, mannitol plasdone XL, Sodium carbonate, colloidal silicon dioxide, Dicalcium phosphate and sodium starch glycolate, polysorbate 80, red iron oxide in the amounts specified and lubricated with magnesium stearate . They are compressed into slugs. The slugs are milled and the resulting granules are passed through 18# and mixed with plasdone XL, bitter mask. Mixed fruit flavor, orange flavor. Aspartame in the above mentioned specified quantities and lubricated with magnesium.stearate. The resultant lubricated granules are compressed into tablets on a rotary tablet compression machine. Advantages of the invention: The invention has the advantage of 1) Rapid onset of action due to the rapid absorption of active ingredient through oral mucosa 2) Reduced dosage as absorption through oral mucosa bypasses the first-pass metabolism 3) Ease of administration 4) Medicament can be taken with out water.

Documents:

759-mas-2002-abstract.pdf

759-mas-2002-claims filed.pdf

759-mas-2002-claims granted.pdf

759-mas-2002-correspondnece-others.pdf

759-mas-2002-correspondnece-po.pdf

759-mas-2002-description(complete) filed.pdf

759-mas-2002-description(complete) granted.pdf

759-mas-2002-form 1.pdf

759-mas-2002-form 19.pdf

759-mas-2002-form 5.pdf