MXPA05009469A - Control release formulation containing a hydrophobic material as the sustained release agent. - Google Patents

Abstract

The present invention is directed to a sustained release pharmaceutical composition in oral dosage form consisting essentially of a pharmaceutically effective amount of a medicament and a hydrophobic material in the absence of a lactose or hydrophobic carbohydrate polymer, said medicament being present in an amount greater than about 25% of the pharmaceutical composition and having a water solubility greater than about 1 gram per 10 mL of water at 25°C, said hydrophobic material having a melting point ranging from at least about 40°C to about 100°C at 1 atm pressure, and being present in an amount ranging from about 3% to about 20% by weight of the pharmaceutical composition and in an amount less than the of the medicament, and said hydrophobic material not being present in coating of said pharmaceutical composition; said pharmaceutical composition being prepared by direct compression in the absence of or melting the hydrophobic material or the use of high shear mixer. The present invention is also directed to a method of preparing said pharmaceutical composition.

Description

CONTROLLED RELEASE FORMULATION CONTAINING A HYDROPHOBIC MATERIAL AS A RELEASE AGENT PROLONGED FIELD OF THE INVENTION The present invention relates to a controlled release formulation in oral dosage form, preferably in the form of a tablet, which contains a hydrophobic material as an extended release agent.

BACKGROUND OF THE INVENTION It is of great advantage for both the patient and the physician that the medication is formulated in such a way that it can be administered in a minimum amount of daily doses from which the drug is released uniformly over a desired extended period of time. This effect is achieved using prolonged or slow release compositions. The prolonged or slow release compositions containing pharmaceutical drugs or other active ingredients, are designed to contain higher concentrations of the drug, and are prepared in such a way as to effect prolonged or slow release in the gastrointestinal tract of humans or animals. , during an extended period of time.

Dosage forms of sustained or slow-release therapeutic drugs have inherent advantages over conventional, immediate-release dosage forms. The advantages include less frequent dosing of a drug, and the resulting compliance of the regimen by the patient, a response to a longer drug level in the blood, therapeutic action with less ingested drug, and mitigation of side effects. By providing a slow and stable release of the drug over time, the peaks in the concentration of drug absorbed are mitigated or eliminated, effecting a smoother and longer response to the level in the blood. For this purpose, a prolonged release formulation has to meet some criteria; that is, it has to effect a uniform and constant dissolution of the drugs, and it has to be effective for an extended period of time. It is also important that this formulation is easy to elaborate, that the manufacturing process is reproducible, and that the product produced by the manufacturing process is uniform. Furthermore, if different drugs are used as active components in the sustained release formulation, it is important that the manufacturing process be easily adaptable to accommodate these various drugs. Various hydrophilic and hydrophobic materials, including polymers, have been used to prepare sustained release formulations. In addition, they have been prepared by several methods, such as solvent evaporation, heat fusion, direct compression and wet granulation. However, it is well known that the materials used to effect the controlled release, as well as the method of manufacture, have a significant effect on the performance control of release of the oral dosage form. For example, ethylcellulose, which is a hydrophobic polymer, has been used to effect the controlled release of drugs. However, the release profile is significantly different when used as a coating material than when used as a directly compressible powder. Moreover, when the matrix-type tablets are made with ethylcellulose using wet granulation methods, the release profile is significantly different from that of the controlled release oral dosage forms, prepared using ethylcellulose as a directly compressible powder, or using ethylcellulose. as coating material. Moreover, if the hydrophobic material is melted in the process of making a sustained release pharmaceutical composition, its release profile is different from that of a controlled release pharmaceutical composition prepared by a different method. These differences in the release profile show that the pharmaceutical compositions prepared by the various methods are not the same, but are different. These differences in the release profile are not unique to pharmaceutical compositions containing ethylcellulose; he Release profile of compositions containing other hydrophobic material, such as waxes or higher fatty acids or alcohols, and the like, as a controlled release agent, depends not only on the identity of the hydrophobic material as a controlled release agent, but also on the method in which the pharmaceutical composition is prepared. Hydrophobic materials have been used to control the release of drugs. For example, waxes and lipids have been used as a coating material to retard the release of drugs. For example, the manufacturer of COMPRITOL® 888 (glyceryl behenate), GATTEFOSSE, investigated the effects of granules and coating spheres containing theophylline with COMPRITOL® 888 as a hot molten coating, using fluid bed equipment at different concentrations. The wax coating levels of the spherules were 2%, 6% and 10% by weight, respectively. The release profile in water was determined. At 2% (w / w) levels of the wax, 85% of the theophylline was released in one hour. However, at 6% levels of the wax, 55% of the theophylline was released in one hour, with 35% of it released in 5 minutes, and at 10% (w / w) levels of the wax, it was released 38% of theophylline in the first hour, with 28% of it released in 5 minutes. Considering the number of steps used to prepare formulations of this type, this is not an efficient way to formulate controlled release products, and the present inventor also sought to find a method to control the release of the product. drug without placing the wax in a coating, but mixing the hydrophobic material with the drug. There has been a great concern in the literature regarding the use of waxes in controlled release compositions, when mixed with medicaments. Common methods of making sustained-release drugs in oral dosage forms that use waxes as a controlled release material, mixed with the drug are (a) melting the drug and the wax together, then cooling and grinding the melt, and finally making tablets after mixing with excipients; (b) using wet granulation techniques, using an organic solvent as a granulation medium; (c) mixing the drug and waxes in a high shear mix and using the heat produced during processing to achieve a homogeneous mixture; and (d) using heat radiation to melt the wax in the presence of the drug. All these methods are uncomfortable and can be dangerous. Most of these techniques use large amounts of waxes to achieve a reasonable controlled release formulation, and the wax is usually present in high concentrations, eg, greater than 30% (w / w) of the dosage form and in a proportion of weight greater than 1: 1 in relation to the drug. For example, Abdallah in Alex.J.Pharm. 1992, 6, 243-246, evaluated three selected lipophilic polymers, Precirol® ATO 5 (glyceryl paimitostearate), Precirol® wL-2155 (glyceryl stearate) and Compritol® 888 (glycerol behenate), for preparation of ibuprofen compositions with prolonged release. The tablets were prepared by melting the drug and other ingredients with the polymers, cooling the melt and compressing the cooled melt. He found that granules having a size of 200 to 315 microns prepared with any of the three polymers at a concentration of 10 or 20 percent by weight did not show a delayed release effect; the formulations with granules prepared with the lipids identified above in these amounts, released the drug completely in 30 minutes. However, at a 50% level of COMPRITOL® 888, the granules showed a somewhat more prolonged release profile. However, making a tablet with this large amount of wax necessarily makes the tablet too big, and therefore more difficult to swallow, especially for older patients. The present inventor therefore sought a means to prepare sustained release formulation containing considerably less hydrophobic material. Pérez and coinvestigadores, in PRHSJ. 1993, 12, 263-267, investigated the effect of varying wax levels and methods of matrix formulation on drug release. The amount of drug in the formulation was maintained at 10% w / w, while the level of wax was varied from 10% to 50% w / w. The drug formulations were prepared by two different methods. In one method, called the physical method, the drug, wax and diluent, were mixed in a Turbula mixer by geometric dilution for 20 minutes, and then the mixture was compressed into a tablet. In the second method, called the solids dispersion method, the wax was melted, and the drug was incorporated in varying concentrations in the molten wax. The molten mixture was allowed to cool until solidified, and then the solidified mass was granulated by a Stokes oscillating granulator, equipped with No. 12 screen. Perez and coinvestigators, found that the tablets prepared by the physical method had the same concentration of wax, They released the drug at a faster rate than that corresponding to the drug prepared by the solid dispersion method. Tablets prepared by the physical mixing system containing 30% (w / w) of wax, released approximately 79% of the drug in approximately six hours. On the other hand, the tablets prepared by dispersion of solids containing 30% (w / w) of wax, showed a drug release of 72% in six hours, while those tablets prepared by the same method, containing 50% ( weight / weight) of wax, released only 30% of the drug in six hours. In addition, they showed that a satisfactory release profile was obtained when the ratio by weight of drug to the waxy material was greater than 1: 1, for example, at least 3: 1. Moreover, Perez and coinvestigators showed that at wax levels of 10% (w / w), regardless of which method was used, the release profile was unsatisfactory; the prolonged release formulation released approximately 80% of the drug in about 2 hours when prepared by any method. The prior art demonstrated that at levels of 30% or more of the waxy material, acceptable prolonged release profiles were obtained, but at lower levels, such as 10%, an unsatisfactory prolonged release profile was obtained. Thus, these prior art references teach that an extended release formulation containing less than 30% wax should not be prepared. Reilly and coinvestigators, in AAPS 1991, investigated the release profile of acetaminophen at the 10% level, using glyceryl behenate in various concentrations, 10%, 30% or 50% in spheres and tablets, with the latter prepared by direct compression or by wet granulation. The reference describes that the simple incorporation of glyceryl behenate into the spheres did not provide slow release. In tablets, however, 10% wax did not provide any sustained release action, but at levels of 30% and 50% by weight (ie, weight ratio of glyceryl behenate to drug of 3: 1 or 5: 1), the tablets showed prolonged release action. Moreover, for the tablet formulations, as the amount of wax increased, the amount of sustained release action also increased. Another researcher, Terrier, investigated the influence of glycerol palmito-stearate on drug release. He noticed that a tablet containing sodium salicylate as a medicament, and glycerol palmitostearate as an excipient at 40% by weight, which was prepared by wet granulation methods, did not show any prolonged release. For example, 50% of the drug was released in water after 20 minutes. The above methods used to prepare the pharmaceutical composition were prepared by other methods than direct compression. However, even if the formulation was prepared by direct compression, the prior art showed that at least 30% wax was required in the formulation to achieve prolonged release. For example, El-Sayed and coinvestigadores, in S.T.P. Pharma Sciences, 196, 6, 398-402, prepared a formulation containing 50% theophylline and 30% glyceryl behenate, HP C or carbopol, and the remaining excipient. Even though the tablet thus prepared showed prolonged release formulation, the present inventor sought a prolonged release formulation containing still less than 30% (w / w) of wax, and a method for preparing it. The present inventor has found a way to solve the drawbacks of the prior art, and to achieve its objective. More specifically, the present invention provides a means for preparing controlled release dosage forms using a simple manufacturing process, such as direct compression, which involves the compression of the various ingredients after a simple mixing procedure. The present inventor has It has been found that effective sustained-release formulations can be prepared in this way, which incorporates significantly less hydrophobic material than that used to date.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to a prolonged-release pharmaceutical composition in the form of a tablet, which contains a pharmaceutically effective amount of a medicament, and a hydrophobic material as a prolonged-release agent, said medicament and hydrophobic material being present in the nucleus of the composition pharmaceutical, said core excludes polymer capable of swelling, which causes disintegration of the tablet; includes hydrophobic carbohydrate polymer, and excludes high concentrations of water-soluble excipients of low molecular weight, including lactose, said medicament is present in an amount greater than about 25% (w / w) of the pharmaceutical composition, and has a solubility in water less than about 1 gram per 10 ml of water at 25 ° C, said hydrophobic material has a melting point ranging from at least about 40 ° C to about 100 ° C at a pressure of 1 atmosphere, and is present in an amount effective to control the release of the drug, said hydrophobic material is present in an amount ranging from about 3% up to about 20% by weight of the pharmaceutical composition, and in an amount by weight less than that of the medicament. It is preferred that the pharmaceutical composition be prepared by direct compression, without melting the hydrophobic material or the use of a high shear mixer. While the pharmaceutical composition can be prepared using wet granulation techniques, it is preferred that it not be prepared in that way. It is also directed to a method for preparing a prolonged release pharmaceutical composition in the form of a tablet, which comprises (a) mixing a medicament and a hydrophobic material, and optionally a lubricant, and optionally an excipient, and optionally an adjuvant, to form a substantially homogeneous and uniform mixture, said mixture excludes polymer capable of swelling, which causes disintegration of the tablet, and high concentrations of water-soluble excipients of low molecular weight, said medicament being present in an amount greater than about 25% by weight of the pharmaceutical composition and has a solubility in water of less than about 1 gram per 10 ml_ of water at 25"C, said hydrophobic material having a melting point ranging from at least about 40 ° C to about 100 ° C under pressure of 1 atmosphere, and is present in an amount ranging from about 3% to about 20% by weight of the pharmaceutical composition; and (b) compressing the product of step (a) to form a tablet therefrom, said pharmaceutical composition being formed without melting the hydrophobic material or using a high shear mixer. While the pharmaceutical composition can be prepared by wet granulation, it is not preferred as such. In another embodiment, the present invention is directed to a method for administering a medicament to a patient, the method comprising (a) preparing a sustained release pharmaceutical composition in the form of a tablet, containing a pharmaceutically effective amount of a medicament, and a effective amount of hydrophobic material, to control the release of the medicament from the pharmaceutical composition by direct compression without melting said hydrophobic material or without using a high shear mixer, said pharmaceutical composition comprising a core containing said medicament and said hydrophobic material, but excludes any polymer capable of swelling, which causes disintegration of the tablet, and high concentration of low molecular weight excipients, soluble in water; said medicament has a solubility in water of less than about 1 gram per 10 mL of water at 25 ° C and is present in the pharmaceutical composition in an amount greater than about 25% by weight, and said hydrophobic material has a melting point ranging from about 40 ° C to about 100 ° C, and is present in an amount ranging from about 3% to about 20% by weight of the pharmaceutical composition, and in an amount by weight less than that of the medication, and (b) administer the product of step (a) to said patient.

DETAILED DESCRIPTION OF THE INVENTION As described above, one aspect of the present invention is directed to a sustained release formulation of a pharmaceutically active medicament containing a hydrophobic material having a melting point greater than about 40 ° C and less than about 100 ° C. As used in the present application, the terms "Drug", "medication" and "active substance" are used interchangeably. Moreover, the terms "controlled release" and "prolonged release" are used interchangeably, by "controlled release" it is meant, for the purposes of the present application, that the therapeutically active drug or drug is released from the formulation at a controlled rate, such that the therapeutically beneficial (below toxic levels) of the blood levels in the blood in an animal are maintained for an extended period of time, for example, by providing dosage forms of 4, 8, 12, 16 or 24 hours.The controlled release formulation of the present invention is to be administered to mammals in need of a treatment wherein the medicament present in the formulation is administered in pharmaceutically effective amounts.For mammals, it is meant a vertebrate of the class mammalia, is say, characterized by the possession of hair and mammary glands. Examples include, among others, cat, dog, horse, pig, goat, cow, humans and the like. The preferred mammal species to which the sustained release formulation of the present invention is to be administered is man. The present pharmaceutical compositions comprise a formulation in dosage unit form. The term "dosage unit form" as used in the present application, refers to a physically discrete unit, suitable as a unit dose for mammals, including humans, each unit containing an amount of active material previously determined, calculated to produce the desired effect in association with the hydrophobic material, the lubricant, if present, the excipient, if present, or other adjuvants, if present, as described herein. The present formulation is applicable to a wide variety of drugs or active medicaments suitable for use in sustained release formulation. Representative medications include antacids, anti-inflammatory substances, coronary vasodilators, cerebral vasodilators, psychotropics, antimaniacs, stimulants, anti-histamines, laxatives, decongestants, vitamins, gastrointestinal sedatives, anti-diarrheal preparations, anti-angina drugs, anti-arrhythmic vasodilators. , anti-hypertensive medications, vasoconstrictors and migraine treatments, anti-coagulants and anti-thrombotic, analgesic, antipyretic, hypnotic, sedative, anti-hemetic, anti-nausea, anticonvulsant, neuromuscular drugs, hyper and hypoglycemic agents, thyroid and anti-thyroid preparations, diuretics, anti-spasms, uterine relaxants , mineral and nutritional additives, anti-obesity drugs, anabolic drugs, erythropoietic drugs, anti-asthmatics, expectorants, cough suppressants, mucolytics, anti-uricémicos drugs and other drugs or substances that act locally in the mouth, such as topical analgesics, local anesthetics, or combination of them and the like. The present formulation may contain more than one active ingredient. The medicament used in the present invention has a low solubility in aqueous solution at 25 ° C and pressure of 1 atm. It has a solubility in water of less than about 1 gram per 10 mL of water at any pH existing in the gastrointestinal tract, typically between a pH of 1 and 7.5. However, if the drug is too insoluble in water, then the extended release formulation prepared therefrom, either too difficult to prepare, or does not effectively function as a sustained release pharmaceutical composition. Thus, the drug should have a solubility greater than about 100 mg / liter of water at 25 ° C. The medicament preferably has an average particle diameter from about 5 to about 300 microns, more preferably from about 20 to about 200 microns, and most preferably from about 30 to about 100 microns. Preferred medicaments are theophylline, ferrous sulfate, niacin, giuaifenesin, clarithromycin, valproic acid salts, especially Group IA salts thereof, for example, divalproex sodium, verapamil, dextromethorphan, diclofenac, or their pharmaceutically acceptable salts, isosorbide mononitrate, levodopa , carbidopa, naproxen, and the like. As known to a person skilled in the art, divalproex is a mixture of approximately 50% sodium (w / w) or another metal salt of group IA of valproic acid, and approximately 50% (w / w) of valproic acid. The drug is present in pharmaceutically effective amounts. It is preferred that the medicament be present in amounts ranging from about 25% to about 97% by weight of the pharmaceutical composition. The pharmaceutical carrier of the present invention is constituted by the hydrophobic material. The hydrophobic material is the prolonged release agent. The present pharmaceutical composition does not contain any hydrophobic prolonged release agent. The hydrophobic component comprises a water-insoluble material, similar to wax. The wax-like material contains a solid substance, generally insoluble, which has a waxy consistency. Of course, this must be ingestible, pharmaceutically acceptable and non-toxic. Many of these materials are known, and include fats and waxes. Wax, as used herein, is an organic low melt, high molecular weight blend or compound, and is solid at room temperature, and generally has a composition similar to grease and oils, except that it does not contain glycerides. The waxes include higher fatty acids, fatty acid esters, higher fatty alcohols, and mixtures thereof. Fats, on the other hand, are glyceryl esters of higher fatty acids. All of these are hydrophobic materials according to the term used in the present application. The hydrophobic material is present in effective amounts to delay the prolonged release. It is present in the pharmaceutical composition of the present invention in amounts ranging from about 3% to about 20% by weight of the pharmaceutical composition, preferably from about 3% to about 15% by weight of the pharmaceutical composition, preferably from about 3% to about 15% by weight, more preferably from about 5 to about 15%, and most preferably, from about 7 to about 12% by weight of the pharmaceutical composition. Thus, it is preferably present in less than 20% by weight. The hydrophobic material can consist of a component, or be a mixture of two or more hydrophobic components, such as they are defined here. The hydrophobic material has a melting scale above the temperature of the human body, which is about 37 ° C. The hydrophobic material used in the present invention has a melting point greater than about 40 ° C, and more preferably greater than about 45 ° C. However, it is critical that the hydrophobic material have a melting point above the temperature of the human body. Waxes with melting points close to body temperature, such as 37 ° C, represent stability problems in storage, as well as represent a risk of dose discharge. Therefore, the minimum temperature of the hydrophobic material is approximately 40 ° C, that is, a temperature above which the aforementioned problems do not manifest themselves. It is preferred that the melting point of the hydrophobic material ranges from about 40 ° C to about 100 ° C, and is even more preferred from about 45 ° C to about 90 ° C., especially more preferably from about 50 ° C to about 80 ° C, and much more preferred from about 55 ° C to about 75 ° C. It is important to note that the presence of lubricants and / or other hydrophobic material can affect the melting range. However, the melting range of the hydrophobic material when associated with these other materials in the formulation should not fall below the temperature of the human body.

It is preferred that the hydrophobic component have an average particle size of about 10 microns to about 200 microns. It is more preferred that the average particle size ranges from about 20 to about 150 microns, and much more preferably, that the average particle size ranges from about 30 to about 100 microns. As indicated hereinabove, the hydrophobic material useful in the present invention includes neutral waxes and fats. As will be described below, the hydrophobic material used in the present invention must contain at least 10 carbon atoms. Useful waxes include those obtained from plants and / or from animal sources, or as petroleum products, that is, obtained from natural sources. Examples of this type of preferred waxes include carnauba wax, candelilla wax, whale white, beeswax, montana wax, hydrogenated vegetable oil, lecithin, hydrogenated cottonseed oil, hydrogenated tallow, paraffin wax, Shellac wax, petrolatum , and the like, as well as synthetic waxes, for example, polyethylene, and the like. The hydrophobic materials also include fatty acid materials. The fatty acid materials are preferably of the class consisting of fatty acids having from 10 to 40 carbons. The fatty acids can be straight chain or branched, but it is preferred that they be straight chain. The fatty acids may not contain carbon-carbon double bonds, or may contain carbon-carbon double bonds. If they contain carbon-carbon double bonds, they preferably contain 1, 2, 3 or 4 carbon-carbon double bonds, and more preferably 1 or 2 carbon-carbon double bonds. Examples include stearic acid, palmitic acid, lauric acid, eleseaaric acids, a mixture of stearic acid and palmitic acid, for example, 85 weight percent stearic acid and 15 weight percent palmitic acid, and the like. The fatty acid materials also include fatty alcohols having from 16 to 44 carbon atoms. They can also be straight or branched chain, but it is preferred that they be straight chain. They can be completely saturated, or contain carbon-carbon double bonds, and more preferably 1 or 2 carbon-carbon double bonds. Examples include stearyl alcohol, cetyl alcohol, palmitoyl and the like. The fatty acid material also includes a fatty amine having from 13 to 45 carbons, and a fatty amide having from 11 to 45 carbons. The hydrophobic material also includes neutral lipids. Neutral lipids are preferably of the class consisting of monoglycerides, diglycerides, triglycerides. The monoglycerides, diglycerides and triglycerides are of the formula: where R-i is hydrogen or R2 is hydrogen or R3 is hydrogen or and R4, R5 and R6 independently are alkyl or alkenyl, said alkyl and alkenyl groups have from 9 to 39 carbon atoms, and wherein at least one of R t R2 and R3 is different from hydrogen. The alkyl groups and the alkenyl groups of R 4, R 5 and R 6 can be branched, and preferably are straight chain. The alkyl groups may contain 1, 2, 3, or 4 carbon-carbon double bonds, and if present, more preferably contain from 1 to 2 carbon-carbon double bonds. Examples include glyceryl behenate, glyceryl palitostearate, glyceryl monostearate, glycerides polyglycolized and the like. Apart from the glycerol esters, the hydrophobic material includes other fatty acid esters of polyhydric alcohols having two or more hydroxy groups in the molecules, which can be esterified to one or more fatty acids, as defined herein, and which have the characteristics described above, such as the melting point in the range indicated above, Examples of said polyhydric alcohols include alkenylene glycols, such as ethylene glycol and propylene glycol. It is preferred that the polyhydric alcohols contain two or three hydroxy groups. The polyhydroxy alcohol is esterified to at least one fatty acid, as defined herein. Preferred fatty acids have the formula R 4 COOH, wherein R 4 in each fatty acid may be the same or different, and is as defined herein above. The hydrophobic material also includes pharmaceutically acceptable salts of fatty acids, so long as the fatty acid has a melting point on the scale indicated hereinabove. The fatty acid is as defined above. Examples include magnesium stearate and calcium and aluminum palmitic acid salts and the like. It is preferred that the hydrophobic material is a fatty acid, or its salt, fatty alcohol, a wax or a neutral lipid. It is more preferred that the hydrophobic material is a mono, di or tri glyceride, which is esterified to a fatty acid. The most preferred hydrophobic materials are behenate of glyceryl, glyceryl palmitostearate, glyceryl monostearate, polycyclic glycerides, stearic acid, hydrogenated vegetable oil, cetyl alcohol or mixtures thereof. The most preferred hydrophobic material is glyceryl behenate. The present pharmaceutical composition excludes in the core of the tablet in which the medicament and the prolonged-release agent described above are present, any ingredient that may cause disintegration of the tablet. This includes any polymer, such as hydrophilic polymers capable of swelling, or hydrophobic carbohydrate polymers, such as those described herein below. Moreover, since high concentrations of water-soluble excipients of low molecular weight can cause disintegration of the tablet, they are also excluded in the core. As used herein, the term "high concentration of low molecular weight water soluble excipients" refers to low molecular weight water soluble excipients that are present in concentrations greater than or equal to about 20% (w / w) of the Tablet. In other words, the core of the pharmaceutical compositions of the present invention may include low molecular weight excipients, provided that their concentration is less than about 20% by weight of the tablet. It is more preferred that the concentration of them be less than about 10% by weight of the tablet (weight / weight). Water-soluble excipients of low molecular weight are well known to a person familiar with the material.

As defined herein, a "low molecular weight water soluble excipient" refers to a water soluble excipient having a molecular weight of less than about 1000 dalton. Examples of low molecular weight water soluble excipients include lactose, sucrose, glucose, citric acid, sodium phosphate, regulating agents and the like. Thus, if the low molecular weight excipient has a solubility in water greater than about 1 g in 20 ml of water at 25 ° C and pressure of 1 atmosphere, and more preferably more than about 1 gram in 10 ml of water at 25 ° C. C and pressure of 1 atmosphere, is not present in the core of the tablet in high concentrations, as defined above. The low molecular weight water soluble excipient is present in less than about 20 percent by weight of the tablet, and more preferably less than about 10% by weight of the tablet. By low molecular weight excipient, it is meant that an excipient has a molecular weight of less than 1000 dalton. Thus, the present compositions preferably do not contain any polymer capable of swelling, or any low molecular weight excipients, such as lactose, in high concentration. Thus, the hydrophobic material excludes hydrophobic carbohydrate polymers, especially since they do not melt in the aforementioned ranges. As defined herein, the hydrophobic carbohydrate polymers are hydrophobic cellulose derivatives in which the R portion of the cellulose-R or the cellulose-ROH or other derivatives R are an aliphatic acyl group of 2 to 100 carbon atoms or more, or aliphatic alkyl containing from 1 to 100 carbons or more, or chitin. Examples of hydrophobic polymers that are excluded from the hydrophobic material as used herein are ethylcellulose, propylcellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate propionate, and the like. Moreover, the hydrophobic material excludes the hydrated alkyl cellulose, for example, hydroxy-alkyl cellulose. Since the sustained release retarding agent of the pharmaceutical composition of the present invention is a hydrophobic material, and excludes swelling polymers, it excludes hydrophilic compounds as a prolonged release agent, including hydrocolloids, as well as any gel forming substances., for example, xanthan gum, guar gum, hydroxypropylmethylcellulose, methacrylate or acrylate polymers, and the like. In addition, it excludes proteins. Without wishing to be limited, it is believed that controlled release of the drug is achieved because of the presence of a non-disintegrating dose, which becomes partially insoluble due to the wax. The wax helps control the release. Being insoluble in water, the wax makes the pharmaceutical composition containing it, at least partially insoluble, if not totally insoluble in water. If the excipient is also insoluble, together the wax and the excipient strengthen the tablet. The rate of dissolution or diffusion is controlled both by controlled erosion and by controlled solubility.

On the other hand, any ingredient that can break the surfaces of the tablet, such as polymers that can swell or disintegrating agents, will weaken the matrix (core) and cause the tablet to disintegrate. In fact, it is believed that the reason for using high concentrations of wax in the prior art is because it contained inflatable or disintegrating agents. Other causes of disintegration result in high levels of soluble ingredients, including low molecular weight water soluble excipients, discussed hereinabove. However, polymers, whether in soluble or insoluble form, which do not swell, are not excluded hereby. invention. Moreover, water-soluble excipients having molecular weights greater than 1000 dalton are also not excluded, and may be present in the tablet of the present pharmaceutical composition, including at its core concentrations greater than or less than 20% (w / w). by weight of the tablet. Thus, for example, maltodextrin is soluble in water, and is a polymer, but does not cause disintegration, because it does not swell. It may be present in the tablet, including the core, in concentrations greater than, or less than, 20% by weight. Also polyethylene glycols of molecular weight greater than 1000 dalton may be present in the pharmaceutical compositions, including the core of the tablet, in concentrations greater than or less than about 20 percent by weight of the tablet. These are completely soluble in water, but can used because they do not swell and the high molecular weight of the polyethylene glycols slows the disintegration. Moreover, if the coating is present, it may contain inflatable polymers, or disintegrating agents, including water-soluble excipients of low molecular weight, since these are outside (on the surface) of the tablet. Thus, polymers capable of swelling, although they may not be present in the core of the tablet, may be present in the coating of the pharmaceutical composition of the present invention. Moreover, the restriction in the concentrations of the water-soluble excipients refers to their presence in the core of the pharmaceutical compositions. There is no restriction on them if the water-soluble excipients are present in the coating. However, it is preferred that the tablet does not contain a coating. But, if a coating is present, the low molecular weight water soluble excipients and the swellable polymers are each preferably present in less than about 20% of the pharmaceutical composition, and more preferably in less than about 10% of the pharmaceutical composition. . In addition, if a coating is present, it is preferred that it does not contain disintegrating agents and it is also preferred that it does not contain polymers that swell with water. Without wishing to be limited, it is believed that the hydrophobic material interacts with the drug and delays its release from the oral dosage form. More specifically, it is believed that the hydrophobic substances used in the present invention form water-insoluble matrices, which remain intact for an extended period of time, allowing the drug to be leached or diffused at a controlled rate. The inventor has found that the amount by weight of the hydrophobic material used is less than that of the drug. Thus, the weight ratio of hydrophobic material to medicament is less than 1: 1 by weight. It is preferred that the weight ratio of medicament to hydrophobic material ranges from about 9: 1 to about 5: 4. Without wishing to be limited, it is believed that the smaller amount of hydrophobic material makes the dosage form more stable and physically stronger. The concentration of hydrophobic material used is reasonably small, allowing the formation of very hard tablets, which can withstand various rigors. It is also believed, without wishing to be limited, that the use of hydrophobic material having melting point ranges higher than the temperature of the human body, also contribute to the stability of the dosage form and to the predictability of the in vivo release of the medicament. Without wishing to be limited, it is believed that the heat generated during compression may cause softening of the wax, helping it to form a continuous matrix and particle coating of the ingredients of the formulation. It is believed that the dosage form produced by the process described above, without wishing to be limited, releases the drug by erosion and diffusion of an essentially non-disintegrating matrix. The present formulation also contains optional components. For example, although it is not necessary, in a preferred embodiment, the present formulation additionally contains a lubricant that is typically used in pharmaceutical techniques for oral tablets. As used herein, the term "lubricant" refers to a material that can reduce friction between the mold walls and the faces of the die, which occurs during compression and ejection of a tablet. The lubricant prevents adhesion of the tablet material to the faces of the die and to the walls of the mold. As used herein, the term "lubricant" includes anti-adherents. Examples of lubricants include stearate salts, for example, alkali metal, alkaline earth metal and transition salts thereof, eg, calcium, magnesium, or zinc, stearic acid, polyethylene oxide, talc, hydrogenated vegetable oil, and vegetable oil derivatives, smoked silica, silicones, high molecular weight polyalkylene glycol, for example, high molecular weight polyethylene glycol, propylene glycol monoesters, saturated fatty acids containing about 8 to 22 carbon atoms and preferably 16 to 20 carbon atoms . Preferred lubricants are stearate salts, stearic acid, talc and the like. When a lubricant is used, it is present in an effective amount to lubricate. Preferably the lubricant is present in amounts ranging from about 0.1% to about 5% by weight, and more preferably from 1% to about 3% by weight of the tablet. Another optional ingredient is an inert filler (excipient). The filler may be substantially water soluble or insoluble in water. A filler is used if needed or desired, although it is not necessary for the present formulation. The bulking agents used in the present formulation are those that are typically used in the pharmaceutical art for oral dosage forms, such as tablets. Examples include calcium salts, such as calcium sulfate, dicalcium phosphate, tricalcium phosphate, calcium lactate, calcium gluconate, and the like, glycerol phosphate, citrates, and mixtures thereof, and the like. However, the inert filler of the sustained release formulation of the present invention may contain a pharmaceutically acceptable saccharide, including a monosaccharide, a disaccharide, or a polyhydric alcohol and / or mixtures of any of the foregoing. Examples thereof include sucrose, dextrose, polydextrose, maltodextrin, microcrystalline cellulose, fructose, xylitol, sorbitol, mixtures thereof and the like. The preferred excipient is maltodextrin. Thus, another embodiment of the present invention contains a pharmaceutically effective amount of a medicament and a hydrophobic material such as sustained release agent and maltodextrin, in the absence of lactose and hydrophobic carbohydrate polymers, said medicament is present in a amount greater than about 25% (w / w) of the pharmaceutical composition, and has a solubility in water of less than about 1 gram per 10 ml of water at 25 ° C and 1 atm pressure, said hydrophobic material has a point of melt spanning from at least about 40 ° C to about 100 ° C at a pressure of 1 atmosphere, and is present in an amount effective to control the release of the drug, said hydrophobic material being present in an amount ranging from about 3% up to about 20% by weight of the pharmaceutical composition and in a smaller amount by weight than that of said medicament. It is also preferred that the pharmaceutical composition does not contain lactose. Lactose is undesirable for several reasons. First, many people who suffer from lactose intolerance will have difficulty digesting an oral dosage form that contains it. further, lactose interacts with several drugs that contain a certain functional group, for example, amines, in them. Although they can be used, it is preferred that the pharmaceutical composition of the present invention does not contain a disaccharide. The bulking agent, if present, is present in amounts ranging from about 0% (but greater than zero) to about 72% by weight. Other optional ingredients (adjuvants), which are also commonly used in pharmaceuticals, may also be present, such as coloring agents, preservatives (e.g. methylparabenos), artificial sweeteners, flavorings, antioxidant agents and the like. Artificial sweeteners include sodium saccharin, aspartame, dipotassium glycyrrhizinate, stevia, thaumatin and the like, but are not limited thereto. The flavors include various colors for food, for example, FD & C, such as Yellow FD & C No. 6, food coloring lacquers, and the like, but are not limited thereto. Examples of antioxidants include ascorbic acid, sodium metabisulfite, and the like. These optional ingredients, if present, are preferably present in amounts ranging from about 0.1% to about 5% by weight of the tablet, and more preferably less than about 3% (w / w) of the tablet. However, it is preferred that the component in the highest concentration be the medicine. Moreover, it is preferred that the sum of medicament and hydrophobic material is greater than 45% by weight of the oral dosage form, and more preferably greater than about 60% by weight of the pharmaceutical composition. The present formulation of the present invention is prepared by mixing the medicament with the hydrophobic and lubricating material, if present, the bulking agent, if present, and the adjuvants, if present. The ingredients are mixed in a typical mixer that is normally used in pharmaceutical techniques, such as a Hobart mixer, V mixer, a planetary mixer, twin drum mixer and the like.

The ingredients are mixed together typically near room temperature; no additional heating is necessary, beyond which slight changes in temperature can be used. It is preferred that the mixture be made at temperatures ranging from about 10 ° C to about 35 ° C. The hydrophobic material is not mixed. Moreover, if the components are heated, the elevated temperature used in the present process is not yet substantially close to the melting point of the hydrophobic material. The pharmaceutical composition of the present invention is not prepared by thermal infusion. The ingredients in the formulation are preferably mixed together in a large batch, using techniques well known in the pharmaceutical arts, and intimately intermixed until the mixture is homogeneous with respect to the drug. The term "homogeneous" with respect to the drug is used to denote that several components are substantially uniform throughout the invention, that is, a substantially homogeneous mixture is formed. When the mixture is homogeneous, the dosage unit form is prepared by techniques known in the art. Thus, the mixture can be made into a granule, capsule, pill, tablet or other form of dosage unit using conventional techniques known in the art. The preferred oral dosage unit form is a tablet. The tablet can be prepared by the following procedure. An amount of unit dose of the homogeneous mixture it is compressed into a tablet form using a tablet machine commonly used in pharmaceutical techniques. More specifically, the mixture is fed into the mold of a tablet press and sufficient pressure is applied to form a solid tablet. This pressure can vary, and typically ranges from about 70.3 kg / cm2 to about 421.84 kg / cm2, and preferably about 140.6 kg / cm2. The solid formulation according to the present invention is compressed to a sufficient hardness to prevent premature entry of the aqueous medium into the tablet. Preferably, the formulation is compressed into a tablet form which is in the order of 5-20 Kp and more preferably 8-20 Kp, as determined by a Schleuniger hardness test. In one variation, all the previous steps are repeated, except that the mixing is done initially in the absence of a lubricant, if a lubricant is going to be added to the formulation. When the mixture is homogeneous with respect to the drug, then the lubricant is added and mixing is continued until the lubricant, if present, can be dispersed of substantially uniform mantle in the mixture. The mixing is then suspended, and the mixture is processed immediately thereafter in a dosage unit form. For example, it can be compressed into a tablet, as described above. Before the mixing step, the individual components can be optionally milled, for example, passed through a sieve, mesh, etc., to reduce the size of its particles. Alternatively, the mixture is substantially uniformly intermixed prior to the formation of the dosage unit form. For example, if it is a tablet, the mixture can be ground before the compression step. In the process described herein, unlike most methods, the hydrophobic material does not melt, either separately from the other components of the pharmaceutical composition or with other components of the pharmaceutical composition. More specifically, in the process of the present invention, the components in the mixing step are not heated to temperatures corresponding to the melting point of the hydrophobic material or substantially close to it. The present invention avoids the disadvantages associated with heat fusion. First, the heat in the labile compounds will decompose the molten hydrophobic material, for example, wax. In addition, it is expensive and dangerous to adopt this molten wax technique for mass production. Apart from the dangers of working with large amounts of molten material, there is the difficulty of working with the solidified hardened drug mixture, which must be removed from the mixing and sizing container. Additionally, the sizing of the solidified drug mixture to harden exposes the previously enclosed medicament, thus departing from its controlled release profile in subsequent dosage forms. A further disadvantage of the method known in the art for preparing Prolonged-release tablets, in particular, by means of the molten heat process, is that a high-dose drug with satisfactory release characteristics can not easily be prepared. The present invention has found that it is capable of preparing a pharmaceutical composition having excellent prolonged release properties, without melting the hydrophobic component, for example, wax. In addition, the present inventor has found that he is able to obtain a substantially homogeneous mixture without subjecting the components to high shear mixing. Moreover, as indicated above, the methodology described above is simple and economical, and avoids the expense associated with the high shear mixer. In addition, the present inventor has found that the present method provides a pharmaceutical composition with excellent prolonged release properties. Moreover, the methodology used in the present invention to prepare the pharmaceutical composition does not use wet granulation. Thus, the present process does not have the disadvantages associated with wet granulation. He avoids the dangers associated with the use of toxic or flammable solvents that are used in wet granulation methods. This method used in the present process for preparing the extended release pharmaceutical composition of the present invention has several advantages. It is a simple and efficient manufacturing method, more if the composition was prepared by melting the hydrophobic material or using a high shear mixer. The method solves the disadvantages of formulation with hydrophobic material, for example, waxes, such as dimensional stability, with respect to heat and abrasion. The hydrophobic material does not melt or heat to just below the melting temperatures, such as by the use of techniques such as radiation heating. In a preferred embodiment, the hydrophobic material is mixed with the other components at temperatures no higher than slightly elevated above room temperature, but substantially lower than the melting temperatures of the hydrophobic material. This technique minimizes heat and energy in the manufacture of dose unit forms of the present invention, relative to those used in the prior art, thereby making the present process more efficient. In a preferred embodiment, granulating solvents are not required, therefore in this embodiment, the present methods avoid the risks of toxicity and fires that are potentially present when wet granulation methods are used to prepare sustained release drugs. After the unit dosage form is formed, for example, tablet, it can be coated with materials that are normally used in the pharmaceutical field, if desired. If they are to be coated, the coating is prepared by techniques known in the art, but the hydrophobic material that is used as an extended release agent is not present in the coating. Without However, the formulation of the present invention is preferably uncoated. The dosage unit form prepared by the present invention has the properties commonly found in the pharmaceutical material. For example, if the dosage unit form is a tablet, the tablet product is obtained with the hardness and brittleness typically desired for pharmaceutical tablets. The hardness is preferably 5-25 Kp, and more preferably 8-20 Kp. The present formulation in dosage unit form, e.g., tablet form, has an excellent drug release profile. The drug release profile of the pharmaceutical formulation of the present invention is non-linear. For example, it has a controlled and prolonged action, and a pattern of regular delay determined previously, in such a way that the medication is available for a period of up to 36 hours, depending on the type of dosage unit form used, the precise size of the medication. the dosage unit form, the identity of the active ingredient, the aqueous solubility of the active ingredient, the hardness and the composition of the particular carrier. For example, according to the process of the present invention, a controlled release pharmaceutical composition can be prepared wherein the release time is from 2 to 4 hours, from 8 to 10 hours, from 15 to 18 hours, from 20 to 24 hours, etc., as desired. Additionally, the release profile of each formulation is substantially uniform.

Finally, if the oral dosage form is a tablet, the tablets prepared according to the present invention are hard and dense, are non-brittle and provide controlled and prolonged release for an extended period. The solid dry forms prepared by the present invention are stable, and their release rate does not change to a significant extent (if changed), during an extended storage period. The extended-release medicament is provided in solid form, conveniently in a dosage unit form. It is preferred to provide the sustained release medicament in the form of a solid dose unit, for oral administration, especially in the form of a tablet. Preferably, it is directed to release the pharmacologically active ingredient slowly or in accordance with a prescribed rate after ingestion within the body, as the formulation progresses along the gastrointestinal tract. With respect to this, it is considered that the gastrointestinal tract is the abdominal part of the alimentary canal, that is, the lower end of the esophagus, the stomach and the intestines. The doses of a formulation administered to a mammal in need thereof according to the invention correspond to the normal doses of the particular active ingredient known to the skilled artisan. The precise amount of drug administered to a patient will depend on a number of factors, including the age of the patient, the severity of the condition and the past medical history, among other factors, and will always rest on discretion of the doctor who administers it. As a guideline on an appropriate dose, reference is made to the Physicians Desk Reference. The pharmaceutical composition formed preferably is not multilayer, but is single layer. Unless otherwise indicated, all percentages are percentages by weight in relation to the oral dosage form. Moreover, unless otherwise indicated, the active ingredient, the hydrophobic material, and any other optional ingredients, eg, lubricant, excipient, and other ingredients, are calculated on a dry weight basis, without reference to water. or to another component present. Also, as used here, the singular will refer to the plural, and vice versa. The following non-limiting examples further illustrate the present invention.

EXAMPLE 1 Ferrous sulfate (160 mg), glyceryl behenate (30 mg) and maltodextrin (110 mg) were thoroughly mixed together in a V mixer for one hour and compressed into a tablet using a rotary tablet press. The solution was determined using I USP apparatus in water. The release profile is as follows: Time (in hours)% drug release (weight / weight) 1 36 2 58 3 72 4 82 EXAMPLES 2 - 6 The following examples were mixed in an appropriate mixer for 1 hour: The resulting mixture was compressed into a tablet using a rotary tablet press. The dissolution of each formulation was determined using I USP apparatus in water. The release profile is as follows: % Released (weight / weight) EXAMPLE 7 Clarithromyne (500 mg), glyceryl behenate (25 mg), silicified microcrystalline cellulose (220.15 mg), and maltodextrin (220.15 mg) were passed twice through a 40 mesh screen. The different ingredients were mixed in a blender. Double cone for 30 minutes. Magnesium stearate (14.7 mg) was added to the mixture, which was stirred for another fifteen minutes. The mixture was compressed in a tablet. The tablets were punched out using a 20 × 10 mm capsule-shaped die. The tablet contained 500 mg of clarithromycin and 980 mg of total weight.

The solution was determined using I USP apparatus in acetate buffer, with pH 5.0. The release profile was as follows: EXAMPLE 8 One tablet of divalproex sodium was prepared as follows: Divalproex sodium (576.21 mg), glyceryl behenate (190 mg), polyvinyl pyrrolidone (47.5 mg), dibasic calcium phosphate dihydrate (44.4 mg), silicified microcrystalline cellulose ( 44.4 mg) and aerosol (19 mg), twice through a 40 mesh screen. The various ingredients were mixed in a double cone mixer for 30 minutes. Magnesium stearate (28.5 mg) was added to the mixture, and the mixture was stirred during another fifteen minutes The mixture was compressed in a tablet. The tablets were punched out using a 20 × 10 mm capsule-shaped die. The tablet contained 576.21 mg of divalproex sodium and 950 mg of total weight. The solution was determined using apparatus I U.S.P in water. The release profile was as follows: The above preferred embodiments and examples are given to illustrate the scope and spirit of the present invention. These modalities and examples will make evident to the experts of the subject, other modalities and examples. The other embodiments and examples are within what is contemplated by the present invention. Therefore, the present invention will only be limited by the appended claims.

Claims (1)

1. CLAIMS 1. A prolonged release pharmaceutical composition in the form of tablets, comprising a coating containing a pharmaceutically effective amount of a medicament, and a hydrophobic material as a prolonged release agent, and excluding a polymer capable of swelling, which causes disintegration of the tablet, and high concentration of water-soluble excipient of low molecular weight, said medicament is present in an amount greater than about 25% of the pharmaceutical composition and has a solubility in water of less than about 1 gram per 10 ml_ of water at 25 ° C and 1 atm, and more than about 100 mg per 1 liter of water at 25 ° C and 1 atm. Said hydrophobic material has a melting point ranging from at least about 40 ° C to about 100 ° C under pressure of 1 atm, and is present in an amount ranging from about 3% to about 20% by weight of the pharmaceutical composition , and in an amount by weight less than that of the medication. 2. The pharmaceutical composition according to claim 1, further characterized in that the tablet is not coated. 3. The pharmaceutical composition according to claim 1, further characterized in that the hydrophobic material is present in an amount ranging from approximately 5% to about 15% by weight of the pharmaceutical composition. 4. The pharmaceutical composition according to claim 3, further characterized in that the hydrophobic material is present in an amount ranging from about 7% to about 12% by weight of the pharmaceutical composition. 5. The pharmaceutical composition according to claim 1, further characterized in that the weight ratio of drug to hydrophobic material ranges from about 9: 1 to about 5: 4. 6. The pharmaceutical composition according to claim 1, further characterized in that the melting point of the hydrophobic material ranges from about 40 ° C to about 90 ° C. 7. The pharmaceutical composition according to claim 6, further characterized in that the melting point of the hydrophobic material ranges from about 50 ° C to about 80 ° C. 8. The pharmaceutical composition according to claim 7, further characterized in that the melting point of the hydrophobic material ranges from about 55 ° C to about 75 ° C. 9. The pharmaceutical composition according to claim 1, further characterized in that the hydrophobic material it has an average particle size ranging from about 10 microns to about 200 microns. 10. The pharmaceutical composition according to claim 9, further characterized in that the hydrophobic material has an average particle size ranging from about 30 to about 100 microns. 11. The pharmaceutical composition according to claim 1, further characterized in that the medicament is present in an amount ranging from about 25% to about 97% by weight of the pharmaceutical composition. 12. The pharmaceutical composition according to claim 11, further characterized in that the medicament is present in an amount ranging from about 35% to about 90% by weight of the pharmaceutical composition. The pharmaceutical composition according to claim 12, further characterized in that the medicament is present in an amount ranging from about 40% to about 85% by weight of the pharmaceutical composition. 14. The pharmaceutical composition according to claim 1, further characterized in that a lubricant is additionally present. 15. The pharmaceutical composition according to the claim 14, further characterized in that an excipient is additionally present. 16. The pharmaceutical composition according to claim 1, further characterized in that an excipient is additionally present. 17. The pharmaceutical composition according to claim 15, further characterized in that the excipient is maltodextrin. 18. The pharmaceutical composition according to claim 16, further characterized in that the excipient is maltodextrin. 19. The pharmaceutical composition according to claim 1, further characterized in that the hydrophobic material is a fatty acid or a salt thereof, or a monoglyceride, diglyceride or triglyceride. 20. The pharmaceutical composition according to claim 1, further characterized in that the hydrophobic material is glyceryl behenate, hydrogenated vegetable oil, stearic acid, glyceryl monostearate, glycerylpalmito stearate or cetyl alcohol. The pharmaceutical composition according to claim 1, further characterized in that the hydrophobic material is a fatty acid having from 10 to 30 carbons or salts thereof, a fatty alcohol having from 10 to 44 carbon atoms, or where Ri is hydrogen or R2 is hydrogen or R3 is hydrogen or R4, R5 and e independently are alkyl or alkenyl, said alkyl and alkenyl groups have from 9 to 29 carbon atoms, and wherein at least one of R; R2 and R3 is different from hydrogen. 22. The pharmaceutical composition according to claim 1, further characterized in that the medicament is theophylline or a pharmaceutically acceptable salt thereof, ferrous sulfate, clarithomycin or divalproex. 23. The pharmaceutical composition according to claim 22, further characterized in that the material Hydrophobic is glyceryl behenate. 24. Method for preparing a prolonged-release pharmaceutical composition in oral dosage form, comprising (a) mixing a medicament and a hydrophobic material, and optionally a lubricant, and optionally an excipient, and optionally a polymeric adjuvant, to form a mixture substantially homogeneous and uniform, said mixture excludes a polymer capable of swelling, which causes disintegration of the tablet, and high concentration of low molecular weight excipient, said medicament being present in an amount greater than about 25% by weight of the pharmaceutical composition, and has a solubility in water of less than about 1 gram per 10 mL of water at 25 ° C and 1 atm, and greater than about 100 mg per liter of water at 25 ° C and 1 atmosphere, said hydrophobic material having a melting point which covers approximately from the least 40 ° C to approximately 100 ° C at a pressure of 1 atmosphere, and is present in an amount that ab arca from about 3% to about 20% by weight of the pharmaceutical composition, and in an amount by weight less than that of the medicament; and (b) compressing the product of step (a) to form a tablet therefrom, said pharmaceutical composition being formed in the absence of melting of the hydrophobic material or the use of a high shear mixer, or heating to temperatures slightly below of the melting point of the hydrophobic material. 25. The method according to claim 24, further characterized in that a lubricant is additionally present. 26. The method according to claim 24, further characterized in that the medicament, hydrophobic material and optionally an excipient and optionally an adjuvant, are mixed together to form a substantially homogenous and uniform first mixture, and a lubricant is added in effective amounts to lubrication, to said first mixture, and mixed with it to form a second substantially uniform and homogeneous mixture, wherein the second mixture is compressed to form a tablet. 27. The method according to claim 24, further characterized in that an excipient is additionally present. 28. The method according to claim 26, further characterized in that an excipient is additionally present. 29. The method according to claim 27, further characterized in that the excipient is maitodextrin. 30. The method according to claim 28, further characterized in that the excipient is maitodextrin. The method according to claim 24, further characterized in that the hydrophobic material is present in an amount ranging from about 5% up to about 15% by weight of the pharmaceutical composition. 32. The method according to claim 31, further characterized in that the hydrophobic material is present in an amount ranging from about 7% to about 12% by weight of the pharmaceutical composition. 33. The method according to claim 24, further characterized in that the weight ratio of the drug to the hydrophobic material ranges from about 9: 1 to about 5: 4. 34. The method according to claim 24, further characterized in that the melting point of the hydrophobic material ranges from about 40 ° C to about 90 ° C. The method according to claim 34, further characterized in that the melting point of the hydrophobic material ranges from about 50 ° C to about 80 ° C. 36. The method according to claim 35, further characterized in that the melting point of the hydrophobic material ranges from about 55 ° C to about 75 ° C. 37. The method according to claim 24, further characterized in that the hydrophobic material has an average particle size ranging from about 10 microns to about 200 microns. 38. The method according to claim 37, further characterized in that the hydrophobic material has an average particle size ranging from about 30 to about 100 microns. 39. The method according to claim 24, further characterized in that the medicament is present in an amount ranging from about 25% to about 97% by weight of the pharmaceutical composition. 40. The method according to claim 39, further characterized in that the medicament is present in an amount ranging from about 35% to about 90% by weight of the pharmaceutical composition. 41. The method according to claim 40, further characterized in that the medicament is present in an amount ranging from about 40% to about 85% by weight of the pharmaceutical composition. 42. The method according to claim 24, further characterized in that the hydrophobic material is a wax, a fatty acid or salt thereof, or a monoglyceride, diglyceride or triglyceride. 43. The method according to claim 24, further characterized in that the hydrophobic material is glyceryl behenate, hydrogenated vegetable oil, stearic acid, glyceryl monostearate, glycerylpalmito stearate or cetyl alcohol. 44. The method according to claim 24, further characterized in that the hydrophobic material is a fatty acid having from 10 to 30 carbons or salt thereof, a fatty alcohol having from 10 to 44 carbon atoms, or CKrOr ^ CH-Ol¾ CH-Oi¾ where † 4 Ri is hydrogen or R2 is hydrogen or R3 is hydrogen or R4, 5 and 6 independently are lower alkyl or lower alkenyl, having from 10 to 29 carbon atoms, and wherein at least one of Ri, R2 and R3 is different from hydrogen. 45. The method according to claim 24, further characterized in that the medicament is theophye or a pharmaceutically acceptable salt thereof, ferrous sulfate, clarithomycin or divalproex. 46. The method according to claim 45, further characterized in that the hydrophobic material is glyceryl behenate.