JP2006514672A - Controlled release formulation containing hydrophobic substance as sustained release agent - Google Patents

Abstract

The present invention is a sustained release pharmaceutical composition in an oral dosage form consisting essentially of a pharmaceutically effective amount of a drug and a hydrophobic substance, wherein no lactose or hydrophobic carbohydrate polymer is present, comprising the drug Is present in an amount greater than about 25% of the pharmaceutical composition and has a water solubility of greater than about 1 gram per 10 mL of water at 25 ° C. and the hydrophobic material is at least about 40 ° C. to about 100 at 1 atm. Having a melting point in the range of 0 ° C. and present in an amount ranging from about 3% to about 20% by weight of the pharmaceutical composition and in an amount less than the drug, wherein the hydrophobic substance is the pharmaceutical composition A sustained release pharmaceutical composition that is not present in the coating of the product; said pharmaceutical composition compresses directly in the absence of a hydrophobic substance, or melts said hydrophobic substance, or Sustained release pharmaceutical composition produced by use of a high cutting stirrer Oriented. The present invention is also directed to a method for producing the pharmaceutical composition.

Description

  The present invention relates to a controlled release formulation in the oral dosage form, preferably in tablet form, containing a hydrophobic substance as a sustained release agent.

BACKGROUND OF THE INVENTION A major advantage for both patients and physicians is that a pharmaceutical product can be administered in a minimal number of daily doses by releasing the drug uniformly over the desired long time. It is to become. This effect is achieved by using a sustained release or slowly releasing composition. A sustained release or slow release composition comprising a pharmaceutical agent or other active ingredient is designed to contain the agent at a higher concentration, and can be used for extended release to the gastrointestinal tract of a human or animal over time. Manufactured in such a way that a slow release is achieved.

  A well-absorbed oral sustained release or slowly releasing therapeutic drug dosage form has inherent advantages over conventional immediate release dosage forms. The benefits include fewer drug doses, and the resulting patient compliance with therapy, a more sustained drug blood concentration response, therapeutic effects from smaller doses of drugs, and reduced side effects. Including. By providing a slow and stable release of the drug over time, a smoother and more sustained blood concentration response is achieved, thereby mitigating or eliminating the sudden rise in absorbed drug concentration Is done.

  For this purpose, a controlled release formulation must meet several criteria; that is, it must provide a uniform and constant dissolution of the drug, and it is long-lasting. Must be effective over time. More importantly, such a formulation is easy to make, the manufacturing method is reproducible, and the products produced by the manufacturing method are uniform. Furthermore, when different drugs are used as active ingredients in the sustained release formulation, it is important that the manufacturing process can be easily adapted and adapted to these various drugs.

  Various hydrophilic and hydrophobic materials, including polymers, are utilized in the manufacture of sustained release formulations. In addition, they are produced by various methods, such as solvent evaporation, heat melting, direct compression and wet granulation. Nevertheless, it is well known that the materials used to achieve such controlled release, as well as the method of manufacture, have a significant effect on the controlled release performance of oral dosage forms. For example, ethylcellulose, a hydrophobic polymer, is used to achieve controlled release of drugs. However, its release profile differs significantly when it is used as a coating material and when it is used as a directly compressible powder. In addition, when matrix type tablets are manufactured using wet granulation with ethylcellulose, the release profile can be obtained by using ethylcellulose directly as a compressible powder or by coating with ethylcellulose. The release profile exhibited by the controlled release oral dosage form produced by use as a substance is significantly different. Moreover, if the hydrophobic material is melted in the process of producing the sustained release pharmaceutical composition, its release profile is different from the controlled release pharmaceutical composition produced by different methods. These differences in release profiles indicate that pharmaceutical compositions produced by various methods are “not the same” and “different”.

  These differences in release profile are not unique to pharmaceutical compositions containing ethylcellulose; the release profile of pharmaceutical compositions containing other hydrophobic substances such as waxes or higher fatty acids or alcohols as controlled release agents is It is not only dependent on the identity of the hydrophobic substance as a controlled release agent, but also on the method of producing the pharmaceutical composition.

  Hydrophobic substances are used to control drug release. For example, waxes and lipids are used as coating materials to delay drug release. For example, GATTEFOSSE, the manufacturer of COMPLITOL 888 (COMPRITOL® 888, glyceryl behenate), has completed Compritol® for granules and spheres containing theophylline. The effect of coating 888 with a fluid bed equipment at different concentrations as hot melt coating was investigated. The wax coating concentrations of the spheres were 2%, 6% and 10% by weight, respectively. The release profile in water was measured. At a concentration of 2% (w / w) of the wax, 85% theophylline was released within 1 hour. However, with 6% wax, 55% theophylline is released within the first hour, 35% of it is released within 5 minutes, and with 10% (w / w) wax, 38% Theophylline was released within the first hour, 28% of which was released in 5 minutes. Given the many processes used in making this type of formulation, this is not an efficient way to form a controlled release product and the inventor A search was conducted to find a more efficient process for producing controlled release tablets containing as The inventor has also conducted a search to find a method for controlling the release of a drug by mixing a hydrophobic substance with the drug without including a wax in the coating.

  There is much literature on the use of waxes in controlled release compositions when mixed with drugs. A common method for the manufacture of sustained release formulations in oral dosage forms using wax as a controlled release material mixed with the drug is as follows: (a) the drug is melted with the wax and then cooled. Crushing the melt and finally tableting after mixing with excipients; (b) using wet granulation techniques and utilizing organic solvent as granulation medium; (C) mixing the drug and wax in a high shear mixture and using the heat generated during the process to achieve a homogeneous mixture; and (d) in the presence of the drug. Use heat radiation to achieve melting of the wax. All of these methods are cumbersome and dangerous.

  Most of these techniques have used many waxes to achieve a suitable controlled release formulation, which wax is generally at a high concentration, for example, from 30% (w / w) of the dosage form. Larger amounts are present in weight ratios greater than 1: 1 with respect to the drug. For example, Abdallah is one of three selected lipophilic polymers, precilol ATO5 (Precirol®), in Alex. J. Pharm. 1992, 6, 243-246. About ATO5, glyceryl palmito stearate), precilol wL-2155 (Precirol® wL-2155, glyceryl stearate) and Compritol 888 (Compritol® 888, glyceryl behenate) Evaluating with respect to the manufacture of extended release compositions of ibuprofen. The tablets were made by melting the drug and other ingredients with the polymer, cooling the melt, and compressing the cooled melt. He found that 200-315 micron-sized granules made using any of the three polymers at concentrations of either 10% by weight or 20% by weight did not show the effect of delaying release. The granule preparations made with the lipids identified above in these amounts completely released the drug within 30 minutes. However, at a 50% concentration of Compritol® 888, the granules exhibited a somewhat adequate sustained release profile. However, producing tablets with such a large amount of wax inevitably results in tablets that are too large, thus making swallowing more difficult and especially more difficult for older patients. The inventors have therefore sought a means to produce sustained release formulations containing considerably smaller amounts of hydrophobic substances.

  Perez et al., In PRHSJ (1993, 12, 263-267) examined the effect of changing wax concentration on drug release and the method of matrix formulation. The amount of drug in the formulation was maintained at 10% w / w, whereas the wax concentration was varied between 10% and 50% w / w. The drug formulation was manufactured by two different methods. The first method is called the physical method, in which the drug, wax and diluent are mixed for 20 minutes in a turbula mixer by geometric dilution, then the method The mixture was compressed into tablets. The second method is called the solid dispersion method, in which the wax is melted and the drug is incorporated into the melted wax at various concentrations. The melted mixture was allowed to cool until solidified, and then the solidified mass was granulated through a Stokes oscillating granulator equipped with screen No. 12. Found that tablets made by physical methods containing the same concentration of wax release the drug at a faster rate than the corresponding drugs made by the solid dispersion method. Tablets containing 30% (w / w) wax made by physical mixing system released about 79% drug within about 6 hours, versus 50% (w / w) wax In the tablet, the drug released 50% of the drug after 6 hours. On the other hand, tablets made by solid dispersion and containing 30% (w / w) wax release 72% drug in 6 hours, while they are made by the same method and contain 50% (w / w) wax. The tablets released only 30% of the drug in 6 hours. Furthermore, they showed that a satisfactory release profile was obtained when the weight ratio of drug to waxy material was greater than 1: 1, for example at least 3: 1.

  In addition, Perez et al. Showed that with 10% (w / w) wax, the release profile was unsatisfactory, regardless of which method was used; Even when manufactured by the method, about 80% of the drug was released in about 2 hours.

  In the prior art, an acceptable sustained release profile can be obtained if the waxy substance is at a concentration of 30% or more, but an unsatisfactory sustained release profile can be obtained at a lower concentration, such as 10%. showed that. Therefore, these prior art references teach away from the manufacture of sustained release formulations containing less than 30% wax.

  (Reilly, et al.) Release of 10% acetaminophen in spheres and tablets with various concentrations, 10%, 30% or 50% glyceryl behenate in AAPS (1991) The profile was investigated. The latter tablet was produced by direct compression or wet granulation. The reference discloses that simple incorporation of glyceryl behenate into the sphere does not provide a slow release. In the tablet, however, 10% by weight of wax does not provide any sustained release effect, but at a concentration of 30% and 50% by weight (ie a glyceryl behenate to drug weight ratio of 3: In the case of 1 or 5: 1), the tablet showed a sustained release effect. Furthermore, with regard to the tablet formulation, as the amount of wax increases, the magnitude of its sustained release effect also increases.

  Another inventor Terrier examined the effect of glyceryl palmitostearate on drug release. He was a tablet containing sodium salicylate as a drug and glyceryl palmitostearate as an excipient at 40% by weight, and the tablet produced by wet granulation did not show any sustained release I pay attention to it. For example, 50% of the drug was released into water after 20 minutes.

  The method used above for producing the pharmaceutical composition was produced by methods other than direct compression. However, even if the formulation was made by direct compression, the prior art showed that at least 30% of the wax was necessary in the formulation to achieve sustained release. For example, El-Sayed, et al., STP. Pharma. In Sciences (STP Pharma. Sciences, 1996, 6, 398-401), a formulation containing 50% theophylline and 30% glyceryl behenate, HPMC or carbopol, and the remaining excipients Manufactured. Although tablets so produced have been shown to be sustained release formulations, the inventors have found that even less sustained release formulations containing less than 30% (w / w) wax, as well as A method for manufacturing was explored.

  The present inventor has discovered a method for overcoming the shortcomings of the prior art and achieving that objective. More particularly, the inventor is a method of manufacturing a controlled release dosage form using a simple manufacturing process, such as direct compression, including compressing the various ingredients after a simple mixing procedure. Provide a method. The inventor has found that effective sustained release formulations can be produced by methods that incorporate significantly less hydrophobic material than previously used.

SUMMARY OF THE INVENTION The present invention is a sustained release pharmaceutical composition in the form of a tablet comprising a pharmaceutically effective amount of a drug and a hydrophobic substance as a sustained release agent, wherein the drug and the hydrophobic substance are the core of the pharmaceutical composition. And the core excludes polymers that may cause swelling that may cause collapse of the pharmaceutical composition, contains a hydrophobic carbohydrate polymer, and contains a high concentration, low molecular weight, water soluble form containing lactose The drug is present in greater than about 25% (w / w) of the pharmaceutical composition, has a water solubility of less than about 1 gram per 10 mL of water at 25 ° C., and the hydrophobic The active substance has a melting point at 1 atm of at least about 40 ° C. to about 100 ° C. and is present in an amount effective to control the release of the drug, and the hydrophobic substance is about 3% of the pharmaceutical composition. In amounts ranging from weight percent to about 20 weight percent and less than the weight of the drug It is directed to sustained release pharmaceutical compositions for standing. Preferably, the pharmaceutical composition is produced by direct compression without melting of the hydrophobic material or the use of a high cutting stirrer. The pharmaceutical composition may be manufactured using wet granulation techniques, but is preferably not manufactured as such.

The present invention is also directed to a method for producing a sustained release pharmaceutical composition in tablet form comprising the following steps;
(A) mixing the drug and hydrophobic substance and any lubricants and any excipients and any adjuvants to form a substantially homogenous and uniform blend; ,
The mixture excludes polymers and high concentrations of low molecular weight water soluble excipients that can cause swelling that can cause the tablet to disintegrate, and the drug is present in greater than about 25% by weight of the pharmaceutical composition. Present and having a water solubility of less than about 1 gram per 10 mL of water at 25 ° C., the hydrophobic material has a melting point at 1 atm of at least about 40 ° C. to about 100 ° C., and the pharmaceutical composition Present in an amount ranging from about 3% to about 20% by weight;
(B) compressing the product of step (a) to form the tablet;
The pharmaceutical composition is formed without melting the hydrophobic material and using a high shear mixer.

The pharmaceutical composition may be produced by wet granulation, but it is preferred that it is not.

In another aspect, the present invention is directed to a method of administering an agent to a patient comprising the following steps;
(A) a sustained release pharmaceutical composition in the form of a tablet comprising a pharmaceutically effective amount of a drug and an effective amount of a hydrophobic substance to control the release of the drug from the pharmaceutical composition; Producing by compressing directly without melting the material or using a high-cut stirrer;
The pharmaceutical composition comprises the drug and the hydrophobic material, but excludes any polymers that may cause swelling that causes the tablet to disintegrate, and high concentrations of water soluble low molecular weight excipients. The drug has a water solubility of less than about 1 gram per 10 mL of water at 25 ° C. and is present in greater than about 25% by weight in the pharmaceutical composition, and the hydrophobic substance is about 40 ° C. Present in an amount ranging from about 3% to about 20% by weight of the pharmaceutical composition and less than the weight of the drug;
(B) administering the product of step (a) to the patient.

DETAILED DESCRIPTION OF THE INVENTION As noted above, one aspect of the present invention is a sustained release formulation of a pharmaceutically active agent that contains a hydrophobic material having a melting point greater than about 40 ° C. and less than about 100 ° C. Oriented.

  As used herein, the terms “drug” and “medicament” and “active substance” are used interchangeably. Furthermore, the terms “controlled release” and “sustained release” are used interchangeably. For the purposes of this application, the term “sustained release” means at a controlled rate so that the active agent or drug useful in the treatment is at a blood concentration (below the toxic concentration) useful for treatment of the agent in the animal. It is meant to be released from the formulation and maintained for an extended period of time, eg, provided in a single dosage form of 4, 8, 12, 16 or 24 hours.

  The controlled release formulation of the present invention should be administered to a mammal in need of such treatment, and the agent present in the formulation is administered in a pharmaceutically active amount. By the term mammal, it is meant to be characterized by having a mammalian class belonging to the vertebrate phylum, ie, hair and mammary gland. Examples include dogs, cats, horses, pigs, goats, cows, humans, among others. The preferred species of mammal to which the sustained release formulation of the invention is to be administered is human.

  The pharmaceutical composition of the present invention comprises a formulation in unit dosage form. The term “unit dosage form” as used herein refers to units that are conveniently physically separated as a single dosage for mammals, including humans, with each unit as described herein. Calculated to produce the desired effect in relation to the hydrophobic substance, if present, a lubricant, if present, an excipient, and if present, other adjuvants. Indicates that it contains a predetermined amount of active substance.

  The formulations of the present invention apply to a wide variety of drugs or active agents suitable for use in sustained release formulations.

  Typical drugs include antacids, anti-inflammatory substances, coronary artery dilators, cerebral vasodilators, psychotropic drugs, antiepileptic drugs, stimulants, antihistamines, laxatives, decongestants, vitamins, gastrointestinal Gastrointestinal sedatives, antidiarrheal drugs, antianginal drugs, vasodilatory antiarrhythmic drugs, antihypertensive drugs, vaconstrictors, and migraine drugs, anticoagulants, antithrombotics, analgesics Antipyretic, hypnotic, sedative, anti-emetics, anti-nauseants, anticonvulsant, neuromuscular, hyperglycemic and hypoglycemic, thyroid and antithyroid, diuretic Antispasm, uterine relaxant, mineral and nutritional supplements, antiobesity, anabolic, erythropoiesis, antiasthma, expectorant, antitussive, mucolytic, hyperuricemia, and other drugs Or substances that act locally in the mouth, such as local analgesics, local anesthetics, or the like Including tailored look. The formulations of the present invention may contain one or more active ingredients.

  The drug used in the present invention exhibits low solubility in an aqueous solution at 25 ° C. and 1 atm. It has a water solubility of less than about 1 gram per 10 mL of water at any pH present in the gastrointestinal tract, typically between pH 1 and 7.5. However, if the drug is too insoluble in water, it may be very difficult to produce it as a sustained-release preparation, or may not function effectively as a sustained-release pharmaceutical composition. Thus, the drug should have a solubility of about 100 mg or more per liter of water at 25 ° C.

  The drug preferably has an average particle diameter of about 5 to about 300 microns, more preferably about 20 to about 200 microns, and most preferably about 30 to about 100 microns.

  Preferred drugs are theophylline, ferrous sulfate, niacin, guaifenesin, clarithromycin, salts of valproic acid, especially salts of the group IA such as divalproex sodium, verapamil, dextromethorphan, diclofenac or Its pharmaceutically acceptable salts are isosorbide mononitrate, levodopa, carbidopa, naproxen and the like. As is well known to those of ordinary skill in the art, divalproex is composed of about 50% (w / w) sodium salt of valproic acid or other group IA metal salt and about 50% (w / w) valproic acid. It is a mixture.

  The agent is present in a pharmaceutically effective amount. Preferably, the agent is present in an amount ranging from about 25% to about 97% by weight of the pharmaceutical composition.

  The pharmaceutical carrier of the present invention contains the hydrophobic substance. The hydrophobic substance is the sustained release agent. The pharmaceutical composition does not contain any hydrophilic sustained release agent. The hydrophobic component includes a water-insoluble waxy material. The waxy material includes a solid, generally insoluble material having a waxy consistency. Of course, it should be ingestible, pharmaceutically acceptable and non-toxic. Many such materials are known and include fats and waxes. Waxes used here are low melting organic mixtures or high molecular weight compounds that are typically solid at room temperature and are typically similar in composition to fats and oils except that they do not contain glycerides. It is. Waxes include higher fatty acids, fatty acid esters, higher fatty alcohols, and mixtures thereof. Viewed another way, fat is a glycerin ester of higher fatty acids. All of these are hydrophobic substances when the term is used herein.

  The hydrophobic material is present in an effective amount that delays sustained release. In the pharmaceutical composition of the present invention, it is about 3% to about 20%, preferably about 3% to about 15%, more preferably about 5% to about 15% by weight of the pharmaceutical composition, Most preferably, it is present in an amount ranging from about 7% to about 12% by weight. Therefore, it is preferably present at less than 20% by weight.

  As defined herein, the hydrophobic substance may consist of one component or a mixture of two or more hydrophobic components.

  The hydrophobic material has a melting range higher than human body temperature, that is, about 37 ° C. or higher. The hydrophobic material used in the present invention has a melting point higher than about 40 ° C, more preferably higher than about 45 ° C. However, it is critical that the hydrophobic material has a melting point higher than human body temperature. Waxes with melting points close to body temperature, such as 37 ° C, have problems with stability during storage, as well as risk of dumping doses. Therefore, the minimum temperature of the hydrophobic material is about 40 ° C., that is, a temperature higher than the temperature at which the above problem does not appear. Preferably the melting point of the hydrophobic material is from about 40 ° C to about 100 ° C, even more preferably from about 45 ° C to about 90 ° C, particularly more preferably from about 50 ° C to about 80 ° C, most preferably from about 55 ° C to about The range is between 75 degrees. It is important to note that the presence of the lubricants and / or other hydrophobic materials of the present invention can affect the melting range. However, when associated with these other substances in the formulation, the melting range of the hydrophobic substance should not decrease below body temperature.

  Preferably, the hydrophobic component has an average particle size from about 10 microns to about 20 microns. More preferably, the average particle size range is from about 20 to about 150 microns, and most preferably the average particle size range is from about 30 to about 100 microns.

  As indicated above, hydrophobic materials useful in the present invention include waxes and neutral fats. As described below, the hydrophobic material used in the present invention must contain at least 10 carbon atoms.

  Useful waxes include those obtained from plant and / or animal sources or as petroleum products, ie, those obtained from natural sources. Examples of such kinds of preferred waxes include carnauba wax, candelilla wax, spermaceti, beeswax, montan wax, hydrogenated vegetable oil, lecithin, hydrogenated cottonseed oil, hydrogenated tallow, paraffin Also included are waxes, shellac wax, petrolatum and the like as well as synthetic waxes such as polyethylene.

  The hydrophobic material also includes fatty acid materials. The fatty acid material is preferably of the type consisting of fatty acids having 10 to 40 carbons. The fatty acids may be linear or branched, but preferably they are linear. They may not contain carbon-carbon double bonds, or they 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, more preferably 1 or 2 carbon-carbon double bonds. Examples include stearic acid, palmitic acid, lauric acid, eleostearic acids, a mixture of stearic acid and palmitic acid, such as a mixture of 85% by weight stearic acid and 15% by weight palmitic acid, etc. It is.

  The fatty acid material also includes aliphatic alcohols having 16 to 44 carbon atoms. They may also be linear or branched, but preferably they are linear. They may be fully saturated or contain carbon-carbon double bonds. If they contain carbon-carbon double bonds, they preferably contain 1, 2, 3 or 4 carbon-carbon double bonds, preferably 1 or 2 carbon-carbon double bonds. Examples include stearyl alcohol, cetyl alcohol, palmitol and the like.

  The fatty acid materials also include fatty amines having 13 to 45 carbons and fatty amides having 11 to 45 carbons.

  The hydrophobic material also includes neutral lipids. The neutral lipid is preferably of the kind consisting of monoglycerides, diglycerides and triglycerides.

The monoglyceride, diglyceride and triglyceride are represented by the following formula:

Where R ₁ is hydrogen or

R ₂ is hydrogen or

R ₃ is hydrogen or

And R ₄ , R ₅ and R ₆ are independently alkyl or alkenyl, wherein the alkyl and alkenyl groups have from 9 to 39 carbon atoms, and at least one of R ₁ , R ₂ and R ₃ is other than hydrogen belongs to.

The alkyl group and alkenyl group of R ₄ , R ₅ and R ₆ may be a branched chain, preferably a straight chain. The alkenyl groups may have 1, 2, 3 or 4 carbon-carbon double bonds, and if present, they more preferably contain 1 or 2 carbon-carbon double bonds.

  Examples include glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, polyglycolyzed glycerides and the like.

Alongside the glycerol ester, the hydrophobic substance includes fatty acid esters of other polyhydric alcohols having two or more hydroxyl groups in the molecule, and one or more of those fatty acids may be esterified, As described above, it has the above-described characteristics, for example, the characteristics such as the melting point in the above-described range. Examples of such polyhydric alcohols include alkylene glycols such as ethylene glycol and propylene glycol. Preferably the polyhydric alcohol contains 2 or 3 hydroxyl groups. The polyhydric alcohol may be esterified with at least one fatty acid as defined herein. Preferred fatty acids are those having the formula R ₄ COOH, where R ₄ in each fatty acid may be the same or different, as defined above.

  The hydrophobic material also includes pharmaceutically acceptable salts of fatty acids, so long as the fatty acids have a melting point in the ranges indicated above. The fatty acid is as defined above. Examples include magnesium stearate and calcium and aluminum salts of palmitic acid.

  Preferably, the hydrophobic substance is a fatty acid or a salt thereof, an aliphatic alcohol, a wax or a neutral lipid. More preferably, the hydrophobic substance is a mono-, di- or triglyceride esterified with a fatty acid.

  The most preferred hydrophobic substances are glyceryl hehenate, glyceryl palmitostearate, glyceryl monostearate, polyglycolized glycerides, stearic acid, hydrogenated vegetable oil, still alcohol or mixtures thereof. The most preferred hydrophobic material is glyceryl behenate.

  The pharmaceutical composition of the present invention excludes any component that may cause the tablet to disintegrate from the core of the tablet in which the drug and sustained release agent as described above are present. This includes any polymer, such as a hydrophilic polymer or hydrophobic carbohydrate polymer that can cause swelling, as described below. In addition, high concentrations of low molecular weight water soluble excipients can cause the tablet to disintegrate, so they are also excluded from the core. As used herein, “high concentration low molecular weight water soluble excipient” indicates that the low molecular weight water soluble excipient is present at a concentration of about 20% (w / w) or more of the tablet. To do. In other words, the core of the pharmaceutical composition of the present invention may include low molecular weight excipients as long as it is at a concentration of less than about 20% by weight of the tablet. More preferably, the concentration (w / w) is less than 10% by weight of the tablet.

  Low molecular weight water soluble excipients are well known to those having ordinary skill in the art. As defined herein, “low molecular weight water soluble excipient” refers to a water soluble excipient having a molecular weight of less than about 1000 Daltons. Examples of low molecular weight water soluble excipients are lactose, sucrose, glucose, citric acid, sodium phosphate, buffering agents and the like. Thus, if the low molecular weight excipient has more than about 1 gram solubility in 20 mL water at 25 ° C., 1 atm, more preferably more than about 1 gram in 10 mL water at 25 ° C., 1 atm. As previously defined, it is not present at high concentration in the core of the tablet. The water soluble low molecular weight excipient is present in less than about 20% by weight of the tablet, more preferably less than about 10% by weight of the tablet. The term low molecular weight excipient means an excipient having a molecular weight of less than 1000 daltons.

  Thus, the compositions of the present invention preferably do not contain any polymers that can cause swelling and do not contain any low molecular weight excipients such as lactose at high concentrations. Thus, the hydrophobic materials eliminate hydrophobic hydrocarbon polymers, especially because they do not melt within the aforementioned ranges. As defined herein, a hydrophobic carbohydrate polymer is a hydrophobic cellulose derivative, wherein the R moiety or R derivative of cellulose-R or cellulose-ROH is an aliphatic of 2 to 100 or more carbons. Either an acyl group, or an aliphatic alkyl group containing 1 to 100 or more carbons, or a chitin. Examples of hydrophobic polymers that are excluded from the hydrophobic material used herein are ethyl cellulose, propyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate propionate, and the like. In addition, the hydrophobic material excludes hydrated alkyl cellulose, such as hydrated alkyl cellulose.

  Since the sustained-release-retarding agent of the pharmaceutical composition of the present invention is a hydrophobic substance, it eliminates swelling polymers, and includes hydrocolloids, as well as any gel-forming substance such as xanthan gum, guar gum Eliminate hydrophilic compounds as sustained release agents including (guar gum), hydroxypropylmethycellulose, methacrylate or acrylate polymers. In addition, it eliminates proteins.

  Except where it is desired to be forced, controlled release of the drug would be achieved because it is present at a non-disintegrating dose that has been partially insoluble by wax. The wax helps control the release. Because it is insoluble in water, it makes the wax at least partially insoluble in pharmaceutical compositions containing the same, even if it is not sufficiently insoluble in water. If the excipient is also insoluble, both the wax and the excipient strengthen the tablet. The degradation or diffusion rate is controlled by both erosion control as well as solubility control.

  On the other hand, any component that can rupture the tablet surface, such as a polymer or a disintegrant that may swell, causes the matrix (core) to become brittle and cause the tablet to disintegrate. In fact, the reason why high concentrations of wax were used in the prior art seems to have been due to the inclusion of a swelling or disintegrant.

  It was concluded that the other cause of disintegration was a high concentration of soluble components including low molecular weight water soluble excipients as discussed above.

  However, it is not excluded from the present invention as long as it does not cause swelling, whether it is an insoluble or soluble polymer. Furthermore, water soluble excipients having a molecular weight greater than 1000 daltons are also not excluded, even in the tablets of the pharmaceutical composition, including the core, at concentrations greater than 20% by weight of the tablets, or Even a concentration of less than 20% by weight (w / w) may be present. Thus, for example, maltodextrin is water soluble and a polymer, but does not swell and therefore does not cause disintegration. It may be present in the tablet, including the core, in concentrations greater or less than 20% by weight. Also, polyethylene glycol having a molecular weight greater than 1000 Daltons may be present in the pharmaceutical composition that also includes the tablet core in concentrations greater or less than about 20% by weight of the tablet. Although they are completely water soluble, they do not swell and can be used because the high molecular weight of PEG delays disintegration.

  Further, even water soluble excipients may be present at concentrations above or below about 20% of the tablet. These include microcrystalline cellulose, dicalcium phosphate and the like.

  In the pharmaceutical composition of the present invention, the sustained release agent is a hydrophobic substance. It is mixed with the active agent and is present in the central core in addition to the pharmaceutical composition. If the pharmaceutical composition comprises a coating, the core does not contain a sustained release agent.

  In addition, if coatings are present, they may be on the outside (on the surface) of the tablet and thus include a swelling polymer or disintegrant that includes a low molecular weight water soluble excipient. Thus, if it is an expandable polymer but cannot be present in the core of the tablet, it may be present in the coating of the pharmaceutical composition of the present invention. Furthermore, the concentration limits of the water soluble excipients also apply to their presence in the core of the pharmaceutical composition. If a water soluble excipient is present in the coating, there is no restriction on it. Preferably, however, the tablet does not contain a coating. However, if a coating is present, the water soluble low molecular weight excipient and swellable polymer are each preferably less than about 20% of the pharmaceutical composition, more preferably about 10% of the pharmaceutical composition. Exists in less than. Furthermore, if a coating is present, it preferably contains no disintegrant and preferably no water-swellable polymer.

  Except where it is desired to be forced, the hydrophobic material will interact with the drug and delay it from being released from the oral dosage form. More particularly, the hydrophobic material used in the present invention forms a water-insoluble matrix that maintains integrity over an extended period of time and allows leaching or diffusion of the drug at a controlled rate. Seem.

  The inventor has found that the weight of the hydrophobic substance used is less than the weight of the drug. Therefore, the weight ratio of hydrophobic substance to drug is less than 1: 1. Preferably the range of the weight ratio of drug to hydrophobic material is from about 9: 1 to about 5: 4. Except where it is desired to be forced, a smaller amount of hydrophobic material would produce a more stable and physically stronger dosage form. The concentration of hydrophobic material used is reasonably low, allowing the formation of very hard tablets that can resist various severities. Also, unless it is desired to be forced, the use of a hydrophobic material having a melting point in the range above human body temperature is expected to stabilize the dosage form and release the drug in vivo. It seems to contribute to what can be done. Except where it is desired to be forced, the heat generated in compression can cause the wax to soften, which can help to coat the formulation ingredients and form a continuous matrix and particles. Seem. Except where it is desired to be forced, the dosage forms produced by the methods described above will release the drug from an essentially non-disintegrating matrix by erosion and diffusion. It is.

  Moreover, the formulation of this invention also contains arbitrary components. For example, although not required, in a preferred embodiment, the formulations of the present invention further comprise a lubricant, which is typically used in the formulation technology for oral tablets. As used herein, the term “lubricant” is used to reduce the friction between die wall and punch faces that occur during tablet compression and ejection. Instruct the substance that can be. The lubricant prevents the tablet substance from adhering to the punched surface or punch wall. As used herein, the term “lubricant” includes anti-adhesive agents. Examples of lubricants include stearates such as alkali, alkaline earth and transition metal salts thereof such as calcium, magnesium or zinc; stearic acid, polyethylene oxide, talc, hydrogenated vegetable oils, and vegetable oils. Derivatives, fumed silica, silicone, high molecular weight polyalkylene glycols such as high molecular weight polyethylene glycols, monoesters of propylene glycol, saturated fatty acids containing about 8 to 22 carbon atoms, preferably 16 to 20 carbon atoms including. Preferred lubricants are stearates, stearic acid, talc and the like.

  If a lubricant is used, it is present in an amount effective for lubrication. Preferably, the lubricant is present in an amount ranging from about 0.1% to about 5%, more preferably from about 1% to about 3% by weight of the tablet.

  The other optional ingredient is an inert filler. The excipient may be substantially water soluble or water insoluble. Although not required for the formulation, excipients are used if necessary or desired. Excipients used in the present formulations are those typically used in pharmaceutical technology for oral dosage forms such as tablets. Examples include calcium salts such as calcium sulfate, dicalcium phosphate, tricalcium phosphate, calcium lactate, calcium gluconate, glycerol phosphate; citrate; and mixtures thereof. However, the inert excipients of the sustained release formulations of the present invention may comprise pharmaceutically acceptable sugars, which comprise monosaccharides, disaccharides or polyhydric alcohols and / or mixtures of any of the foregoing. But you can. Examples include sucrose, dextrose, polydextrose, maltodextrin, microcrystalline cellulose, fructose, xylitol, sorbitol, mixtures thereof, and the like. A preferred excipient is maltodextrin.

  Accordingly, a further aspect of the present invention comprises a pharmaceutically effective amount of a drug and a hydrophobic substance as a sustained release agent and maltodextrin, wherein lactose and hydrophobic carbohydrate polymer are absent, said drug being said drug Present in an amount greater than about 25% (w / w) of the composition, having a water solubility of less than about 1 gram per 10 mL of water at 25 ° C., 1 atm, and about 100 mg / L of water at 25 ° C., 1 atm Having a high water solubility, the hydrophobic substance has a melting point at 1 atm of at least about 40 ° C. to about 100 ° C., and is present in an amount effective to control the release of the drug; The active substance is present in an amount ranging from about 3% to about 20% by weight of the pharmaceutical composition and less than the weight of the drug.

  Also preferably, the pharmaceutical composition does not contain lactose. Lactose is undesirable for several reasons. First, many people with lactose intolerance will have difficulty digesting oral dosage forms containing lactose. In addition, lactose interacts with a variety of drugs on it that contain certain functional groups, such as amines. Although it may be used, preferably the pharmaceutical composition of the invention does not contain a disaccharide.

  If present, the excipient is present in an amount ranging from about 0% by weight (but greater than 0) to about 72% by weight.

  There may also be other optional ingredients (adjuvants) typically used in the formulation, such as colorants, preservatives (eg, methyl parabens), artificial sweeteners, flavors, antioxidants. Agents and the like may also be present. Artificial sweeteners include, but are not limited to, saccharin sodium, aspartame, dipotassium glycyrrhizinate, stevia, thaumatin and the like. Flavorings include, but are not limited to, lemon, lime, orange and menthol. The colorant includes, but is not limited to, various food dyes such as FD & C colors, such as FD & C yellow No. 6, food red and the like. Examples of antioxidants include ascorbic acid, sodium metabisulphite, and the like. These optional ingredients, if present, are preferably in the range of about 0.1% to about 5% by weight of the tablet, more preferably less than about 3% (w / w) of the tablet. Present in the amount of.

  Preferably, however, the highest concentration component is the drug. Furthermore, the sum of drug and hydrophobic substance is preferably greater than 45% by weight of the oral dosage form, more preferably greater than about 60% by weight of the pharmaceutical composition.

  The formulation of the present invention is manufactured by mixing the drug with a hydrophobic substance, a lubricant if present, an excipient if present, and an adjuvant if present. The The components are typically blenders commonly used in the pharmaceutical field, such as Hobart mixers, V-blenders, planetary mixers. mixer), Twin shell blender, etc. The components are typically mixed with each other at approximately ambient temperature; no further heating is required, but then a slight temperature change is also utilized. Preferably, the agitator is managed at a temperature in the range of about 10 ° C to about 35 ° C. The hydrophobic material is not melted. Furthermore, if the composition is heated, the increase in temperature used in this step does not even substantially approach the melting point of the hydrophobic material. The pharmaceutical composition of the present invention is not manufactured by heat infusion.

  The ingredients in the formulation are preferably mixed together in large batches using techniques well known in the formulation art and are essentially mixed until the mixture is homogeneous with respect to the drug. By using the term “homogenous” with respect to the drug, the various components are substantially uniform throughout the present invention, ie, a substantially homogeneous mixture is formed. Is shown.

  If the mixture is homogeneous, the unit dosage form is manufactured by techniques known in the art. Thus, the mixture is made into pellets, capsules, granules, pills, tablets or other dosage forms used to use conventional techniques known in the art. May be.

  A preferred unit oral dosage form is a tablet. The tablet is produced by the following method.

  The unit dose of the homogeneous mixture is compressed into a tablet form using a tablet press typically used in the field of formulation. More particularly, the mixture is fed into a tableting machine and sufficient pressure is applied to form a solid tablet. Such pressure can be varied and is typically varied in a force range of about 1000 psi to about 6000 psi, preferably about 2000 psi. The solid formulation according to the invention is compressed and obtains sufficient hardness to prevent the early entry of the aqueous medium into the tablet. Preferably, the formulation is compressed into a tablet form on the order of 5-20 Kp, more preferably on the order of 8-20 Kp, as measured by the Schleuniger hardness test.

  In the modified method, if a lubricant is to be added to the formulation, all of the above steps are repeated except that the mixing is first performed in the absence of the lubricant. If the mixture is homogeneous with respect to the drug, then if present, lubricant is added and the mixing is continued until the lubricant is substantially evenly dispersed in the mixture. . Mixing is then terminated and the mixture is then immediately made into unit dosage forms. For example, as described above, it may be compressed into a tablet.

  Prior to the mixing step, the individual components may be optionally milled and passed through, for example, a scoon or a sieve to reduce the size of the particles. Alternatively, the mixture may be mixed substantially uniformly prior to formation of the unit dosage form. For example, if it is a tablet, the mixture may be milled prior to the compression step.

  In the steps described herein, unlike many methods, the hydrophobic material may be separate from other components of the pharmaceutical composition or may be present with other components of the pharmaceutical composition. In any case, it is not melted. More particularly, in the process of the present invention, the components in the mixing process are not heated to the melting temperature of the hydrophobic material or are not substantially heated to near that temperature. The present invention avoids the disadvantages associated with heat melting. First, heat labile components will decompose in the molten hydrophobic material, such as wax. Furthermore, employing this melted wax technology for muss production is both expensive and dangerous. Aside from the danger of handling large amounts of molten material, it is difficult to handle a hard coagulation drug mixture that must be removed from the mixing container and sized. In addition, the sizing of the hard coagulated drug mixture exposes the drug previously placed in the container, which then impairs the controlled release profile in the subsequent dosage form. Furthermore, an unresolved disadvantage of the known techniques for producing sustained release formulations, particularly the melting and heating step, is that high dose drugs are not easily produced with satisfactory release characteristics. The inventor has found that it is possible to produce a pharmaceutical composition having excellent sustained release properties without melting hydrophobic components such as waxes.

  In addition, the inventor has found that the components can be obtained in a substantially homogeneous mixture without undergoing high shear mixing. Further, as indicated above, the above methodology is simple and economical and avoids the costs associated with high cutting stirrers. Moreover, the present inventors have found that this method provides a pharmaceutical composition with excellent sustained release properties.

  Furthermore, the methodology used in the present invention for producing the present pharmaceutical composition does not utilize wet granulation. Thus, the method does not have the disadvantages associated with wet granulation. Avoid the dangers associated with the use of toxic or flammable solvents used in wet granulation processes.

  The method used in this step for producing the sustained release pharmaceutical composition of the present invention has several advantages. It is a simpler and more efficient production method compared to the case where the composition is produced by melting a hydrophobic material or utilizing a high cutting stirrer. It overcomes the disadvantages of formulation with hydrophobic materials such as waxes, such as dimensional stability associated with heat and friction. The hydrophobic material is not melted, nor is it heated to a temperature just below the melting temperature, such as by utilizing techniques such as radiaton heating. In a preferred embodiment, the hydrophobic material is mixed with the other ingredients at a temperature not slightly higher than room temperature, but substantially below the melting temperature of the hydrophobic material. This technique minimizes heating and energy in the manufacture of the unit dosage form of the present invention compared to its use in the prior art, thereby making the process more efficient. In a preferred embodiment, by not requiring any granulating solvent, the method in this embodiment eliminates potential toxicity and fire hazards when using wet granulation methods in the manufacture of sustained release pharmaceuticals. Can be avoided.

  After forming the unit dosage form, such as a tablet, it may be coated with materials typically used in formulation, if desired. If coated, the coating may be made by techniques known in the art, however, the hydrophobic material used as a controlled release agent is not present in the coating. However, the formulations of the present invention are preferably not coated.

  The unit dosage form produced according to the present invention has the characteristics typically found in the pharmaceutical field. For example, if the dosage form is a tablet, the tablet product is obtained to have the desired hardness and friability typically found in pharmaceutical tablets. The hardness is preferably 5-25 Kp, more preferably 8-20 Kp.

  The formulations of the present invention are in unit dosage forms, such as tablet forms, and have an excellent drug release profile. The release profile of the pharmaceutical formulation of the present invention is non-linear. For example, it has a pre-determined controlled or maintained action, a regularly delayed manner, whereby the type of unit dosage form used, the precise size of the unit dosage form, Depending on the identity of the active ingredient, the water solubility of the active ingredient, the hardness and the specific unit composition, the drug will be available for a period of up to 36 hours. For example, according to the method of the present invention, a controlled release pharmaceutical composition can be produced as desired, with release times of 2-4 hours, 8-10 hours, 15-18 hours, 20-24 hours, and the like. Furthermore, the release profile of each formulation is substantially uniform. Finally, if the oral dosage form is a tablet, the tablet produced according to the present invention is hard and dense, low friability, and controlled over time. Provides sustained and sustained release. The solid dry forms produced according to the present invention are stable and their release rate does not change to any significant extent over long periods of storage (if any).

  The sustained release formulation is provided in solid form, conveniently in unit dosage form. Preferably, the sustained release formulation in solid unit dosage form for oral administration, particularly in tablet form, is provided. Preferably, when the formulation proceeds along the gastrointestinal tract, it is intended that the pharmaceutically active ingredient is released slowly or according to a defined rate after being taken into the body. In this regard, the gastrointestinal tract is considered to be the abdominal gastrointestinal tract, ie the lower end of the esophagus, the stomach and the intestine.

  The dosage of the formulation administered to a mammal in need thereof according to the present invention corresponds to the usual dosage of a particular active ingredient known to those skilled in the art. The exact amount of drug administered to a patient depends on a number of factors, including factors such as the patient's age, severity of the disease and past medical history, and is always within the reliable discretion of the managing physician. There will be. The Physicians Desk Referance can be used as a guideline for proper dosage.

  The pharmaceutical composition formed is preferably not multi-layered, but not only single-layered.

  Unless otherwise stated, all percentages are weight percent relative to the oral dosage form. In addition, unless otherwise noted, the active ingredient, hydrophobic material and any other optional ingredients such as lubricants, excipients and other ingredients may be any of water or other ingredients. Regardless of its presence, it is calculated based on dry weight.

  Further, as used herein, the singular form may refer to the plural form and vice versa, and the plural form may refer to the singular form.

  The invention is further illustrated by the following non-limiting examples.

Example 1
Ferrous sulfate (160 mg), glyceryl behenate (30 mg) and maltodextrin (110 mg) were carefully mixed together for 1 hour in a V-shaped blender (rotary tablet). press) into tablets. The lysate was measured in water using USP apparatus I. Its release profile is as follows.

Example 2-6
The following ingredients were mixed for 1 hour in a suitable mixer.

The resulting mixture was compressed into tablets using a rotary tableting machine. The solubility of each formulation was measured in water using USP apparatus I. Its release profile is as follows.

Example 7
Clarithromycin (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 various ingredients were mixed for 30 minutes in a double cone blender. Magnesium stearate (14.7 mg) was added to the mixture and stirred for an additional 15 minutes. The mixture was compressed into tablets. The tablets were punched using a 20 × 10 mm capsul shaped punch. The tablet contained 500 mg of clarithromycin and the total weight was 980 mg.

The dissolution was measured in acetate buffer (pH 5.0) using USP apparatus I. Its release profile is as follows.

Example 8
Tablets of divalproex sodium were prepared as follows.

  Divalproex sodium (576.21 mg), glyceryl behenate (190 mg), polyvinylpyrrolidone (47.5 mg), calcium phosphate (2 base) dihydrate (44.4 mg), silicified microcrystalline cellulose (44.4 mg) and aerosol ( aerosol, 19 mg) was passed twice through a 40 mesh screen. The various ingredients were mixed for 30 minutes in a double cone mixer. Magnesium stearate (28.5 mg) was added to the mixture and the mixture was stirred for an additional 15 minutes. The mixture was compressed into tablets. The tablets were punched using a 20x10 mm capsule punch. The tablet contained 576.21 mg divalproex sodium and the total weight was 950 mg.

The dissolution was measured in water using USP apparatus I. Its release profile is as follows.

  The above preferred embodiments and examples are presented to illustrate the scope and spirit of the present invention. It will be apparent to those skilled in the art that these aspects and examples have other aspects and examples. Such other embodiments and examples are also within the intended scope of the present invention. Accordingly, the invention should not be limited only to the appended claims.

Claims (46)

  Excludes polymers and high-concentration water-soluble low molecular weight excipients that contain pharmaceutically effective amounts of drugs and hydrophobic substances as sustained-release agents and that can cause the tablets to disintegrate A sustained release pharmaceutical composition in the form of a tablet with a core, wherein the drug is present in an amount greater than about 25% of the pharmaceutical composition and less than about 1 gram per 10 mL of water at 25 ° C, 1 atm Having a water solubility of greater than about 100 mg / L of water at 25 ° C. and 1 atm, and the hydrophobic material has a melting point at least about 40 ° C. to about 100 ° C. at 1 atm, And a sustained release pharmaceutical composition present in an amount ranging from about 3% to less than about 20% by weight of the pharmaceutical composition and less than the weight of the drug.   The pharmaceutical composition according to claim 1, wherein the tablet is not coated.   The pharmaceutical composition according to claim 1, wherein the hydrophobic substance is present in an amount ranging from about 5% to about 15% by weight of the pharmaceutical composition.   4. The pharmaceutical composition of claim 3, wherein the hydrophobic substance is present in an amount ranging from about 7% to about 12% by weight of the pharmaceutical composition.   2. The pharmaceutical composition of claim 1, wherein the weight ratio of the drug to the hydrophobic material ranges from about 9 to 1 to about 5: 4.   The pharmaceutical composition of claim 1, wherein the hydrophobic substance has a melting point in the range of about 40 ° C to about 90 ° C.   The pharmaceutical composition according to claim 6, wherein the hydrophobic substance has a melting point in the range of about 50 ° C to about 80 ° C.   8. The pharmaceutical composition according to claim 7, wherein the hydrophobic substance has a melting point in the range of about 55 ° C to about 75 ° C.   The pharmaceutical composition of claim 1, wherein the hydrophobic substance has an average particle size in the range of about 10 microns to about 200 microns.   10. The pharmaceutical composition according to claim 9, wherein the hydrophobic substance has an average particle size in the range of about 30 to about 100.   2. The pharmaceutical composition of claim 1, wherein the drug is present in an amount ranging from about 25% to about 97% by weight of the pharmaceutical composition.   12. A pharmaceutical composition according to claim 11, wherein the drug is present in an amount ranging from about 35% to about 90% by weight of the pharmaceutical composition organism.   13. The pharmaceutical composition according to claim 12, wherein the drug is present in an amount ranging from about 40% to about 85% by weight of the pharmaceutical composition.   The pharmaceutical composition according to claim 1, wherein a lubricant is additionally present.   15. A pharmaceutical composition according to claim 14, wherein an excipient is additionally present.   2. The pharmaceutical composition according to claim 1, wherein an excipient is additionally present.   The pharmaceutical composition according to claim 15, wherein the excipient is maltodextrin.   The pharmaceutical composition according to claim 16, wherein the excipient is maltodextrin.   The pharmaceutical composition according to claim 1, wherein the hydrophobic substance is a fatty acid or a salt thereof, a monoglyceride, a diglyceride or a triglyceride.   The pharmaceutical composition according to claim 1, wherein the hydrophobic substance is glyceryl behenate, hydrogenated vegetable oil, stearic acid, glyceryl monostearate, glyceryl palmitostearate, or cetyl alcohol. Composition. The pharmaceutical composition according to claim 1, wherein the hydrophobic substance is a fatty acid having 10 to 30 carbons or a salt thereof, an aliphatic alcohol having 10 to 44 carbon atoms, or

Is the way:
Where R ₁ is hydrogen or

R ₂ is hydrogen or

R ₃ is hydrogen or

R ₄ , R ₅ and R ₆ are independently lower alkyl or lower alkenyl having 9 to 29 carbon atoms, at least _one of R ₁ , R ₂ and R ₃ is other than hydrogen .   The pharmaceutical composition according to claim 1, wherein the drug is theophylline or a pharmaceutically acceptable salt thereof, ferrous sulfate, clarithromycin or divalproex.   23. A pharmaceutical composition according to claim 22, wherein the hydrophobic substance is glyceryl behenate. A method for producing a sustained release pharmaceutical composition in an oral dosage form, comprising the following steps;
(a) mixing a drug, a hydrophobic material, an optional lubricant, an optional excipient, and an optional auxiliary polymer to form a substantially homogeneous and uniform mixture;
The mixture excludes polymers and high concentrations of low molecular weight excipients that can cause swelling that can cause the tablet to disintegrate, and the drug can be as much as about 25% by weight of the pharmaceutical composition. Present and has a water solubility of less than about 1 gram per 10 mL of water at 25 ° C., 1 atm, greater than about 100 mg / L of water at 25 ° C., 1 atm, and the hydrophobic material is at least about 40 ° C. to about at about 1 atm Has a melting point in the range of 100 ° C. and is present in an amount ranging from about 3% to about 20% by weight of the pharmaceutical composition and less than the weight of the drug;
(B) compressing the product of step (a) to form the tablet;
The pharmaceutical composition is formed without melting of the hydrophobic material, using a high cutting stirrer, or by heating to a temperature slightly below the melting point of the hydrophobic material.   25. The method of claim 24, further comprising a lubricant.   25. The method of claim 24, wherein the drug, hydrophobic material, and optional excipients and optional adjuvants are mixed together to form a sufficiently homogeneous and uniform first mixture that is effective for lubrication. A method wherein a sufficient amount of lubricant is added to the first mixture and mixed therewith to form a substantially uniform and homogeneous second mixture, which is compressed to form a tablet.   25. The method of claim 24, further comprising an excipient.   27. The method of claim 26, further comprising an excipient.   28. The method of claim 27, wherein the excipient is maltodextrin.   30. The method of claim 28, wherein the excipient is maltodextrin.   25. The method of claim 24, wherein the hydrophobic material is present in an amount ranging from about 5% to about 15% by weight of the pharmaceutical composition.   32. The method of claim 31, wherein the hydrophobic material is present in the range of about 7% to about 12% by weight of the pharmaceutical composition.   25. The method of claim 24, wherein the weight ratio of the drug to the hydrophobic material ranges from about 9: 1 to about 5: 4.   25. The method of claim 24, wherein the hydrophobic material has a melting point range of about 40 ° C to about 90 ° C.   35. The method of claim 34, wherein the hydrophobic material has a melting point range of about 50 ° C to about 80 ° C.   36. The method of claim 35, wherein the hydrophobic material has a melting point range of about 55 ° C to about 75 ° C.   25. The method of claim 24, wherein the hydrophobic material has an average particle size ranging from about 10 microns to about 200 microns.   38. The method of claim 37, wherein the hydrophobic material has an average particle size in the range of about 30 to about 100 microns.   25. The method of claim 24, wherein the agent is present in an amount ranging from about 25% to about 97% by weight of the pharmaceutical composition.   40. The method of claim 39, wherein the agent is present in an amount ranging from about 35% to about 90% by weight of the pharmaceutical composition.   41. The method of claim 40, wherein the agent is present in an amount ranging from about 40% to about 85% of the pharmaceutical composition.   25. A method according to claim 24, wherein the hydrophobic substance is a wax, a fatty acid or salt thereof, or a monoglyceride, diglyceride or triglyceride.   25. The method of claim 24, wherein the hydrophobic substance is glyceryl behenate, hydrogenated vegetable oil, stearic acid, glyceryl monostearate, glyceryl palmitostearate, or cetyl alcohol. 25. The method of claim 24, wherein the hydrophobic substance is a fatty acid having 10 to 30 carbons or a salt thereof, an aliphatic alcohol having 10 to 44 carbon atoms, or

Is a method;
Where R ₁ is hydrogen or

R ₂ is hydrogen or

R ₃ is hydrogen or

R ₄ , R ₅ and R ₆ are independently lower alkyl or lower alkenyl having 10 to 29 carbon atoms, at least _one of R ₁ , R ₂ and R ₃ is other than hydrogen.   25. The method of claim 24, wherein the agent is theophylline or a pharmaceutically acceptable salt thereof, ferrous sulfate, clarithromycin or divalproex.   46. The method of claim 45, wherein the hydrophobic substance is glyceryl behenate.