WO2006005017A2

WO2006005017A2 - Oral composition comprising carbamylating agent

Info

Publication number: WO2006005017A2
Application number: PCT/US2005/023624
Authority: WO
Inventors: Jekone Zsuzsanna Bentzil; Sabine Gutman
Original assignee: Valeant Research & Development
Priority date: 2004-06-30
Filing date: 2005-06-30
Publication date: 2006-01-12
Also published as: WO2006005017A3; TW200706173A

Abstract

The present invention relates to fast release oral compositions containing a carbamylating agent, such as pyridostigmine bromide, a hydrophobic agent and a diluent, and methods of administering and preparing such compositions.

Description

ORAL COMPOSITION COMPRISING CARBAMYLATING AGENT

Field Of The Invention

The present invention relates to oral compositions with a carbamylating agent. The present invention further relates to methods of administering and preparing such compositions.

Background

Carbamylating agents are often hygroscopic, deliquescent or sensitive to moisture in that they are subject to chemical degradation in presence of water. To process these agents into solid oral pharmaceutical compositions, such as tablets or capsules, is technically demanding and requires strong environmental control of the air humidity. The carbamylating agents' hygroscopic property also affects storage of pharmaceutical products containing such agents, and potentially shorten the shelf life of such products. To protect these agents against moisture or water, traditional approaches are to embed such agents in a water-protecting layer. However, the drawback of these approaches is slow release of carbamylating agents in gastrointestinal tract .

In a publication by Levy G and Gumtow RH, the effect of retarding the dissolution of a drug from a solid dosage form by addition of a hydrophobic agent, such as magnesium stearate, is described. See Levy & Gumtow, J". Pharm. Sc±. 52: 1139-1144 (1963) .

Higher levels of hydrophobic agents, such as magnesium stearate, and long mixing times can result in the formation of hydrophobic powder beds that do not disperse readily and may impair drug release from a composition. See Samyn JC and Jung WY, J. Phαxm. Sc±. 59: 169 - 175 (1970) ; Murthy and Samyn, J. Pharm. Sci. 66: 1215 - 1219 (1977) .

The marketed product (MESTINON^®) contains pyridostigmine bromide (carbamylating agent) , lactose (diluent) , colloidal silicon dioxide (glidant) and stearic acid (lubricant) . However, the carbamylating agent is not protected from moisture in the tablet. Therefore, new formulations which can effectively deliver a carbamylating agent, as well as prolonging their stability, are needed.

Summary Of The Invention The present invention draws upon the surprise discovery that a carbamylating agent when mixed with a hydrophobic agent and a diluent may form a fast release composition which efficiently delivers such carbamylating agent orally. Thus, the first aspect of the present invention is a composition comprising a carbamylating agent, a hydrophobic agent and a diluent useful for treating or preventing a disease or condition in a mammal in need thereof.

The compositions of the present invention may also comprise one or more excipients. Such excipients may include one or combination of two or more agents, such as, sweeteners, lubricants, taste-masking agents, binders or anti-capping agents, coloring agents and salivation stimulants. One advantage of the compositions described in the present invention is that these compositions can be essentially free of disintegrants, which are commonly used in formulating a pharmaceutical composition. Such disintegrants may include i) starches, modified starches and amyloses; ii) homopolymers of acrylic acid, of methacrylic acid, of acrylic acid esters or of methacrylic acid esters, and the copolymers of at least two different monomers selected from acrylic acid, methacrylic acid, acrylic acid esters and methacrylic acid esters in any monomer ratio; iii) uncrosslinked or crosslinked polyvinylpyrrolidone; iv) uncrosslinked or crosslinked carboxymethylcellulose; v) alginates or alginic acid; vi) carbon dioxide releasing compounds; and vii) salts of copolymers of methacrylic acid and divinylbenzene.

In addition, the present invention also describes methods of preparing the compositions and methods of administering the compositions for treating or preventing a disease or condition in a mammal in need thereof.

Detailed Description Of The Invention

The present invention describes an oral composition comprising a carbamylating agent, a hydrophobic agent and a diluent useful for treating or preventing a disease or condition in a mammal, preferably in a human, in need thereof. Preferably, a carbamylating agent is coated with a hydrophobic agent; more preferably, the carbamylating agent is dry coated with a hydrophobic agent so as to prevent water or moisture from affecting the carbamylating agent's activity.

One advantage of the compositions of the present invention is their ability to fast-release a carbamylating agent contained in the compositions. Generally, not less than 80% of a carbamylating agent contained in a composition of the present invention can dissolve within up to 60 minutes when measured in vitro. However, it should be noted that the rate of release may be affected by a multitude of factors, including temperature, pH value, solvent, etc. Thus, the compositions of the present invention should not be limited to the specific rate of release described above. The release rate of an active agent from a solid pharmaceutical composition may be determined by methods described in US Pharmacopeia 25, 2011-2012, 1494 (2002), which is hereby incorporated by reference. Other methods well known in the field may also be used. As used herein, a hydrophobic agent generally refers to a compound that protects a carbamylating agent from being affected by water or moisture. A hydrophobic agent can be obtained by determining whether a candidate compound is able to protect a carbamylating agent against water or moisture. A variety of methods may be used to determine whether a compound is a hydrophobic agent. For example, a candidate compound may be mixed with a carbamylating agent to determine whether such a candidate compound prevents or hinders water or moisture from affecting the carbamylating agent. Certain examples of such methods are described herein. A hydrophobic agent often has water repellant effect and may also be water-insoluble. As used herein, water-insoluble generally refers to a compound that cannot be dissolved in less than 10,000 parts of water. See e.g., US Pharmacopeia 25, Description and Solubility, 2363 (2002) . Preferably, a hydrophobic agent is pharmaceutically acceptable. It should also be noted that a hydrophobic agent may be a combination of two or more compounds, each of which is able to protect a carbamylating agent from being affected by water or moisture.

Examples of such hydrophobic agents, include, but are not limited to (Ci_O-C₂o) fatty acids, preferably saturated ones (such as decanoic acid, lauric acid, myristic acid, hexadecanoic acid, stearic acid and dodecanoic acid) and the alkaline earth or aluminium salts thereof, in particular the magnesium salts. Further examples are (C₄-Ci₀) alkyl-tris (Ci- C₄) alkoxysilanes, wherein the C₄-Cio)alkyl and the alkyl residue in the (C₄-Ci₀)alkoxy ™ay be straight-chain or branched and preferably is saturated. Further examples are hydrophobic silicas (silicas coated with silanes) . Preferred examples of such hydrophobic agent may include, but not be limited to, magnesium stearate, calcium stearate, aluminium stearate, magnesium palmitate and iso-octyltriethoxy silane, with the most preferred one being magnesium stearate.

The amount of a hydrophobic agent used to protect a carbamylating agent may vary. The optimal amount of a hydrophobic agent should be effective to prevent moisture or water from affecting the carbamylating agent. One preferred range of a hydrophobic agent is about 2% to about 3% by weight, more preferably about 2.5% by weight, based on the total weight of the composition. An alternate preferred embodiment is a weight ratio between carbamylating agent and hydrophobic agent of about 7 : 1 to about 2 : 1, preferably about 5 : 1. For example, the range of a hydrophobic agent may be, but not be limited to, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9% or 3%.

Typically a hydrophobic agent has a particle size distribution wherein at most 2% by weight of the particles have more than 70 μm (200 mesh) sieved size, Preferably, a hydrophobic agent has a particle size distribution wherein 1% by weight of the particles have more than 70 μm (200 mesh) sieved size and the remainder of the particles is 70 μm or less in diameter.

It may also be possible for a composition of the present invention to include combination of two or more hydrophobic agents in the same composition. For example, a carbamylating agent may be protected by magnesium stearate and another hydrophobic agent. Sometimes, the cumulative amount of two or more hydrophobic agents may be in the range of 2% to 6% by weight. It is also possible that each of the hydrophobic agent may be in the range of 2% to 3% by weight. The diluent used in the composition of the invention may be water soluble (i.e. soluble to more than 1 g per 100 ml of water at room temperature) or it may be water- insoluble (i.e. soluble to 1 g or less per 100 ml water, preferably 0.5 g or less per 100 ml water at room temperature) . Preferably the diluent is water-insoluble.

The diluent may make up the bulk of a composition of the invention, with a preferred x'ange of about 50% to 90% by weight, more preferably about 70% to 85%, even more preferably about 75% to 80% by weight of a composition.

Examples of water-soluble diluents include, but are not limited to, monosaccharides (such as lactose, dextrose) , disaccharides (such as maltose, sucrose) , soluble polysaccharides (such as dextrin or maltodextrin) or sugar alcohols (such as mannitol or xylitol) .

Examples of water-insoluble diluents include, but not be limited to, hydrated or anhydrous inorganic water- insoluble compounds like oxides or hydroxides (e.g., silicon dioxide or aluminum hydroxide), silicates (e.g., aluminum silicate or magnesium aluminum silicate) , salts of carbonic, sulfuric or phosphoric acid (e.g., calcium or magnesium carbonate, calcium sulfate or calcium phosphate) and combinations thereof. Some preferred examples include at least 90% by weight, more preferably at least 95% by weight, based on the diluent, of a salt of calcium with an oxo acid, e.g. sulfuric or phosphoric acid. Even more preferred examples include calcium dxhydrogenphosphate ("dicalcium phosphate") anhydrous or dihydrate, Ca3 (PO₁J)₂, hydroxyapatite (both the latter also being called "calcium phosphate tribasic") , calcium sulfate anhydrous, hemihydrate or dihydrate, and dicalcium sulfate. The particularly preferred example is dicalcium phosphate anhydrous or dihydrate, with dicalcium phosphate anhydrous being most preferred. The water-insoluble diluent may also comprise colloidal silicon dioxide (colloidal silica) in an amount of 0.01% to about 1%, preferably between 0.2% to 0.6% by weight. The weight ratio between the calcium salt and the colloidal silica, if both are present in the water-insoluble diluent, is preferably in the range of about 8000 : 1 to 100 : 1, more preferably about 200 : 1.

The range of a carbamylating agent present in the compositions described herein may be 5% to 30% by weight. Preferably, the range of a carbamylating agent may be 8% to 15% by weight. Even more preferably, the range of a carbamylating agent may be 11% to 13% by weight. For example, the compositions described herein may comprise 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30% of . at least one carbamylating agent by weight. In an even more preferred embodiment, the composition comprise at least one carbamylating agent in the range of 5% to 30% by weight and at least one water-insoluble diluent in the range of 50% to 90% by weight.

The term "carbamylating agent", as used in the present application, is intended to mean a compound that is capable of inhibiting a mammalian acetylcholine esterase, preferably a human acetylcholine esterase. Preferably, a carbamylating agent is able to reversibly carbamylate an acetylcholine esterase's hydrolytically active site.

Carbamylating agents in the said sense may comprise, in the broadest sense, a functional group X-O-CO-NY1Y2, wherein X-O denotes a leaving group capable of being substituted by the hydroxyl group as present in the hydrolytically active site of acetylcholine esterase. A preferred example of X-O is optionally substituted phenoxy, more preferably with one substituent being cationic (such as a quaternary ammonium group) , thus forming a cationic carbamylating agent, or oxypyridyl, more preferably with the pyridyl nitrogen being quaternized, thus also forming a cationic carbamylating agent. The particle size distribution of a carbamylating agent is typically such that at least 85% by weight are smaller than 400 μm sieved size, at least 45% are smaller than 220 μm and at least 5% are smaller than 150 μm. Preferably, the particle size distribution of a carbamylating agent is such that at least 90% by weight are smaller than 400 μm sieved size, at least 50% are smaller than 220 μm and at least 10% are smaller than 150 μm. A first preferred class of carbamylating agents useful for the composition of the invention are of the following formula (I) :

(D in which formula (I) X-R is C-NMe₃ ⁺ or N⁺-Me; and Y_x and Y₂ are independently selected from hydrogen, straight-chain or branched (Ci-C₄) alkyl such as methyl, ethyl, propyl, butyl or isopropyl; or Yi and Y₂ taken together form an alkylene bridge - (CH₂)_n- _/ with n ranging from 4 to 6. Preferably, both Yi and Y₂ are. equal, and more preferably both Yi and Y₂ are methyl . Accordingly, one preferred embodiment of the present invention is an fast release oral composition suitable for treating or preventing a disease or condition in a mammal, preferably in a human, in need thereof, comprising an effective amount of at least one compound as represented by formula (I) , at least one hydrophobic agent and at least one diluent. Preferably, the compound is coated with a hydrophobic agent, and more preferably the compound is dry coated with a hydrophobic agent.

Even more preferred examples of this first class of carbamylating agents are pyridostigmine salts (in particular the bromide or iodide) and neostigmine salts (in particular the bromide, iodide or methanesulfonate) . Thus, an even more preferred embodiment of the present invention is an oral composition suitable for treating or preventing a disease or condition in a mammal, preferably in a human, in need thereof, comprising an effective amount of at least one pyridostigmine salt or neostigmine salt, at least one hydrophobic agent and at least one diluent. Among the most preferred embodiment, the pyridostigmine salt is pyridostigmine bromide or pyridostigmine iodide.

The compounds of formula (I) may be prepared by starting from the corresponding phenol derivative (X-R = C- NMe3⁺) or hydroxypyridinium derivative (X-R = N⁺-Me) and reacting this with excess phosgene in a solvent such as acetonitrile or methylene dichloride to form an intermediate haloformic acid phenylester or pyridyl ester, then removing the excess phosgene, and then reacting the said intermediate with a secondary amine HNY₁Y2, with the substituents Y_x and Y₂ being as defined above for formula (I) . In the preferred case where both Yi and Y₂ are methyl, the compounds as represented by formula (I) may also be prepared by reacting a said phenol derivative or hydroxypyridine derivative with dimethylcarbamoyl chloride (DMCC) . The said phenol derivative or hydroxypyridinium derivative is known. Detailed information regarding the preparation of these compounds can be found in US Patents No. 1905990 or 2572579. A second preferred class of carbamylating agents useful for the composition of the invention are of the following formula (II) :

(II) in which formula (II) the definition for X-R is as in the above formula (I) ; the definition for Y₃ and Y₄ is the same as the one given for Y_x and Y₂ of the above formula (I) , but excluding alkylene; and m is an integer ranging from 4 to 8 and preferably being 6. Preferably Y₃ and Y₄ are equal, and more preferably Y₃ and Y₄ are both methyl. The most preferred examples of compounds (II) are distigmine salts (X-R = N⁺-Me, Y₃ = Y₄ = methyl, m = 6) , in particular its dibromide or diiodide. Accordingly, another preferred embodiment of the present invention is a fast release oral composition suitable for treating or preventing a disease or condition in a mammal, preferably in a human, in need thereof, comprising an effective amount of at least one compound as represented by formula (II) , at least one a hydrophobic agent, and at least one diluent. Preferably, a compound of formula (II) is coated with a hydrophobic agent, and more preferably the compound is dry coated with a hydrophobic agent. The compounds of formula (II) are obtainable similarly as described above for the compounds of the formula (I) , but instead of using a secondary amine HNYiY₂ a diamine HY₃N- (CH₂)_a-NY₄H is used in preferably about a 1:2 molar ratio with respect to the intermediate haloformic acid phenylester or pyridyl ester. The diamine HY₃N-(CH₂)_In-NY₄H may be obtained, when m = 4, 5 or 6, by opening the corresponding C₄-, C₅- or Cs-lactone with an amine H₂N-Y₃ to the ω-hydroxy- C₄-, C₅- or C₆-carboxamide, converting the ω-hydroxy group to a leaving group, substituting the leaving group with an amine H₂N-Y₄, and reducing the carboxamide group with LiAlH₄ to the amine group. The diamine HNY₃- (CH₂)_m-NY₄H may be obtained, when m = 6, 7 or 8, respectively, by opening the C₄-, C₅- or C₆-lactone, respectively, with a primary amine H₂N-Y₃ to the ω-hydroxy-C₄-, C₅- or C₆-carboxamide, converting the ω-hydroxy group to a leaving group, substituting the leaving group with an organometallic reagent derived from ClCH₂COOEt, reacting the ester group so introduced with an amine H₂N-Y₄, and reducing both carboxamide groups with LiAlH₄. The diamine HNY₃- (CH₂)_m-NY₄H may also be obtained, when m = 4-8 and Y₃ = Y₄, by ozonolysis of a corresponding C₄-C₈-cycloalkene to the corresponding open-chain dialdehyde, followed by reacting this with 2 mol.eq. of a primary amine H₂N-Y₃ (= H₂N-Y₄) to form a diimide, which is reduced by catalytic hydrogenation. Detailed information regarding the preparation of these compounds can be found in US Patent No. 2789981.

A third preferred class of carbamylating agents useful for the composition of the invention are those naturally occurring in calabar bean (Physostigma venenosum) , preferably physostigmine and physovenine. Of these latter the addition salts with pharmaceutically acceptable acids such as with inorganic acids (e.g. hydrochloric, hydrobromic, nitric, sulfuric, phosphoric and carbonic acids) or with organic acids (e.g. acetic, lactic, citric, succinic, malic, maleic, fumaric, acetic, tartaric, benzoic, salicyclic and methanesulfonic acids) may also be used. The extraction procedure of these compounds from calabar beans has been described by Chemnitius in J. Prakt. Chem. 116: 59 (1927) .

Accordingly, another preferred embodiment of the present invention is a fast release oral composition suitable for treating or preventing a disease or condition in a mammal, preferably in a human, in need thereof, comprising an effective amount of at least one naturally occurring carbamylating agent, mixed with at least one hydrophobic agent, and at least one diluent. In an even more preferred embodiment, the naturally occurring carbamylating agent is physostigmine, physovenine and a salt form thereof. Preferably, the naturally occurring carbamylating agent is coated with a hydrophobic agent, and more preferably the naturally occurring carbamylating agent is dry coated with a hydrophobic agent.

A fourth preferred class of carbamylating agents useful for the compositions of the invention are of the following formula (III) :

(III) in which formula Ri, R₂ and R₃ are selected independently from hydrogen and methyl; Yi and Y₂ have the same definition as in formula (I) , and the aminoalkyl substituent is in the ortho, meta or para position, preferably in the meta position, to the carbamoyl group. Preferably, R_x and R₂ are each methyl and R₃ is hydrogen. Preferably, Yi is methyl and Y₂ is ethyl. The most preferred compound is rivastigmine. Addition salts of any of the compounds of formula (III) with pharmaceutically acceptable acids (as exemplified above for physostigmine and physovenine) may also be used, with rivastigmine tartrate being the preferred addition salt.

Accordingly, in yet another preferred embodiment, the present invention provides a fast release oral composition suitable for treating or preventing a disease or condition in a mammal, preferably in a human, in need thereof, comprising an effective amount of at least one compound as represented by formula (III) , at least one hydrophobic agent, and at least one diluent. Preferably, a compound of formula (III) is coated with a hydrophobic agent, and more preferably a compound of formula (III) is dry coated with a hydrophobic agent. In an even more preferred embodiment, the compound is rivastigmine and a salt form thereof. The aminoalkylphenols used as the starting materials are known or can be prepared by methods conventional in the art. Some exemplary known aminoalkylphenols useful for synthesizing compounds (III) are given in the following table:

alkylamino position Ri R₂ R₃ CAS Registry relative to hydroxy Number ortho CH₃ CH₃ H 26050-44 -2 ortho H H CH₃ 365458 -45 -3 ortho H (CH₃ ) CH₃ (H) H 60399 - 05 - 5 meta CH₃ CH₃ H 105601 - 04 - 5 para CH₃ CH₃ H 82965 -48 - 8 para H H H 134855- 87-1

When R₃ = hydrogen, the compounds (III) are chiral and the preferred absolute configuration then is the one shown in formula (III) . The chiral compounds (III) may be prepared from the corresponding racemic compound (III) by racemate resolution using di-0,0-p-toluenesulfonyltartaric acid in analogy to the procedure described in U.S. Patent No. 5602176, hereby incorporated by reference.

Among the carbamylating agents described above, all cationic compounds, i.e. all compounds as represented by formula (I) and (II) , and the acid addition salts of physostigmine and physovenine and of the compounds represented by formula (III) , are preferred. Among them, pyridostigmine bromide is the most preferred example. Preferably, a composition of the invention, when it is a tablet, is simultaneously also a fast-disintegrating composition. Generally, a fast disintegrating composition can disintegrate in the mouth within less than 80 seconds, preferably within less than 60 seconds, and more preferably within 20 to 40 seconds, without requiring but allowing mastication. However, it should be noted that various factors may affect the rate of disintegration. In case of a fast-disintegrating formulation, the diluent included within is preferably water-insoluble. The fast disintegrating behaviour of the compositions of the invention is then brought about by the combination of the water-insoluble diluent and the carbamylating agent coated, preferably dry coated, with a hydrophobic agent. Particularly when a carbamylating agent is cationic, it is often deliquescent and may act as a disintegrant itself, further to being the active compound.

Another advantage of the present invention is that the compositions described herein may be essentially free of disintegrants, which are commonly used in formulating pharmaceutical compositions, especially oral formulations. Examples of such disintegrants include, but are not limited to, the following: i) starches and modified starches (such as carboxymethyl starch or sodium starch glycolate) or amylose; ii) crosslinked polyvinylpyrrolidone; iii) cellulose and modified celluloses, such as carboxymethylcellulose,- iv) alginates and alginic acid; and v) salts of copolymers of methacrylic acid and divinylbensene.

As used herein, the term "essentially free" generally refers to a composition having less than about 2% by weight, more preferably less than about 0.5% by weight or even less than 0.1% by weight, based on the total weight of the composition, of each of the said types of disintegrants. In addition or in alternative, certain embodiments of the present invention may contain-no less than 0.01% of disintegrants by weight.

The compositions of the present invention may further be enhanced by the addition of a salivation stimulant. Thus, another embodiment of the present invention is a pharmaceutical composition as described herein further comprising at least one salivation stimulant. The salivation stimulant generally refers to a compound that enhances secretion of saliva. Examples of such a salivation stimulant may include, but not be limited to, citric acid and its dihydrate, pulverized ginger and aniseed. One of the preferred salivation stimulant is citric acid and its dihydrate.

The amount of a salivation stimulant in a composition described herein may vary. The optimal amount of a salivation stimulant is to enhance secretion of adequate saliva so as to promote disintegration of the composition as described herein after administration. For example, the range of a salivation stimulant may be in the range of about 2% to about 3% by weight, including, but not limited to, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9% or 3%. One preferred range is 2.5% by weight.

Further, the compositions described herein may comprise at least one sweetener. A wide range of sweeteners are available and can be found in the standard pharmaceutical handbooks, such as Pharmaceutical Excipients, edited by R. C. Rowe et a.1. Pharmaceutical Press and American Pharmaceutical Association (2003) . Examples of such a sweetener may include, but not be limited to, potassium acesulfam, aspartame, saccharin and its sodium salt, glycyrrhizic acid and its sodium and potassium salts, sucralose and the mixtures thereof.

The amount of sweetener may vary depending on each composition and its application. The range can be about 0.5% to about 2% by weight, for example, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9% and 2%. A more preferably range of a sweetener in a composition is between 1% and 1.5%.

In addition, when a sweetener and a salivation stimulant are both present in a composition, the weight ratio between the sweetener and the salivation stimulant is preferably in the range of 0.3 : 1 to 0.7 to 1, more preferably about 0.4 : 1 to 0.6 : 1, and most preferably about 0.5 : 1. However, it should be noted that the present invention should not be limited to this range of ratio between a sweetener and a salivation stimulant.

Further, the compositions of the invention may comprise at least one taste-masking agent. Thus, another embodiment of the present invention is a pharmaceutical composition as described herein further comprising at least one taste-masking agent. Examples of such a taste-masking agent may include, but not be limited to, (dl)-, (d) - and (1) -menthol, licorice and eucalyptol. One preferred example of a taste-masking agent is (1) -menthol . Additional examples of taste-masking agents may be found in, for example, The Merck Index, Thirteenth Edition, Merck & Co., Inc., Whitehouse Station, NJ (2001) . The amount of a taste-masking agent in a composition may vary depending on each composition, the application of the composition and the taste-masking agent being used. For example, a taste-masking agent may be in the range of about 0.2% to about 0.5%, including, without limitation, 0.2%, 0.3%, 0.4% or 0.5%. One preferred range of a taste-masking agent is about 0.3% by weight.

A composition of the invention may also comprise at least one binder and/or anti-capping agent, which is to bind the composition together. Thus, another embodiment of the present invention is a composition as described herein further comprising at least one binder or anti-capping agent. Examples of such binders or anti-capping agents include, without limitation, cellulose derivatives like alkylcellulose (e.g., ethylcellulose) and hydroxyalkylcellulose (e.g., hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose) . One preferred example is hydroxylalkylcellulose which is low- substituted hydroxypropylcellulose.

The amount of hydroxyalkylcellulose, if present, may be, but not be limited to, in the range of about 1% to about 10%, preferably about 1% to about 5%, more preferably about 2% to about 3% by weight, and most preferably about 2.5% by weight based on the total weight of the composition. The compositions described herein may further comprise other components which are routinely used in formulating pharmaceutical compositions, including, but not limited to, lubricants and/or coloring agents. Examples of lubricants may include, without limitation, talc, glycerine monostearate and glycerine behenate. The range of a lubricant may be, but not be limited to, about 1% to about 2% by weight, more preferably about 1.25% by weight. Examples of coloring agents may include, without limitation, iron oxides, iron hydroxides, titanium dioxide, chlorophyll, chlorophyllin and indigo carmine. Further examples of coloring agents may also be found in the standard pharmaceutical handbooks, such as Pharmaceutical Excipients, edited by R. C. Rowe et al., Pharmaceutical Press and American Pharmaceutical Association (2003) , which is hereby incorporated by reference.

Furthermore, the compositions described herein may also comprise water-soluble components, some of which may further enhance the fast-disintegrating behavior of the compositions. Such water-soluble components may include, without limitation, flavoring agents and soluble inorganic salts, such as magnesium chloride, calcium chloride and sodium chloride.

The amount of these water soluble components may, for example, be in the range of 0% to 5% of the composition by weight. However, the range of water soluble components in the present invention should not be limited to this range. The pharmaceutical compositions described herein may be in different forms, including, but not limited to, tablet, powder, or granulate. Some of the preferred examples are granulates or tablets.

The process of preparing a composition of the present invention generally comprises first mixing, preferably dry mixing, a carbamylating agent with a sufficient amount of at least one hydrophobic agent. This forms a mixture of carbamylating agent and hydrophobic agent. The hydrophobic agent usually forms a moisture and/or humidity protective coat around the carbamylating agent. The mixing time is often more than ten minutes but less than thirty minutes. However, mixing time may vary based on the amount of the carbamylating agent and the amount of the hydrophobic agent. It may also vary based on other factors such as temperature, pH value, or size of particles.

The mixture of carbamylating agent and hydrophobic agent (wherein the hydrophobic agent preferably coats and more preferably dry coats the carbamylating agent) is then mixed, preferably dry mixed with a diluent and with all other desired components in a suitable blender. Sometimes, it may also be possible to alter the sequence how these components are added to or mixed with the mixture of carbamylating agent and hydrophobic agent.

Examples of suitable mixers include, but are not limited to, mixers of the slant-cone type or overhead shakers, such as the "Reax-2" overhead shaker sold by Heidolph Instruments LLC, 2615 River Road, Unit 4, Cinnaminson, NJ 08077. A carbamylating agent is preferably sieved beforehand, for example, using a suited sieve of e.g. 600 μm mesh size. Optionally, if a tablet is desired, the resulting powder may be compressed with a customary tabletting machine. The compositions according to the invention are particularly suitable for oral administration and for fast release of a carbamylating agent in the mouth. Tablets described herein often have a low friability, which allows such tablets to be packaged in normal containers, such as blister packages, without risking deterioration.

As described herein, the pharmaceutical compositions of the present invention are suitable for treating or preventing a disease or condition. Thus, another embodiment of the present invention is a method of treating or preventing a disease or condition in a mammal, preferably a human, in need thereof, comprising administering to the mammal an effective amount of at least one composition described herein.

Another embodiment of the present invention is a method of treating or preventing a disease or condition in a mammal, preferably a human, in need thereof, comprising administering to the mammal an effective amount of at least one composition described herein, wherein inhibition of acetylcholine esterase is considered beneficial to such disease or condition. These diseases or conditions may be treated or prevented by carbamylating agents as defined herein. Among various carbamylating agents, pyridostigmine bromide is particularly effective in treating or preventing nervous or muscular disorders, such as myasthenia gravis. Thus, a more preferred embodiment of the present invention is a method of preventing or treating nervous or muscular . disorders in a mammal, preferably a human, in need thereof, comprising orally administering to the mammal a composition, wherein the composition comprises an amount of pyridostigmine bromide in the range of 5% to 30% by weight, an amount of a hydrophobic agent in the range of 2% to 3% by weight, and an amount of a diluent in the range of 50% to 90%.

The dosage and dose rate of the compositions described in the present invention effective for treating or preventing a disease or condition will depend on a variety of factors, such as the nature of the carbamylating agent being applied, the size of the patient, the goal of the treatment, the nature of the pathology to be treated, the specific pharmaceutical composition used, and the observations and conclusions of the treating physician.

For example, where the dosage form is a tablet, suitable dosage levels can be between about 0.1 μg/kg and about 50.0 mg/kg body weight per day, preferably between about 1.0 μg/kg and about 5.0 mg/kg body weight per day, more preferably between about 10.0 μg/kg and about 1.0 mg/kg of body weight per day, and most preferably between about 20.0 μg/kg and about 0.5 mg/kg of body weight per day of the active ingredient .

Using representative body weights of 10 kg and 100 kg in order to illustrate the range dosages that might be used as described above, suitable dosage levels of a compound identified in the present invention will be between about 1.0-10.0 μg and 500.0-5000.0 mg per day, preferably between about 5.0-50.0 μg and 5.0-50.0 mg per day, more preferably between about 100.0-1000.0 μg and 10.0-100.0 mg per day, and most preferably between about 200.0-2000.0 μg and about 5.0- 50.0 mg per day of the active_..ingredient. These ranges of dosage amounts represent total dosage amounts of the active ingredient per day for a given patient . The number of times per day that a dose is administered will depend upon such pharmacological and pharmacokinetic factors as the half-life of the active ingredient, which reflects its rate of catabolism and clearance, as well as the minimal and optimal blood plasma or other body fluid levels of said active ingredient attained in the patient that are required for therapeutic efficacy. Information regarding individual carbamylating agent may also be found in the standard pharmaceutical texts, such as Remington's Pharmaceutical

Sciences, 18th ed. , Alfonso R. Gennaro, ed. (Mack Publishing Co., Easton, PA 1990), which is hereby incorporated by reference.

The invention can be illustrated by the following non-limiting examples. In the examples, all amounts are given in percent by weight, based on the total weight of the composition. Detailed Description Of Certain Preferred Embodiments

Example 1

12.5 kg of pyridostigmine bromide are dry mixed with 2.5 kg magnesium stearate for 20 min in a suitable blender. In a second blender, 77.19 kg dicalcium phosphate is mixed with a solution of 0.31 kg (1) -menthol in 0.49 kg ethanol 96%. The ethanol is allowed to evaporate from the mixture. 2.5 kg low-substituted hydroxypropyl cellulose, 1.25 kg talc, 1.25 kg potassium acesulfam, 2.5 kg citric acid and the previously prepared mixture of pyridostigmine bromide and magnesium stearate are added to the blender containing dry mixture of dicalcium phosphate and (1) -menthol, and homogenized. The final powder blend is compressed using a rotary tabletting machine into tablets. Mean dissolution measured according to monograph

Pyridostigmine Bromide Tablets in USP 25, p. 1494 is 88.7% in 60 min. Example 2

Example 2 can be prepared similarly in accordance with the method of Example 1 as described above.

Mean dissolution measured according to monograph Pyridostigmine Bromide Tablets in USP 25, p. 1494 is 84.5' in 60 min.

Example 3

Example 3 can be prepared similarly in accordance with the method of Example 1 as described above.

Mean dissolution measured according to monograph Pyridostigmine Bromide Tablets in USP 25, p. 1494 is 96.6% in 60 min.

Example 4

To determine whether a candidate compound is a suitable hydrophobic agent, the following method may be used: 5 g of pyridostigmine bromide powder is poured into a Petri dish. 6 g of pyridistigmine bromide dry coated with magnesium stearate sampled from the mixture described in Example 1 is poured into another Petri dish. Both dishes are placed in a cabinet with controlled temperature and air humidity. After 15 minutes at 25⁰C and 60% relative humidity, a comparison is made as to whether the pyridostigmine bromide powder dry coated with the candidate compound has the similar water or moisture content, e.g. extent of compound liquifidation, is determined.

Example 5

The following protocol may be used to determine the effect of a representative formulation in patients suffering nervous or muscular disorder. A randomized, double-blind, placebo controlled study is conducted. Approximately 100 patients who have been diagnosed for suffering nervous or muscular disorder are recruited for participation in the study. Patients suffering nervous or muscular disorder may be diagnosed using the method described in Harrison's Fifteenth Edition Principles of Internal Medicine (McGraw Hill, Inc. New York, 2001), which is incorporated by reference.

Patients are randomized to be treated daily with the formulations as described in examples 1-3. After a three month treatment, the primary endpoint is a comparison between treatment and placebo groups.

Claims

CLAIMSWhat is claimed is:

1. A fast release oral composition comprising i) a carbamylating agent coated with at least one hydrophobic agent, and ii) a diluent.

2. The composition of claim 1, wherein the carbamylating agent is dry coated with the hydrophobic agent.

3. The composition of claim 1 or 2, wherein the amount of carbamylating agent is in the range of 5% to 30% by weight, based on the total weight of the composition.

4. The composition of one of claims 1 to 3, wherein the hydrophobic agent is magnesium stearate.

5. The composition of one of claims 1 to 4, wherein the amount of diluent is in the range of 50% to 90% by weight, based on the total weight of the composition.

6. The composition of one of claims 1 to 5, wherein the diluent is a water-insoluble diluent.

7. The composition of claim 6, wherein the water-insoluble diluent comprises at least 90% by weight, based on the weight of diluent, of a salt of calcium with an oxo acid.

8. The composition of claim 7, wherein the calcium salt is selected from the group consisting of calcium dihydrogenphosphate anhydrous, calcium dihydrogenphosphate dihydrate, Ca₃(PO₄J_2/ hydroxyapatite, calcium sulfate anhydrous, calcium sulfate hemihydrate, calcium sulfate dihydrate and dicalcium sulfate.

9. The composition of one of claims 1 to 8, being essentially free of a disintegrant selected from the group consisting of: i) starches and modified starches; ii) crosslinked polyvinylpyrrolidone; iii) cellulose and modified celluloses; iv) alginates and alginic acid; and v) salts of copolymers of methacrylic acid and divinylbenzene.

10. The composition of one of claims 1 to 9, further comprising a salivation stimulant.

11. The composition of one of claims 1 to 10, further comprising a taste-masking agent in an amount which is effective in masking the taste of the carbamylating agent.

12. The composition of one of claims 1 to 11, further comprising a hydroxyalkyl cellulose.

13. The composition of claim 11, wherein the amount of hydroxyalkyl cellulose is in the range of 1% to 10% by weight, based on the total weight of the composition.

14. The composition of one of claims 1 to 13, wherein the carbamylating agent is selected from the group consisting of: i) compounds of the following formula (I) :

(D, in which formula (I) X-R is C-NMe₃ ⁺ or N⁺-Me; and Yi and Y₂ are independently selected from hydrogen and straight-chain or branched (Ci-C₄)alkyl; or Yi and Y₂ taken together form an alkylene bridge - (CH₂)_n-, wherein n is an integer number from 4 to 6; ii) compounds of the following formula (II) :

(II) in which formula (II) X-R has the same meaning as in the above formula (I) ; the definition for Y3 and Y4 is the same as the one given for Yi and Y₂ in the above formula (I) , but excluding alkylene; and m is an integer ranging from 4 to 8; iii) compounds naturally occurring in calabar bean and their addition salts with pharmaceutically acceptable acids; and iv) compounds of the following formula (III) :

(III) in which formula R₁, R₂ and R₃ are selected independently from hydrogen and methyl; Yi and Y₂ have the same definition as in the above formula (I) , and the aminoalkyl substituent is in the ortho, meta or para position, and their addition salts with pharmaceutically acceptable acids.

15. The composition of claim 14, wherein the carbamylating agent is a cationic compound selected from the group consisting of: the compounds of the formulae (I) and (II) as defined in claim 12; the addition salts of the carbamylating agents naturally occurring in calabar bean with pharmaceutically acceptable acids; and the addition salts of the compounds of the formula (III) as defined in claim 12 with pharmaceutically acceptable acids.

16. The composition of claim 14, wherein the carbamylating agent is selected from the group consisting of pyridostigmine bromide, neostigmine bromide or mesylate, rivastigmine tartrate, the addition salts of physostigmine with pharmaceutically acceptable acids, and distigmine dibromide.

17. The composition of claim 14, wherein the carbamylating agent is pyridostigmine bromide.

18. The composition of one of claims 1 to 17, further comprising a sweetener.

19. The composition of claim 10, wherein the salivation stimulant is citric acid.

20. The composition of claim 19, furthermore comprising a sweetener, and wherein the weight ratio of the sweetener to the citric acid is in the range of 0.3 : 1 to 0.7 to 1, and preferably is about 0.5 : 1.

21. A pharmaceutical composition, comprising at least one diluent in the range of 50% to 90% by weight, one carbamylating agent in the range of 5% to 30% by weight, and one hydrophobic agent in the range of 2% to 3% by weight .

22. The composition of claim 21, wherein the carbamylating agent is coated with the hydrophobic agent.

23. The composition of claim 22, wherein the carbamylating agent is dry coated with the hydrophobic agent.

24. The composition of one of claims 21-23, wherein the hydrophobic agent is magnesium stearate.

25. The composition of one of claims 21-24, wherein- the diluent is water-insoluble.

26. The composition of claim 25, wherein the water-insoluble diluent is dicalcium phosphate.

27. The composition of one of claims 21-26, further comprising at least one taste-masking agent.

28. The composition of claim 27, wherein the taste-masking agent is in the range of 0.2% to 0.5% by weight.

29. The composition of claim 27 or 28, wherein the taste- masking agent is (1) -menthol.

30. The composition of one of claims 21-29, further comprising at least one salivation stimulant.

31. The composition of claim 30, wherein the salivation stimulant is in the range of 2% to 3%.

32. The composition of claim 30 or 31, wherein the salivation stimulant is citric, acid.

33. The composition of one of claims 21-32, further comprising at least one sweetener.

34. The composition of claim 33, wherein the sweetener is selected from the group consisting of potassium acesulfam, aspartame, saccharin and its sodium salt, glycyrrhizic acid and its sodium and potassium salts, sucralose and the mixtures thereof.

35. The composition of claim 33 or 34, wherein the sweetener is in the range of 1% to 1.5% by weight.

36. The composition of one of claims 21-35, further comprising at least one binder or anticapping agent.

37. The composition of claim 36, wherein the amount of binder or anti-capping agent is in the range of 1% to 10%, based on the total weight of the composition.

38. The composition of claim 36 or 37, wherein the binder or anti-capping agent is a low-substituted hydroxypropyl cellulose.

39. The composition of one of claims 21-38, wherein the carbamylating agent is pyridostigmine bromide.

40. The composition of claim 39, comprising pyridostigmine bromide in an amount in the range of 5% to 30%, based on the total weight of the composition.

41. The composition of one of claims 21-40, further comprising at least one lubricant in the range of 1% to 2%.

42. The composition of claim 41, wherein the lubricant is . talc.

43. The composition of claim 21, wherein the composition comprises i) pyridostigmine bromide in the range of 8% to 15% by weight, ii) magnesium stearate in the range of 2% to 3% by weight, iii) low-substituted hydroxypropyl cellulose in the range of 1% to 10% by weight, iv) a lubricant in the range of 1% to 2% by weight, v) a sweetener in the range of 0.5% to 2% by weight, vi) (1) -menthol in the range of 0.2% to 0.5% by weight, and vii) dicalcium phosphate in the range of 50% to 90% by weight.

44. A method of treating or preventing a disease or condition in which inhibition of acetylcholine esterase is considered, beneficial, in a human in need thereof, comprising administering to the human an effective amount of the composition of claim 1 or 21.

45. The method of claim 44, wherein the carbamylating agent is pyridostigmine bromide.

46. The method of claim 44, wherein the diluent is dicalcium phosphate.

47. The method of claim 44, wherein the hydrophobic agent is magnesium stearate.

48. The method of one of claims 44-47, wherein the disease or condition is nervous or muscular disorder.

49. The method of claim 48, wherein the disease or condition is myasthenia gravis.

50. A process for preparing the composition of claim 1, comprising a) mixing a carbamylating agent and a hydrophobic agent, and b) mixing the mixture so obtained with a diluent and with the other additives.

51. The process of claim 50, further comprising the step of compressing the composition.

52. A process for preparing the composition of claim 21, comprising a) mixing a carbamylating agent and a hydrophobic agent, and b) mixing the mixture so obtained with a diluent in an amount of 50% to 90% by weight, based on the total weight of the composition, and with the other additives.

53. The process of claim 52, further comprising the step of compressing the composition.

54. The process of one of claims 50 - 53, wherein in step a) the mixing is dry mixing.

55. The process of claim 54, wherein in step b) the mixing is dry mixing.

agent, and b) mixing the mixture so obtained with a diluent in an amount of 50% to 90% by weight, based on the total weight of the composition, and with the other additives.

55. The process of claim 54, wherein in step b) the mixing is dry mixing.