PHARMACEUTICAL COMPOSITIONS CONTAINING DESMOPRESSIN

PRIORITY

[0001] This application claims the benefit under 35 U.S.C. § 119 to U.S.

Provisional Patent Application No. 60/852,552, filed on October 18, 2006, and entitled "NOVEL PHARMACEUTICAL COMPOSITION FOR DESMOPRESSIN", and to Indian Provisional Application No. 1483/MUM/2006, filed on September 18, 2006, and entitled "NOVEL PHARMACEUTICAL COMPOSITION FOR DESMOPRESSIN", the contents of each of which are incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Technical Field

[0002] The present invention generally relates to a novel pharmaceutical composition in solid dosage form containing desmopressin or a pharmaceutically acceptable salt thereof (e.g., acetate) as a therapeutically active ingredient, and processes for its preparation.

2. Description of the Related Art

[0003] Desmopressin (also known as l-desamino-8-D-arginine vasopressin, dDAVP) is an analogue of vasopressin. Desmopressin is a nonapeptide and the therapeutically active ingredient (as the acetate salt) in the pharmaceutical product Minirin ^® , which is marketed inter alia as a nasal spray and a tablet formulation. Desmopressin is primarily used in the treatment of primary nocturnal enuresis, i.e. bedwetting, in children by decreasing nocturnal urine production, but it is approved also for the treatment of nocturia and diabetes insipidus. Chemically, it is designated as l-(3- Mercaptopropanoic acid)-8-D-arginine vasopressin; 8-D-arginine-l-(3-mercaptopropanoic acid) vasopressin; and having the structure of Formula I:

S-CH ₂ -CH ₂ -C-Tyr-Phe-Gln-Asn-Cys-Pro- D-Arg-GlyNH ₂ o (I).

[0004] Desmopressin degrades more slowly than recombinant vasopressin, and requires less frequent administration. In addition, it has little effect on blood pressure, while vasopressin may cause arterial hypertension.

[0005] Desmopressin is also currently marketed under the trade name DDAVP " tablets for treating enuresis and blood disorders that consists of the therapeutically active ingredient desmopressin acetate together with lactose, potato starch, magnesium stearate and povidone as excipients.

[0006] U.S. Patent No. 5,047,398 ("the '398 patent") discloses an anti-diuretic composition of desmopressin with acceptable carrier in solid dosage form for absorption in the gastrointestinal tract of humans. The '398 patent further discloses a composition of desmopressin in tablet form and talc and magnesium stearate as lubricants. [0007] U.S. Patent No. 7,018,653 ("the '653 patent") discloses a method for the preparation of a solid dosage form of desmopressin or a pharmaceutically acceptable salt thereof, e.g., acetate, using a fluid bed granulation technique. The '653 patent further discloses the use of fluid bed granulation for both granulating and drying simultaneously. [0008] U.S. Patent No. 7,022,340 ("the '340. patent"), discloses. ^ pharmaceutical composition in a solid dosage form containing desmopressin or a pharmaceutically acceptable salt thereof and a lubricant in an amount of from 0.05 to less than 0.5 percent by weight of the pharmaceutical composition. The '340' patent further discloses that in order to provide the desired hardness and to reduce friction in a compressing operation in a typical tabletting machinery, the lubricant is added to a powder or granulate that is to be compressed.

[0009] U.S. Patent No. 7,094,545 ("the '545 patent") discloses a method for manufacturing a pharmaceutical composition in a solid dosage form comprising desmopressin acetate, and a disaccharide diluent having an average particle size in the range of 70 to 500 microns. The '545 patent further discloses that the use of such disaccharides allows for a compressing speed of up to about 250,000 tablets/hour with the desired tablet quality and retained low level of wear on the tabletting machinery. [0010] Standard literature (see "Pharmaceutical Dosage Forms; Tablets", vol. 1, pages 297 298, Eds. H. A. Lieberman, L. Lachman and J. B. Schwartz, Marcel Dekker, Inc., New York and Basel, 1989) teaches that the conditions involved in fluid bed granulation may be harmful e.g. to enzymes. More specifically, the heat and moisture combined with the circulating air and particles in a fluid bed granulation process generate significant shearing and abrasion forces with the purpose of providing a granulate having

flow properties ideal for tablet compression at industrial scale and speed. Such flow properties are due to the resulting smooth surface structure of the granulate subjected to said shearing and abrasion forces.

[0011] It would be desirable to provide improved solid dosage pharmaceutical compositions containing at least desmopressin or a pharmaceutically acceptable salt thereof.

SUMMARY OF THE INVENTION

[0012] In accordance with one embodiment of the present invention, a physico- chemically stable pharmaceutical composition in a solid dosage form is provided comprising desmopressin or a pharmaceutically acceptable salt thereof as a therapeutically active ingredient.

[0013] In accordance with a second _^ embodiment of the present invention, a physico-chemically stable pharmaceutical composition comprising desmopressin or a pharmaceutically acceptable salt thereof in tablet form is provided. [0014] In accordance with a third embodiment of the present invention, a physico- chemically stable pharmaceutical composition comprising desmopressin or a pharmaceutically acceptable salt thereof in a capsule is provided.

[0015] In accordance with a fourth embodiment of the present invention, a physico-chemically stable pharmaceutical composition in a solid dosage form is provided comprising desmopressin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0016] In accordance with a fifth embodiment of the present invention, a physico- chemically stable pharmaceutical composition in a solid dosage form is provided comprising desmopressin or a pharmaceutically acceptable salt thereof and one or more lubricants, wherein the lubricant concentration is greater than about 0.5% w/w. [0017] In accordance with a sixth embodiment of the present invention, a physico- chemically stable pharmaceutical composition in a solid dosage form is provided comprising desmopressin or a pharmaceutically acceptable salt thereof and one or more disaccharides having an average particle size of less than about 60 microns.

[0018] In accordance with a seventh embodiment of the present invention, a physico-chemically stable pharmaceutical composition in a solid dosage form is provided comprising desmopressin or a pharmaceutically acceptable salt thereof and dibasic calcium phosphate.

[0019] In accordance with an eighth embodiment of the present invention, a physico-chemically stable pharmaceutical composition in a solid dosage form is provided comprising desmopressin or a pharmaceutically acceptable salt thereof, one or more lubricants, and one or more disaccharides having an average particle size of less than about 60 microns, wherein the lubricant concentration is greater than about 0.5% w/w. [0020] In accordance with a ninth embodiment of the present invention, a physico- chemically stable pharmaceutical composition in a solid dosage form is provided comprising from about 0.05 to about 0.5 mg of desmopressin or a pharmaceutically acceptable salt thereof, one or more lubricants, and one_or more, disaccharides having- an average particle size of less than about 60 microns, wherein the lubricant concentration is greater than about 0.5% w/w.

[0021] In accordance with a tenth embodiment of the present invention, a physico- chemically stable pharmaceutical composition in a solid dosage form is provided comprising from about 0.05 to about 0.5 mg of desmopressin or a pharmaceutically acceptable salt thereof, one or more lubricants, one or more disaccharides having an average particle size of less than about 60 microns and dibasic calcium phosphate, wherein the lubricant concentration is greater than about 0.5% w/w.

[0022] In accordance with an eleventh embodiment of the present invention, a physico-chemically stable pharmaceutical composition in a solid dosage form is provided comprising from about 0.1 to about 0.2 mg of desmopressin or a pharmaceutically acceptable salt thereof, one or more lubricants, and one or more disaccharides having an average particle size of less than about 60 microns, wherein the lubricant concentration is greater than about 0.5% w/w.

[0023] In accordance with a twelfth embodiment of the present invention, a physico-chemically stable pharmaceutical composition in solid dosage form is provided comprising from about 0.1 to about 0.2 mg of desmopressin or a pharmaceutically acceptable salt thereof, one or more lubricants, one or more disaccharides having an

average particle size of less than about 60 microns and dibasic calcium phosphate, wherein the lubricant concentration is greater than about 0.5% w/w.

[0024] In accordance with a thirteenth embodiment of the present invention, a physico-chemically stable pharmaceutical tablet is provided comprising desmopressin or a pharmaceutically acceptable salt thereof, one or more lubricants, and one or more disaccharides having an average particle size of less than about 60 microns, wherein the lubricant concentration is greater than about 0.5% w/w and wherein the tablet has a friability not greater than about 1% w/w as per the United States Pharmacopoeia (USP) friability test.

[0025] In accordance with a fourteenth embodiment of the present invention, a process for preparing a stable pharmaceutical composition in a solid dosage form comprising desmopressin or a pharmaceutically acceptable salt thereof by slugging/dry granulation is provided.

[0026] In accordance with a fifteenth embodiment of the present invention, a process for preparing a stable pharmaceutical composition in a solid dosage form is provided comprising desmopressin or a pharmaceutically acceptable salt thereof by direct compression.

[0027] In accordance with a sixteenth embodiment of the present invention, a process for preparing a stable pharmaceutical composition in solid dosage form is provided comprising desmopressin or a pharmaceutically acceptable salt thereof by wet granulation.

[0028] In accordance with a seventeenth embodiment of the present invention, a process for preparing a stable pharmaceutical composition in a solid dosage form is provided comprising mixing desmopressin or a pharmaceutically acceptable salt thereof with one or more lubricants, wherein the lubricant concentration is greater than about

0.5% w/w in a high shear mixer.

[0029] In accordance with an eighteenth embodiment of the present invention, a process for preparing a stable pharmaceutical composition in a solid dosage form is provided comprising mixing desmopressin or a pharmaceutically acceptable salt thereof with one or more disaccharides having an average particle size of less than about 60 microns in a high shear mixer.

[0030] In accordance with a nineteenth embodiment of the present invention, a process for preparing a stable pharmaceutical composition in solid dosage form is provided comprising mixing desmopressin or a pharmaceutically acceptable salt thereof with one or more lubricants and one or more disaccharides having an average particle size of less than about 60 microns, wherein the lubricant concentration is greater than about 0.5% w/w in a high shear mixer.

[0031] In accordance with a twentieth embodiment of the present invention, a package that protects the tablets and/or capsules from moisture, and assists the solid dosage form to retain its physicochemical stability is provided.

DETAILED DESCRIPTION OF THE INVENTION

[0032] The present invention relates to a pharmaceutical composition in a solid dosage form such as in the form of tablets or capsules containing at least a therapeutically effective amount of desmopressin or a pharmaceutically acceptable salt thereof, e.g., desmopressin acetate, as a therapeutically active ingredient together with a pharmaceutically acceptable excipient, carrier, or mixture thereof. Suitable pharmaceutically acceptable excipients and carriers include, but are not limited to, diluents, binders, lubricants, glidants, disintegrants, and the like and mixtures there of. [0033] The term "diluent" or "filler" as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of tablets and capsules. Such compounds include dibasic calcium phosphate, kaolin, lactose, sucrose, mannitol, microcrystalline cellulose, corn starch, mannitol, pregelatinized starch, powdered cellulose, precipitated calcium carbonate, sorbitol, potato starch, lactose, mono or di or oligo or polysaccharide or combinations thereof and other such materials known to those of ordinary skill in the art. [0034] The term "binders" is intended to mean substances used to cause adhesion of powder particles in tablet granulations. Suitable binders according to the present invention can be selected from hydroxypropyl cellulose, pregelatinized starch, polyvinyl pyrrolidone, acacia alginic acid, tragacanth, carboxymethylcellulose sodium, poly (vinylpyrrolidone), compressible sugar (e.g., NuTab), hydroxypropyl methyl cellulose, ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and starch, poly

(ethylene glycol), guar gum, polysaccharide, bentonites, sugars, invert sugars, collagen, albumin, celluloses in nonaqueous solvents, combinations thereof and the like. Other binders include, for example, poly (propylene glycol), polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, poly (ethylene oxide), microcrystalline cellulose, dibasic calcium phosphate, or combinations thereof and other such materials known to those of ordinary skill in the art.

[0035] The term "lubricant" as used herein is intended to mean substances used in tablet formulations to reduce friction during tablet compression. Suitable lubricants according to the present invention can be selected from calcium stearate, magnesium stearate, talc, mineral oil, stearic acid, zinc stearate, colloidal silicon dioxide or combinations thereof and other such materials known to those of ordinary person skilled in the art. The pharmaceutical compositions of the present invention contain the lubricants in a concentration of more than abut 0J5% w/w. _.

[0036] The term "glidant" as used herein is intended to mean agents used in tablet and capsule formulations to improve flow-properties and to produce an anti-caking effect. Such compounds include colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc and combinations thereof and other such materials known to those of ordinary skill in the art.

[0037] The term "disintegrant" is intended to mean a compound used in solid dosage form to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Suitable disintegrants according to the present invention can be selected from starches such as corn starch, potato starch, crospovidone, croscarmellose sodium, pre-gelatinized and modified starch, sweeteners, clays such as bentonite, microcrystalline cellulose (e.g., Avicel™), carsium (e.g., Amberlite™), alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth or combinations thereof and other such materials known to those of ordinary skill in the art.

[0038] Most of these excipients are described in detail in Howard C. Ansel et al.,

Pharmaceutical Dosage Forms and Drug Delivery Systems, (7th Ed. 1999); Alfonso R. Gennaro et al., Remington: The Science and Practice of Pharmacy, (20th Ed. 2000); and

A. Kibbe, Handbook of Pharmaceutical Excipients, (3rd Ed. 2000), which are incorporated by reference herein.

[0039] As one skilled in the art would readily appreciate, the terms "excipient" and

"carrier" can be used interchangeably, and they may even refer to one and the same substance, or to a mixture of similar such substances. The proper use and understanding of these terms is self-explanatory and lies well within the ability of a person skilled in the art of pharmaceutical formulation.

[0040] The foregoing excipients and carriers are merely exemplary and the pharmaceutical compositions of the present invention but can include any excipient known to a person skilled in the art for use in making the desmopressin solid dosage forms of the present invention.

[0041] In one embodiment, the pharmaceutical compositions of the present invention will include one or more onejjr more saccharides.- Useful saccharides include monosaccharides, disaccharides, oligosaccharides and polysaccharides and mixtures thereof. In one embodiment, the saccharides are disaccharides. Representative examples of saccharides are lactose, starch, starch 1500, mannitol, cellulose derivatives such as hydroxyproylcellulose, microcrystalline cellulose and combinations thereof. The saccharides for use herein have an average particle size of less than about 60 microns, e.g., from 1 micron to less than 60 microns.

[0042] Dosage forms of the pharmaceutical compositions of the present invention may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes. Representative examples of solid dosage forms for use herein include, but are not limited to, tablets, pills, capsules, powders, and the like. In one preferred embodiment, a stable solid pharmaceutical composition includes tablets, capsules, and pills.

[0043] The pharmaceutical compositions of the present invention can advantageously be prepared in a solid dosage form, e.g., a tablet or capsule, using slugging/dry granulation, wet granulation or direct compression. In general, slugging/dry granulation will involve (a) blending all the ingredients and preparing slugs with, for example, a slugging machine; (b) sizing and lubricating the slugs; and (c) compressing the

lubricated slugs into tablets using a suitable compression machine or filling the lubricated slugs into capsules of a suitable size.

[0044] When using wet granulation in forming the pharmaceutical composition of the present invention, a solvent such as isopropyl alcohol (IPA), ethanol, acetone, methylene chloride, water and mixtures thereof are advantageously employed. Wet granulation typically involves weighing and mixing the ingredients, granulating the ingredients, screening them damp, drying, dry screening, lubricating, and compressing the resultant admixture into tablets or filling the admixture into capsules of a suitable size. [0045] Direct compression involves blending all the ingredients, lubricating the blend and compressing the lubricated blend into tablets or filling into capsules of a suitable size.

[0046] Capsule dosages will contain the the pharmaceutical composition of the present invention within a capsule which jnay be.coated with gelatin. -Tablets and powders may also be coated with an enteric coating. The enteric-coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxy methyl ethyl cellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents. A coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric-coating. [0047] The pharmaceutical composition of the present invention is advantageously provided as a stable product using a rapid mixer granulation technique. While not wishing to be bound by any particular theory, it is believed that the rapid mixer granulation technique works by (a) spinning close to the bottom of the mixing bowl; and (b) the impeller sets the entire mixture in a whirling-rising tumbling motion which may lead to a quick and even distribution of all dry components resulting in an even wetting of every granule. Due to a rapid action of the blade and chopper and rapid speed of granulation, the drug remains in contact with the granulation fluid for a relatively short period of time, resulting in improving the stability of the product. Thus, a tablet with good physicochemical properties may be achieved.

[0048] In addition, it is believed that by using a high shear mixer, such as a rapid mixer granulator, with a high lubricant concentration (i.e., lubricants used at a concentration more than about 0.5% w/w), and lowering the particle size of disaccharides (i.e., disaccharides having an average particle size of less than about 60 microns), stable desmopressin tablets with the desired disintegration and dissolution properties could be obtained. Thus, a stable capsule dosage form may also be prepared using the same blend prepared for tablets and the thus obtained capsules are believed to be bioequivalent to that of the innovator's tablet composition of DDAVP.

[0049] A rapid mixer granulator for use in a process of the present invention is a

Model: H.S.M.G 3 Bowls (General Mechanical Industries).

[0050] In one embodiment, the tablets of the present invention have a friability not greater than about 1% w/w as per the United States Pharmacopoeia (USP) friability test. [0051] In one embodiment, the ..pharmaceutical - compositions - of the present invention can be packed in a high density polyethylene (HDPE) container thereby allowing for the finished product to be protected by moisture ad retain its physicochemical stability for the desired period of time. Desmopressin is a highly moisture sensitive drug and in the presence of solvents like alcohol and water can degrade and the effective therapeutic dose of drug is not available for desired effect.

[0052] The invention is further exemplified with following examples and is not intended to limit the scope of the inventions. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

EXAMPLE 1 [0053] The formulation that can be used for this example is set forth in Table 1.

TABLE 1

Ingredients % by total wt

Desmopressin acetate 0.1/0.2 mg

Lactose 75%

Corn starch 15%

Polyvinylpyrrolidone (PVP) 5%

Water qs

Isopropyl alcohol qs

Crospovidone 5%

Colloidal silicon dioxide 0.5%

Talc 4 %

Magnesium stearate 1%

[0054] Preparation by wet granulation [0055] Addition of drug into the binder solution [0056] a) In one vessel, polyvinylpyrrolidone is dissolved in isopropyl alcohol.

[0057] b) In another vessel, desmopressin acetate is dissolved in water/isopropyl alcohol solvent mixture, followed by mixing (a) with (b).

[0058] c) In a rapid mixer granulator (RMG), lactose and corn starch are added and the blend is granulated with a mixture of (b).

[0059] d) The granules of (c) were dried in a tray drier or fluid bed drier.

[0060] e) The granules were sized after drying using a mechanical sifter.

[0061] f) Colloidal silicon dioxide and crospovidone were added with the granules of (e) and blended in a suitable blender.

[0062] g) The blend of (f) is lubricated with talc and magnesium stearate.

[0063] h) The lubricated blend of (g) is compressed into tablets using a suitable compression machine or filled into capsules of a suitable size.

[0064] Addition of drug with the diluent

[0065] a) Polyvinylpyrrolidone is dissolved in a solvent.

[0066] b) In a RMG, desmopressin acetate, lactose and corn starch were added and granulated with the mixture of (a).

[0067] c) The granules of (b) were dried in a tray drier or fluid bed drier.

[0068] d) The granules were sized after drying using a mechanical sifter.

[0069] e) Colloidal silicon dioxide and crospovidone were added with the granules of (d) and blended in a suitable blender.

[0070] f) The blend of (e) is lubricated with talc and magnesium stearate.

[0071] The lubricated blend of (f) is compressed into tablets using a suitable compression machine or filled into capsules of a suitable size.

EXAMPLE 2

[0072] The formulation that can be used for this example is set forth in Table 2.

TABLE 2

[0073] Preparation by dry granulation

[0074] a) Desmopressin acetate, lactose, mannitol and microcrystalline cellulose are blended in a suitable blender geometrically and slugs are prepared with a slugging machine. Optionally, some portion of croscarmellose sodium is added into the blend above prior to slugging process.

[0075] b) The slugs of (a) are sized with a suitable sizing machine such as an oscillatory granulator or multi-mill.

[0076] c) The sized blend of (b) is mixed with croscarmellose sodium in a suitable blender.

[0077] d) The blend of (c) is lubricated with magnesium stearate and talc.

[0078] e) The lubricated blend of (d) is compressed into tablets using a suitable compression machine or filled into capsules of a suitable size.

EXAMPLE 3

[0079] The formulation that can be used for this example is set forth in Table 3.

TABLE 3

[0080] Preparation by dry granulation

_[0081] _. a) Desmopressin- acetate, lactose, hydroxypropyl cellulose (HPC) ^~ aiid dibasic anhydrous calcium phosphate (DCP) are blended in a suitable blender geometrically and slugs are prepared with a slugging machine. Optionally, some portion of croscarmellose sodium is added into the blend of above prior to slugging process.

[0082] b) The slugs of (a) are sized with a sizing machine such as an oscillatory granulator or multi-mill.

[0083] c) The sized blend of (b) is mixed with croscarmellose sodium in a suitable blender.

[0084] d) Lubricated the blend of (c) with magnesium stearate and talc.

[0085] e) The lubricated blend of (d) is compressed into tablets using a suitable compression machine or filled into capsules of suitable size.

EXAMPLE 4 [0086] The formulation that can be used for this example is set forth in Table 4.

TABLE 4

[0087] Preparation by direct compression

[0088] a) Desmopressin acetate, mannitol, colloidal silicon dioxide and pregelatinized starch are blended in a suitable blender geometrically.

[0089] b) Mixed croscarmellose sodium with the blend of (a).

[0090] c) Lubricated the blend of (b) with magnesium stearate and talc.

[0091] d) The blend of (c) is compressed into tablets using a suitable compression machine or filled into capsules of suitable size.

EXAMPLE 5

[0092] The formulation that can be used for this example is set forth in Table 5.

TABLE 5

[0093] Preparation by direct compression

[0094] a) Desmopressin acetate and partially pregelatinized starch are blended in a suitable blender geometrically.

[0095] b) Lubricated the blend of (a) with magnesium stearate and talc.

[0096] c) The blend of (b) is compressed into tablets using a suitable compression machine or filled into capsules of suitable size.

EXAMPLE 6

[0097] The formulation that can be used for this example is set forth in Table 6.

TABLE 6

[0098] Preparation by wet granulation and capsule filling

[0099] Addition of drug into binder solution (Granulation in either RMG or FBP)

[00100] a) In one vessel, polyvinylpyrrolidone is dissolved in ethanol.

[00101] b) In another vessel, desmopressin acetate is dissolved in water/ethanol solvent mixture, followed by mixing of (a) with (b).

[00102] c) Lactose and potato starch are added and granulated in RMG or a fluid bed processor (FBP) with the mixture of (b).

[00103] d) Granules of (c) were dried in the tray drier/fluid bed processor in the case of a RMG granulation or in a fluid bed processor in the case of FBP granulation.

[00104] e) The granules were sized after drying using a mechanical sifter.

[00105] f) The blend of (e) is lubricated with magnesium stearate.

[00106] g) The lubricated blend of (f) is filled into hard gelatin capsules using a manual or automated capsule filling machine.

[00107] Addition of drug with the diluent

[00108] a) Polyvinylpyrrolidone is dissolved in a solvent.

[00109] b) In a RMG, added desmopressin acetate, lactose and potato starch and granulated with the mixture of (a).

[00110] c) Granules of (b) were dried in a tray drier or fluid bed drier.

[00111] d) The granules were sized after drying using mechanical sifter.

[00112] e) The blend of step (d) is lubricated with magnesium stearate.

[00113] f) The lubricated blend of (e) is filled into hard gelatin capsules using a manual or automated capsule filling machine.

EXAMPLE 7

[00114] The formulation that can be used for this example is set forth in Table 7.

TABLE 7

[00115] Preparation by blending and capsule filling

[00116] a) Desmopressin acetate and lactose were blended in a suitable blender geometrically.

[00117] b) Lubricate the blend of (a) with magnesium stearate and talc.

[00118] c) Filled the blend of (b) in hard gelatin capsule using a manual or automated capsule filling machine.

[00119] It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the features and advantages appended hereto