JP2002521322A - Wet granulation process for the production of stable pharmaceutical formulations - Google Patents

Abstract

  (57) [Summary] The present invention relates to novel granules and novel solid dosage formulations comprising an active ingredient and one or more carriers. Furthermore, the present invention relates to a wet granulation method for producing said granules and a wet granulation method for producing a solid dosage form. The method comprises granulating the mixture, wherein the granulation is performed in a high shear stress mixer having temperature control means to maintain the temperature below 40 ° C.

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION This invention relates to novel granules and novel oral solid dosage formulations comprising an active ingredient and one or more carriers. Furthermore, the present invention relates to a wet granulation method for producing said granules and a granulation method for producing oral solid dosage forms.

BACKGROUND OF THE INVENTION High shear stress mixers are widely used in the pharmaceutical industry for compounding and granulation (Handbook of pharmaceutical granulation technology, chapter 7, "Dr.
ugs and pharmaceutical sciences ", vol. 81, 1997). Blending and wet assembling are achieved by vigorous mechanical agitation with impellers and shredders. It has applications other than wet granulation so that it can be used for dissolution granulation and small spheroidization.When performing dissolution granulation or small spheroidization, the energy for dissolving the binder is the stirring of the impeller. And supplied by external heating of the container.

Formula I

Embedded image Compounds (where R is hydrogen or C _1-6 alkyl) or pharmaceutically acceptable salts thereof are described in US Pat. No. 5,280,040. This patent describes the preparation of these compounds and their use for reducing and preventing bone loss. The manufacture of a pharmaceutical composition is also described.

[0004] Saint chroman is 3,4-trans-2,2-dimethyl-3-phenyl-4-.
[4- (2-Pyrrolidin-1-yl) ethoxy) phenyl] -7-methoxychroman, a nonsteroidal compound known to have antiestrogenic activity. It is used as a birth control pill in India (eg, Salman e
t al; U.S. Patent No. 4,447,622; Singh et al; Acta Endocrinal (Copenh) 126 (19
92), 444-450; Grubb, Curr Opin Obstet Gynecol 3 (1991), 491-495; Sankaran
et al; Contraception 9 (1974), 279-289; Indian Patent Specification No. 129187). St. chroman has also been studied as an anticancer drug for the treatment of advanced breast cancer (Misra et al; Int J Cancer 43 (1989), 781-783). Recently, centroman as a racemic mixture has been shown to be a potent,
It was discovered as a pharmaceutical preparation that lowers cholesterol (SDBain et al; J Mi
n Bon Res 9 (1994), S394).

[0005] Levormeloxifene, (-)-3R, 4R-trans-7-methoxy-2,
2-Dimethyl-3-phenyl-4- [4- [2- (pyrrolidin-1-yl) ethoxy] phenyl] chroman is a particularly preferred compound from this series of 3,4-diarylchromans. Revolmeloxifene can be used in human and veterinary medicine for the control of bone metabolism. It includes, for example, osteoporosis (including postmenopausal osteoporosis and glucocorticoid-related osteoporosis), Paget's disease,
It can be used to treat patients suffering from bone loss due to hyperparathyroidism, malignant hypercalcemia and other conditions characterized by excessive rates of bone resorption and / or reduced bone formation.

The aforementioned 3,4-diarylchromans can be prepared by known methods, for example, Carney.
U.S. Pat. No. 3,340,276 to Bolger, U.S. Pat.
287, and Ray et al., J Med Chem 19 (1976), 276.
-279, the contents of which are incorporated herein by reference. The conversion of the cis configuration to the trans configuration by organometallic base catalyzed transfer is disclosed in U.S. Pat. No. 3,822,287. The optically active d and l enantiomers are disclosed in US Pat. No. 4,447,622 to Salman et al. By forming an optically active acidic salt that is subjected to alkaline hydrolysis to produce the desired enantiomer. (Incorporated herein by reference). (+/-)-3,4-trans-7-
Methoxy-2,2-dimethyl-3-phenyl-4- [4- [2- (pyrrolidine-
The decomposition of 1-yl) ethoxy] phenyl] chloroman in its optical antipode is described in US Pat. No. 4,447,622, which is incorporated herein by reference. Example 1 of U.S. Pat. No. 4,447,622 describes the preparation of said negative enantiomer, which has the formula II:

Embedded image (In this specification, the compound of formula II means levormeloxifene). In Example 2 of U.S. Pat. No. 4,447,622, revolmeloxifene is obtained as a free base and hydrochloride.

The compound of formula I may be administered as a pharmaceutically acceptable salt. A particularly useful pharmaceutically acceptable salt of levormeloxifene is hydrogen fumarate.
This salt form comprises fumaric acid and (-)-3R, 4R-trans-7-methoxy-2,
2-Dimethyl-3-phenyl-4- [4- [2- (pyrrolidin-1-yl) ethoxy] phenyl] chloroman is dissolved in a common solvent, such as methanol, and the salt resulting from the solution is crystallized. It is manufactured by doing.

[0008] Thiagabine is disclosed in US Pat. No. 5,010,10, which is incorporated herein by reference.
No. 090. (2E) -5-Amino-5-methylhex-2-enoic acid N-methyl-N-((1R) -1- (N-methyl-N-((1R) -1-
(Methylcarbamoyl) -2-phenylethyl) carbamoyl) -2- (2-naphthyl) ethyl) amide is described in WO 97/2, which is incorporated herein by reference.
3508. Raloxifene is disclosed in US Pat. No. 4,418,068 and US Pat. No. 4,133,814, which are incorporated herein by reference.
Iodoxifene is disclosed in EP 260066B, which is incorporated herein by reference.
1 and US 4,839,155. Tamoxifen is disclosed in US Pat. No. 4,536,516, which is incorporated herein by reference. 4-Hydroxy tamoxifen is disclosed in US 4,62, incorporated herein by reference.
No. 3,660. Toremifene is disclosed in US 4,996,225, which is incorporated herein by reference. Droloxifene is disclosed in EP792640, which is incorporated herein by reference.

It is an object of the present invention to provide new granular or oral solid dosage forms having improved stability properties.

[0010] It is a further object of the present invention to provide new tablets or capsules with a long shelf life and the possibility of extension.

[0011] Further objects of the present invention will become clear from the description.

Accordingly, the present invention relates to a wet granulation process for producing granules comprising an active ingredient and one or more carriers, said method comprising: a) forming a mixture of the active ingredient and one or more carriers. B) granulating the mixture; and c) drying the mixture, wherein the granulating comprises maintaining the temperature in the mixture below about 40 ° C. during granulation. This is done with high shear stress mixing means having temperature control means.

In another aspect of the present invention, a wet granulation method for producing granules comprising an active ingredient and one or more carriers further comprises processing the granules into an oral solid dosage formulation. Consists of In other words, the present invention relates to wet granulation for the manufacture of an oral solid dosage formulation comprising the active ingredient and one or more carriers, the method comprising: a) forming a mixture of the active ingredient and one or more carriers. B) granulating the mixture; c) drying the mixture; and d) processing the granules into an oral solid dosage formulation, wherein the granulation is carried out during granulation in the mixture. The temperature of about 40
This is done with high shear stress mixing means, having temperature control means to maintain the temperature below ℃.
In one embodiment, the oral solid dosage formulation is a tablet. In another embodiment, the oral solid dosage formulation is a capsule. In a further embodiment, the oral solid dosage formulation, eg, tablet or capsule, is film-coated.

[0014] In a further aspect of the method, the temperature in the granulation mixture is less than about 35 ° C. In certain embodiments, the temperature is about 0 ° C. to about 35 ° C., more preferably about 0 ° C.
To about 30C, even more preferably from about 0C to about 25C, even more preferably from about 15C to about 30C, and most preferably from about 20C to about 25C. In a still further aspect of the method (which aspects should be considered independent of each other), the temperature in the granulated mixture is from about -20C to about 40C.
° C, about -10 ° C to about 40 ° C, about -10 ° C to about 0 ° C, about 0 ° C to about 10 ° C, about 10 ° C
About 20C, about 20C to about 30C, about 30C to about 40C, about 0C to about 40C, about 10C to about 35C, about 15C to about 25C, or about 20C to About 25 ° C.

[0015] In a further embodiment of the method, the active ingredient is selected from non-peptidic organic molecules, small peptides and peptidomimetics. In one embodiment, the active ingredient is a non-peptidic organic molecule. In another embodiment, the active ingredient is a small peptide. In a further embodiment, the active ingredient is a peptidomimetic. In a further embodiment, the active ingredient has a molecular weight of 1500 daltons or less, for example 200-1500 daltons, preferably 500-1000 daltons.

In a further embodiment of the method, the active ingredient is a non-peptidic organic molecule, a small peptide and a peptidomimetic such as St. chroman, levormeloxifene, tiagabine, (2E) -5-amino-5-methylhexa- 2-enoic acid N-methyl-N
((1R) -1- (N-methyl-N-((1R) -1- (methylcarbamoyl)
Selected from -2-phenylethyl) carbamoyl) -2- (2-naphthyl) ethyl) amide, ipamorelin, raloxifene, iodoxifene, tamoxifen and droloxifene or pharmaceutically acceptable salts thereof; Each is considered a separate aspect. In a preferred embodiment, the active ingredient is revolmeloxifen or a pharmaceutically acceptable salt thereof, more preferably revolmeloxifen hydrogen fumarate or revolmeloxifen hydrogen maleate, most preferably revolmeloxyphen It is hydrogen fenfumarate.

In a still further aspect of the method, the active ingredient is of the formula I

Embedded image Wherein R is hydrogen or C _1-6 alkyl, or a pharmaceutically acceptable salt thereof. In one embodiment, R is methyl. In another embodiment, the compound of formula I is in the trans configuration. In a further embodiment, the compound of Formula I is 3,4-trans-2,2-dimethyl-3-phenyl-4- [4- (2
-Pyrrolidin-1-yl) ethoxy) phenyl] -7-methoxychroman (centchroman). In an even further aspect, the compound of Formula I is the isolated 1 enantiomer. In a further embodiment, the compound of formula I is (-)-3R, 4R-
Trans-7-methoxy-2,2-dimethyl-3-phenyl-4- [4- [2-
(Pyrrolidin-1-yl) ethoxy] phenyl] chroman (levolmeloxifene). In a still further aspect, the compound of Formula I is in the form of hydrogen fumarate. In a further embodiment, the compound of formula I is in the form of the maleic acid hydrogen salt.

The one or more carriers are those commonly used in medicinal chemistry for producing granules, for example, Remington: The Science and Practice of Pharmacy, 19t
h Edition (1995) and / or Handbook of pharmaceutical granulation technolo
gy, chapter 7, “Drugs and the pharmaceutical sciences”, vol. 81, 1997. In a further embodiment of the method, the one or more carriers are a hydrophilic binder, a water-soluble diluent, a surfactant, a detergent, a lubricant, a disintegrant, an antioxidant, a water-insoluble diluent. And / or other fillers known to those skilled in the art. In certain embodiments, the one or more carriers comprise at least a hydrophilic binder and a water-soluble diluent.

In a further aspect, the invention comprises an active ingredient and one or more carriers.
A granulate obtainable by a wet granulation process for producing granules comprising an active ingredient and one or more carriers, said method comprising: a) forming a mixture of said active ingredient and one or more carriers, b. C.) Granulating the mixture; and c) drying the mixture, wherein the granulation comprises maintaining the temperature in the mixture during granulation at about 40 ° C.
It is performed with high shear stress mixing means having temperature control means to maintain the temperature below ° C. In one embodiment, the granulation is obtained by the method.

In a still further aspect, the present invention relates to an oral solid dosage formulation comprising an active ingredient and one or more carriers, which manufactures an oral solid dosage formulation comprising the active ingredient and one or more carriers. A) forming a mixture of the active ingredient and one or more carriers, b) granulating the mixture, c) drying the mixture, and d) processing the granules into an oral solid dosage formulation, wherein the granulation comprises temperature control means for maintaining the temperature in the mixture below about 40 ° C. during granulation; This is done with high shear stress mixing means. In one embodiment, the oral solid dosage formulation is obtained by the method described above. In another embodiment, the oral solid dosage form is a tablet or capsule, preferably a tablet. In certain embodiments of the oral solid dosage formulation, a preferred total amount range may be from about 40 mg to about 500 mg, depending on the strength of the formulation;
More preferably, from about 80 mg to about 320 mg, most preferably, from about 80 mg to about 120 mg.

In a particular aspect of the above process, if the wet assembling step is eliminated in the disclosed wet granulation process, a stable powder (instead of stable granulation) is obtained, which powder is It may be used for administration to a patient in solution or suspension, or it may be compressed into an oral solid dosage form, such as a tablet.

An oral solid dosage formulation or composition containing the active ingredient, eg, a compound of Formula I, may be administered one or more times per day or week. An effective amount of such an active ingredient, eg, a compound of Formula I, is that amount necessary to effect the prevention or treatment of the associated disease state. Such an amount will depend, in part, on the particular disease state and its suffering, as well as the patient's age, weight, and general health, and other factors apparent to those skilled in the art. It can be determined routinely by those skilled in the art in view of the knowledge. A typical daily dose will contain a toxic dosage range of about 0.0001 to about 75 mg / kg per patient per day for an active ingredient such as a compound of Formula I, especially revolmeloxifen. A suitable dosage for a compound of formula I, for example, levormeloxifene, is, for example, 0.01 to 2.5 mg per day for a patient, for example a woman.

Definitions As used herein, the term “C _1-6 alkyl” refers to a straight or branched chain alkyl radical containing from 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl. ,
Isopropyl, n-butyl, tert-butyl, n-amyl, sec-amyl,
n-hexyl, 2-ethylbutyl, 2,3-dimethylbutyl and the like.

The term “wet granulation method” refers to a conventional method of producing granules and is described, for example, in Remington: The Science and Practice of Pharmacy, 19th Edition (1995).
And / or Handbook of pharmaceutical granulation technology, chapter 7,
"Drugs and the pharmaceutical sciences", vol. 81, 1997. The wet process typically comprises the steps of weighing, mixing, granulating, screening for moisture, drying, and optional drying screening, lubrication and compression.

The term “granules” is intended to mean granules obtainable using the wet granulation method described above, and includes, for example, Remington: The Science and Practic
e of Pharmacy, 19th Edition (1995) and / or Handbook of pharmaceutical gr
anulation technology, chapter 7, “Drugs and the pharmaceutical sciences
Vol. 81, 1997. The granules may have any suitable size depending on the carrier and / or equipment used, And the production of granules having a particular size and structure is within the technical knowledge of a person skilled in the art.

The term “active ingredient” is intended to mean any compound that has a therapeutic effect and includes oral solid dosage forms such as non-peptidic organic molecules, small peptides and peptidomimetics, and the like. Pharmaceutically acceptable salts thereof, especially, but not limited to compounds of formula I, such as centchroman or levormeloxifene; tiagabine, N-methyl- (2E) -5-amino-5-methylhex-2-enoate. N ((1R) -1- (N-methyl-N-((1R) -1- (methylcarbamoyl) -2-phenylethyl) carbamoyl) -2- (2-naphthyl) ethyl) amide, ipamorelin, raloxifene, Iodoxifene, tamoxifen, 4-hydroxy tamoxifen, toremifene, or droloxifene or as a medicament As salts thereof volume suitable for administration. The active ingredient itself,
It appears to be stable under storage or stress conditions, but when prepared with one or more carriers, it exhibits stability problems, eg, it starts to degrade.

The term “one or more carriers” is intended to mean a carrier as commonly used in medicinal chemistry to produce granulated and oral solid dosage forms, eg, Remingto
n: The Science and Practice of Pharmacy, 19th Edition (1995) and / or Han
dbook of pharmaceutical granulation technology, chapter 7, “Drugs and t
he pharmaceutical sciences ", vol. 81, 1997. In particular,
Or, the plurality of carriers may be, but are not limited to, hydrophilic binders, water-soluble diluents, surfactants, lubricants, disintegrants, antioxidants, water-insoluble diluents and / or are known to those skilled in the art. Selected from other fillers.

The term “formation of a mixture of the active ingredient and one or more carriers” has its customary meaning, ie, it is intended that the active ingredient and the carrier be mixed in a suitable container to form a mixture. I do. For example, the container may be a high shear mixing means, where granulation of the mixture takes place, but is not limited here.

The term “granulation of a mixture” is described, for example, in Remington: The Science and Practice
of Pharmacy, 19th Edition (1995) or Handbook of pharmaceutical granulatio
n technology, chapter 7, “Drugs and the pharmaceutical sciences”, vol.
81, 1997, and has its ordinary meaning and is intended to include dry compounding, wet assembly, and subsequent granulation.

The term “drying the mixture” refers to Remington: The Science and Practice of Pharm
acy, 19th Edition (1995) or Handbook of pharmaceutical granulation techno
logy, chapter 7, “Drugs and the pharmaceutical sciences”, vol.81, 1997
And drying the granule mixture either internally or externally in a high shear mixing means in a conventional manner, as disclosed in US Pat. By, but not limited to, placing the wet granulation mixture in a drying cabinet with airflow circulation and thermostatic heat regulation.

The term “high shear stress mixing means” refers to a high shear mixer, a high speed mixer or a high shear crusher or Remington: The Science and Practice of P.
harmacy, 19th Edition (1995) or Handbook of pharmaceutical granulation te
chnology, chapter 7, “Drugs and the pharmaceutical sciences”, vol.81,
It is intended to mean a similar mixer / crusher as disclosed in 1997 and without limitation high shear mixers, such as high speed, high shear mixers, e.g. , High shear mixers or horizontal axis, high shear mixers. The high shear stress mixer is of the following type, Gral, Lodige / Littlefor
d, Diosna, Fielder or Baker-Perkins.

The term “temperature control means” is intended to comprise any means capable of increasing or decreasing the temperature in the mixture, for example, high shear stress mixing means. included. Such temperature control means include, but are not limited to, internal or external temperature control means, such as an external cooling shroud with a liquid, eg, cold water (4-5 ° C.), or an internal cooling pipe, or the aforementioned high shear stress. Or the high shear stress mixing means may be located in a larger container that operates as a freezer.

The term “high shear mixing means with temperature control means” means that the high shear mixing means can be an integral part of the temperature control means or the high shear stress mixing means. Separating from the mixing means, and further comprising, for example, any of the temperature control means capable of controlling the temperature located in a larger vessel operating as a freezer, wherein said high shear mixing means is provided. It is intended to mean:

The term “between granules” is intended to mean the entire granulation period, or a portion of one or more granulation periods, such as, but not limited to, during wet assembly.

The term “processing of granules” is used, for example, in Remington: The Science and Practice of P
harmacy, 19th Edition (1995) or Handbook of pharmaceutical granulation te
chnology, chapter 7, “Drugs and the pharmaceutical sciences”, vol.81,
As disclosed in 1997, it is intended to mean more conventional processing of the granules into an oral solid dosage formulation and, without limitation, reducing the granules to a particular size, lubricating, and Comprising compressing into tablets or filling into gelatin capsules.

The terms “oral solid dosage form” or “oral solid dosage form” include, for example, Remington
: The Science and Practice of Pharmacy, 19th Edition (1995) or Handbook o
f pharmaceutical granulation technology, chapter 7, “Drugs and the phar
tablets, capsules, pills, lozenges, troches, cachets, including but not limited to solid tablets, as disclosed in Maceutical sciences ", vol. 81, 1997. And a small pill.

“Pharmaceutically acceptable salt” refers to the salt forms of an active ingredient, eg, a compound of Formula I, suitable for use as a medicament. Pharmaceutically acceptable salts can be used with compounds of formula I, such as acid addition primary, secondary, tertiary or quaternary ammonium, alkali metal or alkaline earth metal salts. Can exist. In general, the above acid addition salts are prepared by reacting the active ingredient, for example a compound of formula I, with an acid. The alkali metal and alkaline earth metal salts are generally prepared by the reaction of a metal hydroxide of the desired metal salt with a compound of formula I, wherein R is hydrogen.

In the present invention, the active ingredient, eg the compound of formula I, can be prepared in the form of salts, eg, pharmaceutically acceptable salts, especially acid addition salts, including salts of organic and inorganic acids. Examples of such salts are organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, maleic acid, tartaric acid, citric acid, benzoic acid, Including salts such as salicylic acid. Suitable inorganic acid addition salts include hydrochloric, hydrobromic, sulfuric, phosphoric, and the like. The above-mentioned acid addition salts can be obtained as a direct product of compound synthesis. Alternatively, the free base can be dissolved in a suitable solvent containing a suitable acid, and the salt is obtained by evaporating the solvent or otherwise separating the salt and solvent.

The term “hydrophilic binder” refers to a binder commonly used in pharmaceutical formulations,
For example, polyvinylpyrrolidone, copolyvidone (crosslinked polyvinylpyrrolidone), polyethylene glycol, sucrose, dextrose, corn syrup, polysaccharides (including acacia, tragacanth, guar, and alginates), gelatin, and cellulose derivatives (hydroxypropylmethylcellulose, hydroxy Propylcellulose, and sodium carboxymethylcellulose).

The term “water-soluble diluent” includes compounds typically used in the preparation of medicaments, such as sugars (including lactose, sucrose and dextrose), polysaccharides (dextrates and maltodextrins) ), Polyols (mannitol, xylitol, and sorbitol), and cyclodextrin.

The term “water-insoluble diluent” refers to compounds typically used in the preparation of a medicament, such as calcium phosphate, calcium sulfate, starch, modified starch and microcrystalline cellulose.

The term “water-insoluble diluent with non-swelling properties” refers to a water-insoluble diluent as described above, but excludes starch and modified starch.

The term “surfactant” as used herein refers to ionic and nonionic surfactants or wetting agents commonly used in the preparation of medicaments, such as ethoxylated castor oil, polyglycol Glyceride, acetylated monoglyceride, sorbitan fatty acid ester, polyoxamer, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene derivative, monoglyceride or ethoxylated derivative thereof, diglyceride or polyoxyethylene derivative thereof, sodium docosanate, sodium lauryl sulfate , Cholic acid or a derivative thereof,
Represents lecithin, alcohol and phospholipid.

The term “antioxidants” refers to three classes of antioxidants, true antioxidants, reducing agents and antioxidant synergists, such as tocopherol, tocopherol esters, alkyl gallates, butylated hydroxyanisole , Butylated hydroxytoluene, ascorbic acid, citric acid, edetic acid and its salts, lecithin and tartaric acid.

The term “disintegrant” refers to starch, clay, cellulose, alginates, gums, crosslinked polymers (eg, crosslinked polyvinylpyrrolidone and crosslinked sodium carboxymethylcellulose), sodium starch glycolate, low substituted hydroxypropylcellulose, and soy polysaccharide. And the like. Preferably, the disintegrant is a modified cellulose gum, such as crosslinked sodium carboxymethylcellulose.

The term “lubricants” often refers to lubricants or glidants (gl
compounds used as identants, such as talc, magnesium stearate, calcium stearate, stearic acid, colloidal silicon dioxide, magnesium carboxylate, magnesium oxide, calcium silicate, microcrystalline cellulose, starch, mineral oil, wax, glyceryl behenate , Polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, and hydrogenated vegetable oil. Preferably, the lubricant is magnesium stearate or talc, and more preferably, a combination of magnesium stearate and talc.

In one preferred embodiment of the invention, the hydrophilic binder is gelatin, a cellulose derivative, polyvinylpyrrolidone or copolyvidone.

In another preferred embodiment of the invention, said water-soluble diluent is a sugar, polysaccharide or cyclodextrin.

In another preferred embodiment of the invention, said formulation (granular or oral solid dosage formulation)
Further comprises a water-insoluble diluent. In one embodiment, the water-insoluble diluent is a water-insoluble diluent having non-swelling properties, and is preferably microcrystalline cellulose.

[0050] In another preferred embodiment of the invention, the formulation further comprises an antioxidant.
Preferably, the antioxidant is a tocopherol, for example alpha tocopherol succinate.

[0051] In another preferred embodiment of the invention, the formulation further comprises a surfactant. If said surfactant is present, it is preferably an anionic or non-ionic surfactant. Representative surfactants from this preferred group include sodium lauryl sulfate, polyglycolized glycerides, polyoxyethylene sorbitan fatty acid esters, monoglycerides, diglycerides or glycerol.

[0052] In another preferred embodiment of the invention, the formulation further comprises a lubricant and / or a disintegrant.

Certain formulations of the present invention are more preferred. More preferably, said hydrophilic binder is polyvinylpyrrolidone or copolyvidone. More preferably, said water-soluble diluent is a sugar, such as lactose, sucrose, dextrose. More preferably, said surfactant, when present, is a non-ionic surfactant, such as a polyoxyethylene sorbitan fatty acid ester or glycerol.

Certain formulations of the present invention are most preferred. Most preferably, said hydrophilic binder is copolyvidone. Most preferably, said water-soluble diluent is lactose.

[0055] The amount of hydrophilic binder in the pharmaceutical formulation according to the invention is preferably from about 1% to about 25%
(W / w), more preferably about 1% to about 15% (w / w), and most preferably about 2.5% to about 15% (w / w).

[0056] The amount of water-soluble diluent in the pharmaceutical formulation according to the present invention is preferably from about 20% to about 98%.
% (W / w), and more preferably from about 20% to about 80% (w / w).

The water-insoluble diluent in the pharmaceutical preparation according to the present invention is preferably from about 1% to about 50% (
w / w), and more preferably from about 5% to about 30% (w / w).

The amount of active ingredient, eg, compound of Formula I, in a pharmaceutical formulation according to the present invention is preferably from about 0.05% to about 50% (w / w), such as from about 0.1% to about 40% (w / w). w / w).

The following formulation examples are merely illustrative and are not intended to limit the scope of the invention in any way.

The tablets for the present invention are manufactured utilizing conventional tableting techniques. A common method of manufacture involves the compounding of Formula I, or a salt thereof, a water-soluble diluent, a hydrophilic binder, and optionally a portion of a disintegrant. This formulation is subsequently granulated with an aqueous solution of the hydrophilic binder or an aqueous solution of the hydrophilic binder and surfactant, and if necessary, pulverized. The granules are dried and reduced to a suitable size. Any other ingredients, such as a lubricant (eg, magnesium stearate) and an additional disintegrant, are added to the granules and mixed. The mixture is subsequently compressed to a suitable size and shape using a conventional tableting machine, for example a rotary tablet press. The tablets may be film-coated by techniques known to those skilled in the art.

The capsules for the present invention are manufactured using conventional methods. A common method of manufacture involves the compounding of Formula I, or a salt thereof, a water-soluble diluent, a hydrophilic binder, and optionally a portion of a disintegrant. This formulation is subsequently granulated with an aqueous solution of the hydrophilic binder or an aqueous solution of the water-soluble binder and surfactant in water and, if necessary, milled.

The granules are dried and reduced to a suitable size. Any other ingredients, such as a lubricant, are added to the granules and mixed. The resulting mixture is then filled into hard capsules of suitable size in gelatin capsules using conventional capsule filling machines.

A preferred range of strength for the pharmaceutical formulation (eg, oral solid dosage form, eg, capsule or tablet) is from about 0.1 mg to about 40 mg of the compound of Formula I, more preferably, about 0.25 mg.
mg to about 5 mg of a compound of formula I, preferably revolmeloxifen.

A preferred range for the total amount may be from about 40 mg to about 500 mg, more preferably from about 80 mg to about 320 mg, depending on the strength of the formulation.

Tablets and capsules may be manufactured using the components and methods described below.

The following examples and embodiments are merely illustrative and are not intended to limit the scope of the invention in any way.

Experimental During the production of batches for clinical trials, a granulation temperature of more than 60 ° C. was obtained. While these batches were stable, an increase in degradation products was observed and a high granulation temperature was assumed.

The study of the effect of the granulation temperature was carried out on the following temperature intervals: below 0 ° C., below 10 ° C.,
Started at 25 ° C, 40-45 ° C, above 70 ° C. The experiment was performed on a laboratory scale with a 1 L high shear mixer and a tablet formulation having the following composition (see Formulation 1). After manufacture, the formulations were stored in open containers at 60 ° C. under pressurized conditions.

Preliminary studies have shown that the granulation temperature has an effect on degradation products. 2
At temperatures below 0 ° C., no further improvement in the stability of the revolmeloxifene product was observed.

Based on the results of the observations, further studies were initiated and the results are listed in Tables 1 and 2.

[0071]

[Table 1]

[0072]

[Table 2]

The stability of a revolmeloxifene formulation, for example the formulation disclosed in WO 98/23270, is such that the processing temperature in a high shear stress mixer, in particular the granulation temperature, is 40
It can be improved by lowering the temperature to not more than ° C. The most optimal temperature interval is 20-25 ° C.

From the experiments in Tables 1 and 2, it may be observed that the stability of the revolmeloxifen formulation is improved by reducing the total amount.

[0075]

[Table 3]

The mixture of revolmeloxyfen fumarate, lactose, microcrystalline cellulose, and a portion of croscarmellose sodium and copolyvidone is granulated with an aqueous solution of copolyvidone. Cool during granulation. The granules are dried, reduced to a suitable size, and mixed with magnesium stearate, talc and the remaining croscarmellose sodium. The mixture is compressed into separate tablets, yielding a tablet weight of 320 mg. 1.2 with a total weight ranging from 160 mg to 320 mg
It is possible to produce revolmeloxifen tablets with strengths ranging from 5 mg to 40 mg.

[0077]

[Table 4]

The mixture of revolmeloxyfen fumarate, lactose, microcrystalline cellulose, and part of croscarmellose sodium and copolyvidone is granulated with an aqueous solution of copolyvidone. Cool during granulation. The granules are dried, reduced to a suitable size, and mixed with magnesium stearate, talc and the remaining croscarmellose sodium. The mixture is compressed into separate tablets, yielding a tablet weight ranging from 80 mg to 160 mg. It is possible to produce revolmeloxifen tablets having a strength in the range from 0.1 mg to 5 mg, with a total weight in the range from 80 mg to 160 mg.

In all of the following Formulations 3-22, cooling is applied (increased) during granulation.

[0080]

[Table 5]

The revolmeloxifen fumarate, lactose, microcrystalline cellulose, and part of croscarmellose sodium and copolyvidone are granulated with an aqueous solution of copolyvidone containing dissolved sodium lauryl sulfate. The granules are dried, reduced to a suitable size, and mixed with magnesium stearate, talc and the remaining croscarmellose sodium. The mixture is compressed into separate tablets, yielding a tablet weight of 320 mg. 1.25 mg, with a total weight ranging from 160 mg to 320 mg
It is possible to produce revolmeloxifen tablets of strength ranging from 範 囲 40 mg.

[0082]

[Table 6]

Revolmeloxifen fumarate, lactose, microcrystalline cellulose, and a portion of croscarmellose sodium and copolyvidone are granulated with an aqueous solution of copolyvidone containing dissolved sodium lauryl sulfate. The granules are dried, reduced to a suitable size, and mixed with magnesium stearate, talc and the remaining croscarmellose sodium. The mixture is compressed into separate tablets, yielding a tablet weight ranging from 80 mg to 160 mg. It is possible to produce revolmeloxifen tablets having a strength in the range from 0.1 mg to 5 mg, with a total weight in the range from 80 mg to 160 mg.

[0084]

[Table 7]

[0085] Revolmeloxifen fumarate, dextrose, microcrystalline cellulose, and a portion of croscarmellose sodium and copolyvidone are granulated with an aqueous solution of copolyvidone. The granules are dried, reduced to a suitable size, and mixed with magnesium stearate, talc and the remaining croscarmellose sodium. The mixture is compressed into separate tablets, yielding a tablet weight of 320 mg. 160mg ~ 32
It is possible to produce revolmeloxifen tablets having a strength in the range of 1.25 mg to 40 mg with a total weight in the range of 0 mg.

[0086]

[Table 8]

The revolmeloxifen fumarate, dextrose, microcrystalline cellulose, and part of croscarmellose sodium and copolyvidone are granulated with an aqueous solution of copolyvidone. The granules are dried, reduced to a suitable size, and mixed with magnesium stearate, talc and the remaining croscarmellose sodium. The mixture is compressed into separate tablets, yielding a tablet weight ranging from 80 mg to 160 mg.
It is possible to produce revolmeloxifen tablets having a strength in the range from 0.1 mg to 5 mg, with a total weight in the range from 80 mg to 160 mg.

[0088]

[Table 9]

A portion of revolmeloxifen fumarate, lactose, microcrystalline cellulose, and a portion of croscarmellose sodium are granulated with an aqueous solution of gelatin. The granules are dried, reduced to a suitable size, and mixed with magnesium stearate, talc and the remaining croscarmellose sodium. The mixture is compressed into separate tablets, yielding a tablet weight of 400 mg. It is possible to produce revolmeloxifen tablets having a strength ranging from 1.25 mg to 40 mg, with a total weight ranging from 160 mg to 400 mg.

[0090]

[Table 10]

[0091] Revolmeloxifen fumarate, lactose, microcrystalline cellulose, and a portion of croscarmellose sodium are granulated with an aqueous solution of gelatin. The granules are dried, reduced to a suitable size, and mixed with magnesium stearate, talc and the remaining croscarmellose sodium. The mixture is compressed into separate tablets, yielding a tablet weight ranging from 80 mg to 160 mg. It is possible to produce revolmeloxifen tablets having a strength in the range from 0.1 mg to 5 mg, with a total weight in the range from 80 mg to 160 mg.

[0092]

[Table 11]

[0093] Revolmeloxifen fumarate, dextrose, microcrystalline cellulose, and a portion of croscarmellose sodium are granulated with an aqueous solution of gelatin. The granules are dried, reduced to a suitable size, and mixed with magnesium stearate, talc and the remaining croscarmellose sodium. The mixture is compressed into separate tablets, yielding a tablet weight of 400 mg. It is possible to produce revolmeloxifen tablets having a strength ranging from 1.25 mg to 40 mg, with a total weight ranging from 160 mg to 400 mg.

[0094]

[Table 12]

[0095] Revolmeloxifen fumarate, dextrose, microcrystalline cellulose, and a portion of croscarmellose sodium are granulated with an aqueous solution of gelatin. The granules are dried, reduced to a suitable size, and mixed with magnesium stearate, talc and the remaining croscarmellose sodium. The mixture is 80mg-160mg
Compressed into separate tablets yielding tablet weights in the range It is possible to produce revolmeloxifen tablets having a strength in the range from 0.1 mg to 5 mg, with a total weight in the range from 80 mg to 160 mg.

[0096]

[Table 13]

Revolmeloxifen fumarate, lactose, microcrystalline cellulose, and part of croscarmellose sodium and copolyvidone are granulated with an aqueous solution of copolyvidone including Tween 80. The granules are dried, reduced to a suitable size, and mixed with magnesium stearate, talc and the remaining croscarmellose sodium. The mixture is compressed into separate tablets, yielding a tablet weight of 400 mg. It is possible to produce revolmeloxifen tablets having a strength ranging from 1.25 mg to 40 mg, with a total weight ranging from 160 mg to 400 mg.

[0098]

[Table 14]

Revolmeloxifen fumarate, lactose, microcrystalline cellulose, and a portion of croscarmellose sodium and copolyvidone are granulated with an aqueous solution of copolyvidone, including Tween 80. The granules are dried, reduced to a suitable size, and mixed with magnesium stearate, talc and the remaining croscarmellose sodium. The mixture is compressed into separate tablets, yielding a tablet weight ranging from 80 mg to 160 mg. 0.1 mg to 5 mg, with a total weight ranging from 80 mg to 160 mg
It is possible to produce revolmeloxifen tablets in the strength range of

[0100]

[Table 15]

Revolmeloxifen fumarate, lactose, microcrystalline cellulose, and a portion of croscarmellose sodium and copolyvidone are granulated with an aqueous solution of copolyvidone including glycerol. The granules are dried, reduced to a suitable size, and mixed with magnesium stearate, talc and the remaining croscarmellose sodium. The mixture is compressed into separate tablets, yielding a tablet weight of 400 mg.
It is possible to produce revolmeloxifen tablets having a strength ranging from 1.25 mg to 40 mg, with a total weight ranging from 160 mg to 400 mg.

[0102]

[Table 16]

Revolmeloxifen fumarate, lactose, microcrystalline cellulose, and a portion of croscarmellose sodium and copolyvidone are granulated with an aqueous solution of copolyvidone including glycerol. The granules are dried, reduced to a suitable size, and mixed with magnesium stearate, talc and the remaining croscarmellose sodium. The mixture is compressed into separate tablets, yielding a tablet weight ranging from 80 mg to 160 mg. It is possible to produce revolmeloxifen tablets having a strength in the range from 0.1 mg to 5 mg, with a total weight in the range from 80 mg to 160 mg.

[0104]

[Table 17]

Revolmeloxifen fumarate, dextrose, microcrystalline cellulose, and a portion of croscarmellose sodium are granulated with an aqueous solution of gelatin and glycerol. The granules are dried, reduced to a suitable size, and mixed with magnesium stearate, talc and the remaining croscarmellose sodium. The mixture is
Compressed into separate tablets resulting in a tablet weight of 400 mg. It is possible to produce revolmeloxifen tablets having a strength ranging from 1.25 mg to 40 mg, with a total weight ranging from 160 mg to 400 mg.

[0106]

[Table 18]

Revolmeloxifen fumarate, dextrose, microcrystalline cellulose, and a portion of croscarmellose sodium are granulated with an aqueous solution of gelatin and glycerol. The granules are dried, reduced to a suitable size, and mixed with magnesium stearate, talc and the remaining croscarmellose sodium. The mixture is
Compressed into separate tablets yielding tablet weights ranging from 80 mg to 160 mg. 80mg
It is possible to produce revolmeloxifen tablets with a strength ranging from 0.1 mg to 5 mg, with a total weight ranging from １６０160 mg.

[0108]

[Table 19]

Revolmeloxifen fumarate, dextrose, hydroxypropyl-beta-cyclodextrin, microcrystalline cellulose, and a portion of croscarmellose sodium are granulated with an aqueous solution of gelatin containing glycerol. The granules are dried, reduced to a suitable size, and mixed with magnesium stearate, talc and the remaining croscarmellose sodium. The mixture is compressed into separate tablets, yielding a tablet weight of 500 mg. Having a total weight ranging from 160 mg to 500 mg,
It is possible to produce revolmeloxifen tablets with strengths ranging from 1.25 mg to 80 mg.

[0110]

[Table 20]

Revolmeloxifen fumarate, lactose, hydroxypropyl-beta cyclodextrin, microcrystalline cellulose, and a portion of croscarmellose sodium are granulated with an aqueous solution of gelatin containing glycerol. The granules are dried, reduced to a suitable size, and mixed with magnesium stearate, talc and the remaining croscarmellose sodium. The mixture is compressed into separate tablets, yielding a tablet weight ranging from 80 mg to 160 mg. It is possible to produce revolmeloxifen tablets having a strength in the range from 0.1 mg to 5 mg, with a total weight in the range from 80 mg to 160 mg.

[0112]

[Table 21]

The revolmeloxifen fumarate, lactose and microcrystalline cellulose are granulated with an aqueous solution of polyvinylpyrrolidone or copolyvidone. The granules are dried, reduced to a suitable size, and mixed with magnesium stearate. The mixture is then filled into size 0 hard capsule gelatin capsules using conventional encapsulation equipment. Different amounts are weighed in the range 15 mg to 500 mg to obtain different capsule strengths in the range 0.18 mg to 7.50 mg.

[0114]

[Table 22]

Revolmeloxifen fumarate, lactose, microcrystalline cellulose, antioxidants, and a portion of croscarmellose sodium and copolyvidone are granulated with an aqueous solution of copolyvidone. The granules are dried, reduced to a suitable size, and mixed with magnesium stearate, talc and the remaining croscarmellose sodium. The mixture is compressed into separate tablets, yielding a tablet weight of 80 mg. 80mg-1
It is possible to produce revolmeloxifen tablets having a strength in the range of 0.125 mg to 10 mg with a total weight in the range of 60 mg.

[0116]

[Table 23]

Revolmeloxifen fumarate, lactose, microcrystalline cellulose, antioxidants, and a portion of croscarmellose sodium and copolyvidone are granulated with an aqueous solution of copolyvidone. The granules are dried, reduced to a suitable size, and mixed with magnesium stearate, talc and the remaining croscarmellose sodium. The mixture is compressed into separate tablets, yielding a tablet weight of 100 mg. 100mg
It is possible to produce revolmeloxifen tablets of strength ranging from 0.125 mg to 20 mg with a total weight of

[Procedural Amendment] Submission of translation of Article 34 Amendment of the Patent Cooperation Treaty

[Submission date] July 15, 2000 (2000.7.15)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Correction contents]

[Claims]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/4025 A61K 31/4025 31/4535 31/4535 // A61P 5/32 A61P 5/32 15/18 15/18 35/00 35/00 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT , SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG , BR, BY, A, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP , KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZA, ZWF term (reference) 4C076 AA31 AA36 AA44 AA53 BB01 CC09 CC21 CC27 CC30 DD25 DD41 DD67 EE16 EE31 EE33 FF02 FF04 FF06 GG12 GG14 4C086 AA01 AA02 BB02 BC07 GA02 GA12 MA03 MA05 MA35 MA37 MA52 ZA96 4C206 AA01 AA02 FA22 MA02 MA05 MA55 MA57

Claims (16)

[Claims] 1. A wet granulation process for producing granules comprising an active ingredient and one or more carriers, wherein the granulation is such that the temperature in the mixture during granulation is below about 40 ° C. A granulation of the mixture, performed with high shear stress mixing means, having temperature control means to maintain the temperature of the mixture. 2. The method of claim 1, further comprising processing the granules into an oral solid dosage formulation. 3. A wet granulation method for producing an oral dosage formulation comprising an active ingredient and one or more carriers, comprising granulating said mixture and processing said granules into an oral dosage formulation. Wherein the granulation is performed with a high shear stress mixing means having temperature control means to maintain the temperature in the mixture below 40 ° C. during granulation. 4. The method according to claim 1, wherein the temperature in the granulation mixture is between about −10 ° C. and 35 ° C. 5. The active ingredient is a non-peptidic organic molecule, small peptide and peptidomimetic such as centchroman, levormeloxifene, tiagabin.
e), (2E) -5-amino-5-methylhex-2-enoic acid N-methyl-N
-((1R) -1- (N-methyl-N-((1R) -1- (methylcarbamoyl) -2-phenylethyl) carbamoyl) -2- (2-naphthyl) ethyl) amide, raloxifene , Iodoxifen
fene), toremifene, tamoxifen (tam)
oxyfene), 4-hydroxy tamoxifen and droloxifene (dr
or a pharmaceutically acceptable salt thereof. 6. A compound of formula I (Wherein, R represents a hydrogen or C _1-6 alkyl) comprising a salt and one or more acceptable carriers compound or pharmaceutically, a wet granulation process for preparing granules A) forming a mixture of the compound of formula I and one or more carriers, b) granulating the mixture and c) drying the mixture, wherein the granulation is carried out during the granulation. A high shear stress mixing means, having temperature control means to maintain the temperature of the mixture at or below about 40 ° C. 7. The method of claim 6, further comprising processing the granules into an oral solid dosage formulation. 8. The method according to claim 6, wherein the temperature in the granulation mixture is between about -10 ° C. and 35 ° C. 9. The compound of formula I wherein (-)-3R, 4R-trans-7-
Methoxy-2,2-dimethyl-3-phenyl-4- [4- [2- (pyrrolidine-
9. The method according to any one of claims 6 to 8, wherein the compound is 1-yl) ethoxy] phenyl] chroman. 10. The method according to claim 1, wherein the one or more carriers comprise a hydrophilic binder and a water-soluble diluent. 11. The composition according to claim 1, comprising an active ingredient and one or more carriers.
A granule obtainable by the method according to any one of claims 10 to 10. 12. The composition according to claim 2, comprising an active ingredient and one or more carriers.
An oral solid dosage form obtainable by the method according to any one of 5 or 7 to 10. 13. The oral solid dosage formulation according to claim 12, wherein said formulation is a tablet or a capsule. 14. The oral solid dosage formulation according to claim 13, wherein said formulation is a tablet. 15. The oral solid dosage formulation according to claim 13 or 14, wherein the formulation further comprises a film coating. 16. The total amount of the formulation ranges from about 40 mg to about 500 mg.
An oral solid dosage formulation according to claims 12-15.