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WO2007011349A1 - Nouveau procede de granulation et granule produit par ce procede - Google Patents

Nouveau procede de granulation et granule produit par ce procede Download PDF

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Publication number
WO2007011349A1
WO2007011349A1 PCT/US2005/025326 US2005025326W WO2007011349A1 WO 2007011349 A1 WO2007011349 A1 WO 2007011349A1 US 2005025326 W US2005025326 W US 2005025326W WO 2007011349 A1 WO2007011349 A1 WO 2007011349A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
granulate
acceptable sugar
active pharmaceutical
pharmaceutical ingredient
Prior art date
Application number
PCT/US2005/025326
Other languages
English (en)
Inventor
Ilan Zalit
Julia Hrakovsky
Ruth Tenengauzer
Sagit Shalom-Klein
Original Assignee
Teva Pharmaceutical Industries Ltd.
Teva Pharmaceutical Usa, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Teva Pharmaceutical Industries Ltd., Teva Pharmaceutical Usa, Inc. filed Critical Teva Pharmaceutical Industries Ltd.
Priority to EP05772375A priority Critical patent/EP1793801A1/fr
Priority to JP2008512255A priority patent/JP2008540644A/ja
Priority to CA002614468A priority patent/CA2614468A1/fr
Priority to CNA2005800510501A priority patent/CN101222911A/zh
Priority to PCT/US2005/025326 priority patent/WO2007011349A1/fr
Publication of WO2007011349A1 publication Critical patent/WO2007011349A1/fr
Priority to IL188177A priority patent/IL188177A0/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • the present invention relates to granulates containing an active pharmaceutical ingredient having poor water solubility intimately associated with a pharmaceutically acceptable sugar, useful for pharmaceutical formulations, as exemplified by formulations of bicalutamide or fenofibrate suitable for tablets manufacture.
  • the solubility of an active pharmaceutical ingredient influences the bioavailability of the drug and the dissolution of the drug can often set an upper limit on the rate of absorption of the drug.
  • Many active pharmaceuticals have poor solubility in water and typically, thus lower bioavailability.
  • Reduction in the particles size and concomitant increase in surface area of an active pharmaceutical ingredient has been used, with some success, to improve the dissolution of active pharmaceutical ingredients.
  • this approach is limited by the particle size that can be achieved and by poor bulk flow and handling characteristics of finely powdered active pharmaceutical ingredients.
  • One of the aspects of the invention concerns a granulate for a pharmaceutical composition, useful for making, among other things, oral solid dosage forms such as capsules and tablets, wherein the granulate comprises an active pharmaceutical ingredient (i.e. "API), which has poor water solubility, intimately associated with at least one pharmaceutically acceptable sugar, e.g., a pyranosyl pyranose such as lactose, and, optionally, at least one pharmaceutically acceptable excipient other than the at least one pharmaceutically acceptable sugar.
  • API active pharmaceutical ingredient
  • the active pharmaceutical ingredient having poor water solubility includes fenofibrate, bicalutamide, atorvastatin, fluvastatin, simvastatin, candesartan, ezetimibe, oxcarbazepine, meloxicam, celecoxib, rofecoxib, valdecoxib, raloxifene, aripiprazole or glyburide.
  • the at least one pharmaceutically acceptable excipient other than the at least one pharmaceutically acceptable sugar is preferably included in the granulate.
  • the present invention also relates to a process for making a granulate of a pharmaceutical composition, useful for making, among other things, oral solid dosage forms, comprising the steps of (a) combining an active pharmaceutical ingredient (i.e. "API") having poor water solubility with a solution of at least one pharmaceutically acceptable sugar, for example a pyranosyl pyranose such as lactose, and optionally at least one pharmaceutically acceptable excipient other than the at least one pharmaceutically acceptable sugar to form a combined mixture, wherein the solution comprises the at least one pharmaceutically acceptable sugar and at least one solvent; (b) drying the combined mixture of step (a); and (c) comminuting the product of step (b) to obtain the granulate.
  • API active pharmaceutical ingredient having poor water solubility
  • a solution of at least one pharmaceutically acceptable sugar for example a pyranosyl pyranose such as lactose
  • excipient other than the at least one pharmaceutically acceptable sugar
  • the at least one pharmaceutically acceptable excipient other than the at least one pharmaceutically acceptable sugar is preferably included in the combining step (a).
  • the at least one solvent in the solution of the at least one pharmaceutically acceptable sugar is preferably water.
  • Suitable pharmaceutically acceptable excipients include a polymer or copolymer of vinyl pyrrolidone and a wetting agent, for example sodium lauryl sulfate.
  • Other pharmaceutically acceptable excipients, especially microcrystalline cellulose, can be and preferably are combined in the process.
  • the product of comminution is termed a granulate and can be used directly as a pharmaceutical formulation, or it can be and preferably is blended with one or more additional pharmaceutically acceptable excipients prior to use, which can be one or more of pharmaceutically acceptable sugars and pharmaceutically acceptable excipients other than the one or more of pharmaceutically acceptable sugars.
  • additional pharmaceutically acceptable excipients can be one or more of pharmaceutically acceptable sugars and pharmaceutically acceptable excipients other than the one or more of pharmaceutically acceptable sugars.
  • the present invention relates to a process for making a granulate of a pharmaceutical composition, useful for making, among other things, oral solid dosage forms whereby bicalutamide, a known non-steroidal anti-androgen agent, is combined with a solution of at least one pharmaceutically acceptable sugar, for example lactose, and at least one pharmaceutically acceptable excipient other than the at least one pharmaceutically acceptable sugar.
  • Suitable pharmaceutically acceptable excipients include a polymer or copolymer of vinyl pyrrolidone and a wetting agent, for example sodium lauryl sulfate.
  • Other pharmaceutically acceptable excipients, especially microcrystalline cellulose can be, and preferably are, combined in the process.
  • the combined product is dried and comminuted to form a particulate.
  • the particulate is a granulate of the present invention and can be used directly as a pharmaceutical formulation, or it can be and preferably is blended with one or more additional pharmaceutically acceptable excipients prior to use, which can be one or more of pharmaceutically acceptable dissaccahrides and pharmaceutically acceptable excipients other than sugars.
  • the present invention relates to a process for making a granulate of a pharmaceutical composition, useful for making, among other things, oral solid dosage forms, whereby an active pharmaceutical ingredient, especially bicalutamide, having poor water solubility is combined with microcrystalline cellulose, at least one non-crosslinked polymer of vinyl pyrrolidone, at least one disintegrant and wetting agent and an aqueous solution (for example, ca. 1:1, wt.:wt.) of lactose.
  • the combined product is then dried and comminuted, for example by high-energy milling, to form a particulate that is a granulate of the present invention and can be used directly or it can be, and preferably is, blended with one or more additional pharmaceutically acceptable excipients prior to use, which can be one or more of pharmaceutically acceptable disaccharides and pharmaceutically acceptable excipients other than sugars.
  • the present invention relates to the granulate prepared by any of the processes described above.
  • the present invention relates to a granulate prepared by combining bicalutamide, microcrystalline cellulose, croscarmellose sodium, povidone (polyvinylpyrrolidone, "PVP"), sodium lauryl sulfate and an aqueous solution of lactose monohydrate to form a combined product, drying the combined product, blending the dried combined product with colloidal silicon dioxide, and comminuting the resulting blend to obtain the granulate.
  • PVP polyvinylpyrrolidone
  • Figure 1 depicts the dissolution profile of fenofibrate tablets prepared from Formulation 1 described below, and the dissolution profile of commercial fenofibrate tablets, Tricor 160 mg.
  • the present invention provides granulates of a pharmaceutical composition having an active pharmaceutical ingredient, i.e. a drug, having poor water solubility and a method for making the granulate.
  • the granulates are useful for making oral solid dosage forms, for example capsules and compressed tablets in a variety of shapes.
  • the advantages of the present inventive composition and method are notable with active pharmaceutical ingredients that have poor solubility in water.
  • An API or drug is considered poorly water soluble if it has a solubility of less than about 20 mg per ml of water at about 25 0 C.
  • active pharmaceutical ingredient, which has poor water solubility or “active pharmaceutical ingredient having poor water solubility” means an API or drug having a solubility in water of less than about 20 mg per ml at about 25 0 C.
  • active pharmaceutical ingredient, which has poor water solubility or “active pharmaceutical ingredient having poor water solubility” include fenofibrate, bicalutamide, atorvastatin, fluvastatin, simvastatin, candesartan, ezetimibe, oxcarbazepine, meloxicam, celecoxib, rofecoxib, valdecoxib, raloxifene, aripiprazole or glyburide.
  • Bicalutamide is a poorly water soluble active pharmaceutical agent particularly well suited for use in the present invention.
  • the active pharmaceutical ingredient (API) having poor water solubility and the at least one pharmaceutically acceptable sugar are intimately associated or in intimate association.
  • the term "intimately associated” or “intimate association” refers to a state produced by a process comprising mixing the API and a solution of the at least one pharmaceutically acceptable sugar to form a mixture and drying the mixture.
  • the API and the at least one pharmaceutically acceptable sugar in the dried mixture are intimately associated or in intimate association.
  • the dried mixture in intimate association can be comminuted later to obtain granulates of an appropriate size.
  • the state of being "intimately associated” or in “intimate association” is different from an ordinary state resulting from mixing powders of the API and powders of the at least one pharmaceutically acceptable sugar, optionally followed by compaction of the powder mixture.
  • the intimate-association state differs from the ordinary state generated by mixing the API powders and sugar powders at least in that the at least one pharmaceutically acceptable sugar is more tightly adhered to the API in the intimate-association state than the ordinary state.
  • the at least one pharmaceutically acceptable sugar forms a fairly or substantially continuous solid phase around a powder or granule of the API.
  • the API having poor water solubility and the at least one pharmaceutically acceptable sugar are in intimate association, with the API and the at least one pharmaceutically acceptable sugar combined in a matrix having a fairly or substantially continuous phase achieved by drying a mixture of the API and a solution of the at least one pharmaceutically acceptable sugar.
  • the matrix of the intimate association of the API and the at least one pharmaceutically acceptable sugar achieves a consistency and stable adherence between the API and sugar(s) not achievable with the prior art process of mixing powders of the corresponding API with powders of the least one pharmaceutically acceptable sugar.
  • the pharmaceutical composition of the invention has superior dissolution properties than the prior art powder mix of the corresponding API and the at least one pharmaceutically acceptable sugar.
  • compositions of the invention are distinguished from the prior art products of classic lyophilization or freeze-drying where in contrast to the compositions of the present invention, the resultant product of that prior art technique generally results in a "cake" of a fluffy fragile matrix that can reportedly achieve improved dissolution by the "airy” and or porous nature of the matrix resulting from the lyophilization technique. It is however contemplated that, in the process for making the granulate of a pharmaceutical composition according to the present invention, the step of drying the combined mixture may include procedures where this drying is achieved at least partially by sublimation.
  • a poorly water soluble active pharmaceutical agent incorporated, by being intimately associated with at least one pharmaceutically acceptable sugar, into the granulate of the pharmaceutical composition of the present invention dissolves faster and to a greater extent in aqueous media than does the same poorly water soluble active pharmaceutical agent incorporated into a granulate or tablet made by conventional methods and/or by direct compression methods.
  • the improved dissolution of the active pharmaceutical ingredient having poor water solubility in the granulate of the present invention can be determined by tests conducted under conditions at least as stringent as using 1000 ml of a 1% aqueous solution of sodium lauryl sulfate at 37° C with the USP paddle method rotating at 50 rpm and sampling time of 15, 30, 45 or 60 min, wherein if the active pharmaceutical ingredient is bicalutamide the amount of bicalutamide released is determined with a UV detector at 272 nm.
  • the granulate prepared by the method of the present invention can be fabricated into a compressed tablet and the dissolution of the active pharmaceutical ingredient determined by a suitable technique, for example dissolution test ⁇ 711> of the United States Pharmacopoeia, and compared to the dissolution measured for a tablet compressed using conventionally produced granulate.
  • a suitable technique for example dissolution test ⁇ 711> of the United States Pharmacopoeia
  • a pharmaceutical dosage form comprising the granulate of the invention can have a dissolution property in which at least 50% of the bicalutamide dissolves in about 15 minutes, preferably at least about 65% of the bicalutamide dissolves in about 30 minutes, and more preferably at least 75% of the bicalutamide dissolves in about 45 minutes when tested under conditions at least as stringent as 1000 ml of a 1% aqueous solution of sodium lauryl sulfate at 37° C using a USP paddle method rotating at 50 rpm when measured by a UV detector at 272 nm.
  • the pharmaceutical dosage form of the invention can release about 80% of the bicalutamide in about 15 minutes or about 95% of the bicalutamide in about 30 minutes, when tested under conditions at least as stringent as 1000 ml of a 1% aqueous solution of sodium lauryl sulfate at 37° C using a USP paddle method rotating at 50 rpm when measured by a UV detector at 272 nm.
  • the term "at least one pharmaceutically acceptable sugar” refers to a pharmaceutically acceptable monosaccharide, disaccharide or mixtures thereof, with the "at least one pharmaceutically acceptable sugar” comprises preferably at least a pharmaceutically acceptable disaccharide.
  • the "at least one pharmaceutically acceptable sugar” include mannitol, sorbitol, glucose, fructose, galactose and, preferably, a disaccharide such as sucrose and, more preferably, a pyranosyl pyranose (e.g., maltose, isomaltose, cellobiose, melibiose, gentiobiose and, most preferably, lactose).
  • the "at least one pharmaceutically acceptable sugar" to be combined with the API is in the form of a solution, preferably an aqueous solution or water/organic solution, in a sugar-to- solvent ratio generally between about 0.05: 1 to about 1 :0.05, preferably about 0.1 : 1 to about 1 :0.1 , more preferably about 0.5: 1 to about 1 :0.5 and most preferably about 1 : 1 (wt/wt; based on the total weight of the at least one pharmaceutically acceptable sugar : the weight of the solvent in the sugar solution).
  • the weight ratio of the sugar (originated from the granulation solution) and the API having poor water solubility in the granulate can be from about 0.1 : 1 to about 1000: 1 , and preferably from about 0.1 : 1 to about 100:1 or from about 0.1 :1 to about 10:1, e.g. about 0.5:1, about 1 :1, about 2:1, about 3:1, about 5:1, about 10:1 or about 50:1.
  • relatively high dose products e.g.
  • the weight ratio of the sugar and the API having poor water solubility in the granule is preferably about 0.5:1 to about 5:1, e.g. about 0.5:1, about 1:1, about 2:1 or about 3:1, and more preferably about 0.7:1.
  • the present invention provides tablets comprising the granulate of the present invention, wherein the active pharmaceutical ingredient having poor water solubility in the granulate is bicalutamide, wherein the weight ratio of the sugar and bicalutamide can be about 0.7:1.
  • Many active pharmaceutical ingredients can be administered to a subject, particularly a human, in need of treatment with that active pharmaceutical ingredient in the form of an oral solid dosage form.
  • Oral solid dosage forms are rarely fabricated from neat active pharmaceutical ingredient. Rather, they are often fabricated of a granulate made by combining an active pharmaceutical ingredient with one or more pharmaceutically acceptable excipients. It is well known that pharmaceutically acceptable excipients can be broadly classified according to their intended function in the granulate or oral solid dosage form.
  • pharmaceutical formulation knows that a given excipient may perform more than one function and the function of an excipient can depend on the kind and amount of other excipients used, as well as the particular active pharmaceutical ingredient used.
  • Classes of pharmaceutically acceptable excipients other than the at least one pharmaceutically acceptable sugar include diluents, binders, lubricants, glidants, disintegrants, wetting agents and coloring and flavoring agents.
  • Common diluents are microcrystalline cellulose (e.g. Avicel®), lactose and starch among many others well known in the art.
  • Binders also may be included in tablet formulations to help hold the tablet together after compression. Some typical binders are carboxymethylcellulose sodium, ethylcellulose, gelatin, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), povidone (e.g.
  • a tablet may further include a disintegrant to accelerate disintegration of the tablet in the patient's stomach.
  • Disintegrants may typically include croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), microcrystalline cellulose, pregelatinized starch, sodium starch glycolate (e.g. Explotab®) among many others well known in the art.
  • a pharmaceutical composition for making compressed tablets may further include glidants, lubricants, flavorings, colorants and other commonly used pharmaceutically acceptable excipients.
  • a novel process of preparing a pharmaceutical granulate that includes the steps of combining an active pharmaceutical ingredient having poor water solubility with a solution, preferably aqueous, of at least one pharmaceutically acceptable sugar and optionally at least one or, preferably more than one, pharmaceutically acceptable excipients other than the at least one pharmaceutically acceptable sugar; drying the product of the combining step; and comminuting the dried product.
  • Suitable pharmaceutically acceptable excipients include a polymer or copolymer of vinyl pyrrolidone and a wetting agent, for example sodium lauryl sulfate.
  • the combining can be by any mixing or dispersing means as is known in the art.
  • weighed ingredients including the aqueous solution of the at least one sugar, can be combined using a twin-shell mixer of the Patterson-Kelly type, a planetary mixer of the Glen type, or a high shear/high intensity or high speed mixer of the Henschel, Lodige/Littleford, or Baker-Perkins types, to mention just a few.
  • a high shear/high intensity mixer is the preferred means of combining.
  • At least one pharmaceutically acceptable excipient that is a polymer of vinyl pyrrolidone is included in the combining step and incorporated into the granulate.
  • Suitable polymers of vinyl pyrrolidone include the povidones and crospovidones, available from, for example, the BASF Corporation of Mt. Olive NJ or International Specialty Products of Wayne NJ, USA.
  • Povidone is example of preferred polymers of vinyl pyrrolidone.
  • microcrystalline cellulose e.g., Avicel®, available from FMC Corporation
  • the product of the combining step can be dried, for example in a tray drier or fluidized bed drier, optionally sieved, then comminuted to obtain the granulate.
  • the comminuting can be by any means known in the art, for example milling. A Fitzpatrick mill with 0.5 mm screen is suitable for use in the comminuting step.
  • the rate and extent of dissolution are preferably measured on tablets compressed from granulate and using methods well known in the art and published, for example, in the United States Pharmacopeia.
  • collodial silicon dioxide is blended with the dried combined product prior to comminution.
  • the blending can be by any means known in the art, for example with a planetary mixer or high speed mixer.
  • the granulate obtained can be used directly, or it can be blended with one or more additional pharmaceutically acceptable excipients prior to use.
  • granulate is blended with lubricant prior to use, for example prior to being compressed into tablets.
  • a preferred combining step the following are combined in a high shear mixer: from about 0.3 to about 75 wt.-% of the API having poor water solubility, from about 5 to about 45 wt.-% of diluent(s), from about 5 to about 15 wt.-% of disintegrant(s), from about 0.5 to about 8 wt.-% binder(s), from about 1 to about 10 wt.-% of wetting agent(s), and from about 1 to about 50 wt-% of the solution (ca. 1:1, sugar weightsolvent weight) of the at least one pharmaceutically acceptable sugar.
  • the at least one pharmaceutically acceptable sugar used in the preferred combining step above is preferably lactose.
  • An aqueous solution of lactose is particularly preferred as the solution of sugar used in the above preferred combining step.
  • a person skilled in the art can optimize the amount of the aqueous lactose solution used to obtain a mixture with the desired consistency and comminuting characteristics.
  • the product from combining the above ingredients is dried, blended with a glidant (about 0.5 to 1.5 wt.-% based on the weight of the product from combination), and the resultant mixture comminuted using a suitable mill exemplified by a Fitzpatrick impact mill.
  • the comminuted mixture is processed directly (e.g. pressed into tablet cores), or it can be and preferably is blended with lubricant before processing.
  • Example 1 and 2 are for comparison purposes.
  • Examples 3 and 4 are working examples.
  • the dry ingredients were dry mixed in a blender and compressed into tablets.
  • the dissolution rates of the resultant tablets were too low, i.e. only about 50% of the active pharmaceutical ingredients dissolved after 45 min, when tested in 1000 mL of 0.05 M aqueous SLS solution, padddle at 75 rpm, at 37 0 C .
  • the resultant tablet's dissolution rate was also too low in that only about 55% of the active pharmaceutical ingredient dissolved after 45 min on average when tested in 1000 mL of 0.05 M aqueous SLS solution, padddle at 75 rpm, at 37 0 C.
  • Experimental batch K-31557 was manufactured by using a solution of lactose monohydrate in purified water as a granulation solution.
  • the formulation ingredients (bicalutamide, microcrystalline cellulose, povidone, croscarmellose sodium and sodium lauryl sulfate) were combined in a high speed mixer with a solution (1 :1, lactose monohydrate wt: water wt) of lactose monohydrate in purified water.
  • the product from the combining step was dried, blended with colloidal silicon dioxide, and milled in a Fitzpatrick impact mill.
  • the granulate so obtained was blended with microcrystalline cellulose and magnesium stearate and compressed into tablet cores in the usual way and the tablet cores were coated.
  • Example 4 (working example):
  • a fenofibrate composition, Formulation 1, was made by the wet granulation process of the present invention.
  • the ingredients in Table 3 were wet granulated and then compressed into tablets each weighing 750 mg.
  • the process of preparing Formulationl is an example of applying the basic concept of the invention using a solution of lactose (lactose : water, 1 : 1 , v: v) as a binder in the granulation process, followed by drying the mixture and milling the resulting granules. All other non-API components in the granulation mixture may have an effect on the final results but are not critical for applying the concept of the invention and therefore can be replaced (by different components of the same type) or partially omitted.
  • the weight ratios of the granulation components versus the API can be higher or lower than that in Formulation 1.
  • the weight ratios are higher than that in Formulation 1 in order to at least maintain or even increase the dissolution rate compare to the dissolution of Formulation 1.
  • the amount and concentration of the lactose solution used are important.
  • the making of Formulation 1 used a solution of lactose (lactose : water, 212 mg : 212 mg) equal to 424 mg which is 40% of the total granulation mixture (solids and water) by weight.
  • the solution of the at least one pharmaceutically acceptable sugar can be between about 15 to about 60%, by weight, of the total granulation mixture, and more preferably between about 35 to about 50% of the total granulation mixture.
  • An increase in the amount of lactose (added as a solution) used can further improve the final results of the invention.
  • Example 4 the granules were intensively milled with FitzmillTM Communitor equipped with a 0.5 mm screen resulting in powder with particle size distribution shown in Table 4, wherein the particle size was determined with sonic filter methodology using ATM Sonic filter or GilsonAutosiever GA equipped with sieves of 60, 80,100,140,170, and Pan. Table 3
  • Pruv (Sodium Stearyl Fumarate) 12 1.6
  • the granulates were prepared with a method comprising the following steps:
  • Lactose of Part II was dissolved in 212 mg of water heated to about 7O 0 C.
  • step 1 was granulated by adding the lactose and SLS solutions of steps 2 and 3 to form granules.
  • step 4 The granules of step 4 were dried in a Fluidized Bed Drier (FBD) (inlet air 55°C, outlet air Not More Than 4O 0 C ) .
  • BBD Fluidized Bed Drier
  • Aerosil of Part III was blended with the dried granules of step 5 and then milled with FitzmillTM fitted with a 0.5 mm aperture screen. 7. The Part IV ingredients were then blended with the milled granules of step 6 for about 2 minutes to form a final blend. 8. The final blend was compressed into tablets. Table 4
  • Table 4 shows that at least about 72% of the milled granules passed through the 80 mesh screen and at least about 66% passed through the 100 mesh screen.
  • the pharmaceutical granulates of the present invention comprising the active pharmaceutical ingredient, e.g. fenofibrate, of poor aqueous solubility intimately associated with the at least one pharmaceutically acceptable sugar can have particle size distribution in that at least about 70% passes through a 80 mesh screen, at least about 60% passes through a 100 mesh screen and at least about 50% passes through a 140 mesh screen.
  • the solid pharmaceutical formulations, e.g., tablets, of the present invention can display dissolution properties such that after about 10 minutes at least about 50%, preferably at least about 60%, is dissolved; after about 20 minutes at least about 70%, more preferably at least about 75%, is dissolvoed; after about 30 minutes at least about 80%, more preferably at least about 85%, is dissolved; and after about 40 minutes at least about 90%, preferably at least about 95%, and more preferably about 98% to about 100%, is dissolved, when determined under conditions at least as stringent as 1000 mL of 0.05 M aqueous SLS solution, padddle at 75 rpm, at 37 0 C.

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention a trait, entre autres, à une composition pharmaceutique sous la forme d'un matière granulée, dans laquelle les granulés comportent un ingrédient pharmaceutique actif présentant une faible solubilité dans l'eau intimement associé à un sucre pharmaceutiquement acceptable, et éventuellement ou préférablement, au moins un excipient pharmaceutiquement acceptable, ledit ingrédient pharmaceutiquement actif présentant une solubilité dans l'eau inférieure à environ 20 mg/ml. Ledit au moins un excipient pharmaceutiquement acceptable autre que ledit au moins un sucre pharmaceutiquement acceptable est choisi parmi le groupe constitué d'agents de désintégration, d'agents de mouillage, de diluants, de liants, de lubrifiants, d'agents de glissement, d'agents colorants et d'aromatisants. Ledit un sucre pharmaceutiquement acceptable est choisi de préférence parmi les pyranoses de pyranosyle tels que le lactose. L'invention a également trait à un procédé pour la préparation d'un granulé pharmaceutique, comprenant: (a) la combinaison d'un ingrédient pharmaceutique actif présentant une faible solubilité dans l'eau avec une solution d'au moins un sucre pharmaceutiquement acceptable, par exemple un pyranose de pyranosyle telle que le lactose, et un solvant, et éventuellement au moins un excipient pharmaceutiquement acceptable autre que ledit au moins un sucre pharmaceutiquement acceptable pour former un mélange combiné; (b) le séchage du mélange combiné de l'étape (a); et (c) la fragmentation du produit de l'étape (b) pour obtenir le granulé.
PCT/US2005/025326 2005-07-15 2005-07-15 Nouveau procede de granulation et granule produit par ce procede WO2007011349A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP05772375A EP1793801A1 (fr) 2005-07-15 2005-07-15 Nouveau procede de granulation et granule produit par ce procede
JP2008512255A JP2008540644A (ja) 2005-07-15 2005-07-15 新規粒質化方法及びそれから生成される粒質物
CA002614468A CA2614468A1 (fr) 2005-07-15 2005-07-15 Nouveau procede de granulation et granule produit par ce procede
CNA2005800510501A CN101222911A (zh) 2005-07-15 2005-07-15 新的制粒方法及由此制备的颗粒
PCT/US2005/025326 WO2007011349A1 (fr) 2005-07-15 2005-07-15 Nouveau procede de granulation et granule produit par ce procede
IL188177A IL188177A0 (en) 2005-07-15 2007-12-17 Novel granulation process and granulate produced therefrom

Applications Claiming Priority (1)

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PCT/US2005/025326 WO2007011349A1 (fr) 2005-07-15 2005-07-15 Nouveau procede de granulation et granule produit par ce procede

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WO2007011349A1 true WO2007011349A1 (fr) 2007-01-25

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EP (1) EP1793801A1 (fr)
JP (1) JP2008540644A (fr)
CN (1) CN101222911A (fr)
CA (1) CA2614468A1 (fr)
IL (1) IL188177A0 (fr)
WO (1) WO2007011349A1 (fr)

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WO2007141806A1 (fr) * 2006-06-02 2007-12-13 Jubilant Organosys Ltd Formulations pharmaceutiques comprenant de l'oxcarbazépine et procédés correspondants
EP1889610A3 (fr) * 2006-08-17 2008-02-27 Dr. Reddy's Laboratories Ltd. Compositions à base de bicalutamide
WO2008099160A1 (fr) * 2007-02-14 2008-08-21 Pliva Hrvastka D.O.O. Forme posologique orale solide contenant du bicalutamide et procédé de préparation
JP2009029713A (ja) * 2007-07-24 2009-02-12 Kobayashi Kako Kk ビカルタミドを含有する医薬組成物及びその製造方法
US7756534B2 (en) 2006-05-19 2010-07-13 Alcatel-Lucent Usa Inc. Provision of location-based services utilizing user movement statistics
JP2012502987A (ja) * 2008-09-17 2012-02-02 マイラン インコーポレイテッド 粒状体、それらの調製方法、およびそれらを含む医薬品
US8865722B2 (en) 2006-01-05 2014-10-21 Teva Pharmaceutical Industries Ltd. Wet formulations of aripiprazole
CN111759820A (zh) * 2020-08-24 2020-10-13 武汉人福药业有限责任公司 一种奥卡西平片剂及其制备方法
WO2020219406A1 (fr) * 2019-04-22 2020-10-29 Mylan Specialty L.P. Compositions de co-cristaux de méloxicam
US12115222B2 (en) 2023-01-23 2024-10-15 Villya LLC Compositions and methods for improving the solubility of erectile dysfunction therapeutics
US12390417B2 (en) 2020-08-12 2025-08-19 Villya LLC Praziquantel formulations

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SI2165702T1 (sl) 2008-09-17 2012-05-31 Helm Ag Stabilni in z lahkoto raztopljeni sestavki kandesartan cileksetila pripravljeni z vlažno granulacijo
US20120010216A1 (en) * 2010-07-06 2012-01-12 Brown Arthur M Pharmaceutical compositions containing vanoxerine
ES2969014T3 (es) * 2015-06-30 2024-05-16 Genentech Inc Comprimidos de liberación inmediata que contienen un fármaco y procesos para la formación de los comprimidos
CN108524527B (zh) * 2017-03-02 2020-08-04 北京德立福瑞医药科技有限公司 塞来昔布药物组合物及其制备方法

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8865722B2 (en) 2006-01-05 2014-10-21 Teva Pharmaceutical Industries Ltd. Wet formulations of aripiprazole
US7756534B2 (en) 2006-05-19 2010-07-13 Alcatel-Lucent Usa Inc. Provision of location-based services utilizing user movement statistics
WO2007141806A1 (fr) * 2006-06-02 2007-12-13 Jubilant Organosys Ltd Formulations pharmaceutiques comprenant de l'oxcarbazépine et procédés correspondants
EP1889610A3 (fr) * 2006-08-17 2008-02-27 Dr. Reddy's Laboratories Ltd. Compositions à base de bicalutamide
WO2008099160A1 (fr) * 2007-02-14 2008-08-21 Pliva Hrvastka D.O.O. Forme posologique orale solide contenant du bicalutamide et procédé de préparation
JP2009029713A (ja) * 2007-07-24 2009-02-12 Kobayashi Kako Kk ビカルタミドを含有する医薬組成物及びその製造方法
EP2331074A4 (fr) * 2008-09-17 2012-09-19 Mylan Inc Granulés, leur procédé de préparation et produits pharmaceutiques les contenant
JP2012502987A (ja) * 2008-09-17 2012-02-02 マイラン インコーポレイテッド 粒状体、それらの調製方法、およびそれらを含む医薬品
WO2020219406A1 (fr) * 2019-04-22 2020-10-29 Mylan Specialty L.P. Compositions de co-cristaux de méloxicam
CN113710231A (zh) * 2019-04-22 2021-11-26 麦兰专业有限合伙公司 美洛昔康共晶组合物
US12390417B2 (en) 2020-08-12 2025-08-19 Villya LLC Praziquantel formulations
CN111759820A (zh) * 2020-08-24 2020-10-13 武汉人福药业有限责任公司 一种奥卡西平片剂及其制备方法
CN111759820B (zh) * 2020-08-24 2022-04-19 武汉人福药业有限责任公司 一种奥卡西平片剂及其制备方法
US12115222B2 (en) 2023-01-23 2024-10-15 Villya LLC Compositions and methods for improving the solubility of erectile dysfunction therapeutics

Also Published As

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JP2008540644A (ja) 2008-11-20
CN101222911A (zh) 2008-07-16
CA2614468A1 (fr) 2007-01-25
IL188177A0 (en) 2008-03-20
EP1793801A1 (fr) 2007-06-13

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