CN101222911A - Novel pelletization process and particle produced by the same - Google Patents

Novel pelletization process and particle produced by the same Download PDF

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Publication number
CN101222911A
CN101222911A CNA2005800510501A CN200580051050A CN101222911A CN 101222911 A CN101222911 A CN 101222911A CN A2005800510501 A CNA2005800510501 A CN A2005800510501A CN 200580051050 A CN200580051050 A CN 200580051050A CN 101222911 A CN101222911 A CN 101222911A
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CN
China
Prior art keywords
pharmaceutically acceptable
granule
sugar
active pharmaceutical
pharmaceutical ingredient
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CNA2005800510501A
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Chinese (zh)
Inventor
I·扎利特
J·赫拉科夫斯基
R·特嫩高泽
S·沙洛姆-克莱因
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Teva Pharmaceutical Industries Ltd
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Teva Pharmaceutical Industries Ltd
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Publication of CN101222911A publication Critical patent/CN101222911A/en
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    • 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

Abstract

One of the objects of the invention relates to a pharmaceutical composition in the form of a granulate, wherein the granulates comprises an active pharmaceutical ingredient (API) having a poor water solubility intimately associated with at least one pharmaceutically acceptable sugar, and optionally or preferably at least one pharmaceutically acceptable excipient other than the at least one pharmaceutically acceptable sugar, wherein the active pharmaceutically ingredient has a water solubility less than about 20 mg/ml. The at least one pharmaceutically acceptable excipient other than the at least one pharmaceutically acceptable sugar is selected from the group consisting of disintegrants, wetting agents, diluents, binders, lubricants, glidants, coloring agents and flavoring agents. The at least one pharmaceutically acceptable sugar is preferably selected from pyranosyl pyranoses, such as lactose. Another object of the invention relates to a process for preparing a pharmaceutical granulate, comprising (a) combining an API having poor water solubility with a solution comprising at least one pharmaceutically acceptable sugar, for example a pyranosyl pyranose such as lactose, and a solvent, and optionally at least one pharmaceutically acceptable excipient other than the at least one pharmaceutically acceptable sugar to form a combined mixture; (b) drying the combined mixture of step (a); and (c) comminuting the product of step (b) to obtain the granulate.

Description

New method of granulating and the granule for preparing thus
Technical field
The present invention relates to be used for the granule of pharmaceutical preparation, it comprises active pharmaceutical ingredient with poorly water-soluble and the pharmaceutically acceptable sugar of combining closely, and illustrates as bicalutamide or the fenofibrate that is suitable for preparation tablets by preparation.
Background technology
The dissolubility of active pharmaceutical ingredient (API) influences bioavailability of medicament, and the dissolution of medicine can be determined the upper limit of drug absorption rate usually.Many active medicines have poor dissolubility in water, typically, thereby reduced bioavailability.Adopted the particle diameter that reduces active pharmaceutical ingredient and increased the dissolution that surface area improves active pharmaceutical ingredient accordingly, it has obtained certain success.Yet, particle diameter and the whole flow (bulk flow) of difference and the influence of machining feature that this method can be obtained by the fine-powdered active pharmaceutical ingredient.
Firmly grind conventional granulates and can increase the surface area that is included in active component wherein.This can produce fine powder powdered fully, that be difficult to process.This powder of granulating again can cause that surface area reduces in order to improve processing.The use of the hard binding agent of high level can cause that dissolution increases, and may be because surface area increases, but the degree of improving is limited.In July, 2002 open name be called in the anonymous article of " Formulations Comprising Lipid-Regulating Agents " and the publication that is designated " JJPCOM000008767D " published in August, 2002 IP.com the 2nd daily record the 8th phase of rolling up in the article that occurs, mention that use " syrup solution of lactose " can increase surface area and dissolution rate as " stronger " granule that binder solution grinds preparation, but can not obtain to make a kind of material to obtain required result's important detailed content, and the hint of the useful content that is used for any other API that can not obtain to determine.The content of this piece article all is incorporated herein by reference with it.
Undoubtedly, have the needs of the improved method be used to obtain medicament composition granule, wherein active pharmaceutical ingredient demonstrates the surface area of maximum possible to promote stripping.The inventor find surprisingly mixed sugar for example the solution of lactose prepare a kind of granule with the branch that becomes of medicine granule for treating as described herein, it can be pulverized to obtain to can be used for forming the granule of oral dosage form, and the stripping that described oral dosage form demonstrates active pharmaceutical ingredient surprisingly increases.
Summary of the invention
One aspect of the present invention relates to the granule that is used for pharmaceutical composition, especially oral dosage form is useful such as capsule and tablet for preparing for it, wherein said granule comprises active pharmaceutical ingredient (i.e. " API ") with poorly water-soluble and at least a pharmaceutically acceptable sugar of combining closely, for example pyrans glycosyl pyranose (pyranosyl pyranose) is such as lactose with randomly be different from least a pharmaceutically acceptable excipient of described at least a pharmaceutically acceptable sugar.Described active pharmaceutical ingredient with poorly water-soluble comprises fenofibrate, bicalutamide, atorvastatin, fluvastatin, simvastatin, Candesartan, ezetimibe, oxcarbazepine, meloxicam, celecoxib, rofecoxib, valdecoxib, raloxifene, Aripiprazole or glibenclamide.Preferably, will be different from least a pharmaceutically acceptable excipient of described at least a pharmaceutically acceptable sugar adds in the described granule.
The present invention also relates to be used for the particulate method of pharmaceutical compositions, especially oral dosage form is useful to preparing for described granule, it comprise step (a) mix active pharmaceutical ingredient (i.e. " API ") with poorly water-soluble and at least a pharmaceutically acceptable sugar for example pyrans glycosyl pyranose such as the solution of lactose with randomly be different from least a pharmaceutically acceptable excipient of described at least a pharmaceutically acceptable sugar, form blended mixture, wherein said solution comprises described at least a pharmaceutically acceptable sugar and at least a solvent; (b) the blended mixture of drying steps (a); (c) product of pulverising step (b) obtains granule.Preferably, will be different from least a pharmaceutically acceptable excipient of described at least a pharmaceutically acceptable sugar adds in the described blend step (a).At least a solvent in described at least a pharmaceutically acceptable sugar juice is preferably water.
Suitable pharmaceutically acceptable excipient comprises for example sodium lauryl sulphate of the polymer of vinyl pyrrolidone or copolymer and wetting agent.In the method, can mix and preferably mix other pharmaceutically acceptable excipient, especially microcrystalline Cellulose.The product of pulverizing is called granule, it can be used as pharmaceutical preparation and directly uses, perhaps before use with its can and preferably with one or more other pharmaceutically acceptable mixed with excipients, described excipient can be one or more pharmaceutically acceptable sugar and be different from the pharmaceutically acceptable excipient of described one or more pharmaceutically acceptable sugar.Only when granule is the product of pulverizing as defined above, just can realize advantage of the present invention.
In yet another aspect, the present invention relates to be used for the particulate method of pharmaceutical compositions, especially oral dosage form is useful to preparing for described granule, wherein with bicalutamide, a kind of known non-steroidal androgen antagonist reagent and at least a pharmaceutically acceptable sugar is the solution and at least a pharmaceutically acceptable mixed with excipients that is different from described at least a pharmaceutically acceptable sugar of lactose for example.Suitable pharmaceutically acceptable excipient comprises for example sodium lauryl sulphate of the polymer of vinyl pyrrolidone or copolymer and wetting agent.In the method, can mix and preferably mix other pharmaceutically acceptable excipient, especially microcrystalline Cellulose.Drying is also pulverized described product of mixing, forms granule.Described granule is a granule of the present invention, it can be used as pharmaceutical preparation and directly uses, perhaps its can and preferably before use with one or more other pharmaceutically acceptable mixed with excipients, described other pharmaceutically acceptable excipient can be one or more pharmaceutically acceptable disaccharide and the pharmaceutically acceptable excipient that is different from sugar.
In yet another aspect, the present invention relates to be used for the particulate method of pharmaceutical compositions, especially oral dosage form is useful to preparing for described granule, and the active pharmaceutical ingredient that wherein will have a poorly water-soluble is aqueous solution (for example about 1: 1 wt: wt) mix of bicalutamide and the non-cross-linked polymer of microcrystalline Cellulose, at least a vinyl pyrrolidone, at least a disintegrating agent and wetting agent and lactose especially.Then, drying is also pulverized described product of mixing, for example pass through high energy milling, to form granule, it is granule of the present invention, it can directly use, perhaps its can and preferably before use with one or more other pharmaceutically acceptable mixed with excipients, described other pharmaceutically acceptable excipient can be one or more pharmaceutically acceptable disaccharide and the pharmaceutically acceptable excipient that is different from sugar.
In yet another aspect, the present invention relates to granule by aforesaid any method preparation.
In yet another aspect, the present invention relates to granule: mix bicalutamide, microcrystalline Cellulose, cross-linked carboxymethyl cellulose sodium, polyvidone (polyvinylpyrrolidone by following process preparation, " PVP "), the aqueous solution of sodium lauryl sulphate and lactose monohydrate to be to form product of mixing, dry this product of mixing, the product that mixes this dry mixed and colloidal silica, and pulverize the mixture that obtains, obtain granule.
Description of drawings
Fig. 1 has described from the dissolution feature of the fenofibrate tablet of preparation as described below 1 preparation and the dissolution feature of commercially available fenofibrate tablet Tricor 160mg.
Detailed Description Of The Invention
The invention provides the particle of pharmaceutical composition and for the preparation of the method for this particle, it is medicine that described pharmaceutical composition contains the active pharmaceutical ingredient with poorly water-soluble. Described particle can be used for preparing oral dosage form, for example the compressed tablets of capsule and various shapes. The advantage of the compositions and methods of the invention is significant to have poor water miscible active pharmaceutical ingredient in water. If at about 25 ℃, the solubility that API or medicine have is less than the water of the every ml of about 20mg, then think its poorly water-soluble.
In this application, term " active pharmaceutical ingredient, it has poorly water-soluble " or " active pharmaceutical ingredient with poorly water-soluble " refer to be less than in about 25 ℃ of solubility that have in water API or the medicine of the every ml of about 20mg. " active pharmaceutical ingredient, it has poor water-soluble " or the example of " active pharmaceutical ingredient with poorly water-soluble " comprise fenofibrate, Bicalutamide, Atorvastatin, Fluvastatin, Simvastatin, Candesartan, ezetimibe, Oxcarbazepine, Meloxicam, celecoxib, rofecoxib, valdecoxib, Raloxifene, Aripiprazole or glibenclamide. Bicalutamide is a kind of active pharmaceutical agent of poorly water-soluble, is specially adapted to the present invention.
At the particle for pharmaceutical composition of the present invention, active pharmaceutical ingredient (API) and at least a pharmaceutically acceptable sugar with poorly water-soluble are combined closely. Term " is combined closely " and is referred to by comprising that the solution that mixes API and at least a pharmaceutically acceptable sugar forms the state of mixture and dry this mixture generation. Described API and described at least a pharmaceutically acceptable sugar are combined closely in the mixture of drying. Afterwards, can pulverize the drying composite of combining closely to obtain the particle of suitable size. " combine closely " powder of state and the powder that mixes API and at least a pharmaceutically acceptable sugar, it is different to suppress the normality that this mixture of powders obtains after randomly. Described state of combining closely is different from the normality of mixing the generation of API powder and Icing Sugar end, compares with normality at least, and wherein at least a pharmaceutically acceptable sugar adheres to the API that is in the intimate-association state more tightly. In the intimate-association state of pharmaceutical composition of the present invention, at least a pharmaceutically acceptable sugar forms completely around the powder of API or particle or continuous solid phase basically.
Be to be understood that and comprise that with the non-pharmaceutical preparation of combining closely of medicine be that drug world is known. On the contrary, in pharmaceutical composition of the present invention, API and at least a pharmaceutically acceptable sugar with poorly water-soluble are combined closely, described API and described at least a pharmaceutically acceptable sugar mix in matrix, described matrix have that mixture by the described API of drying and described at least a pharmaceutically acceptable sugar obtains fully or basic continous mutually. The matrix of combining closely of API and at least a pharmaceutically acceptable sugar has realized denseness between API and the sugar and stable adhesion, and its method with the prior art of the powder of the powder that mixes corresponding API and at least a pharmaceutically acceptable sugar can not obtain. As the result of combine closely (with the particle that grinds described drying), pharmaceutical composition of the present invention has the Dissolution behaviours better than the prior art mixture of powders of corresponding API and at least a pharmaceutically acceptable sugar.
Pharmaceutical composition of the present invention is different from classical freeze-drying or cryodesiccated prior art product, wherein, compare with composition of the present invention, the final products of prior art produce " block (cake) " of soft fragility matrix (fluffy fragile matrix) usually, it is reported that it can cause the porous of matrix to improve dissolution rate by " ventilating (airy) " and/or Freeze Drying Technique and obtain. Yet, expectedly be that in the method for the preparation of medicament composition granule according to the present invention, the step of the mixture of dry mixed can comprise that wherein this drying is at least part of process that obtains by distillation. By closely being combined with at least a pharmaceutically acceptable sugar; join the active pharmaceutical agent of the poorly water-soluble in the particle of pharmaceutical composition of the present invention in aqueous medium; than joining the faster of active pharmaceutical agent dissolving by conventional method and/or the particle by direct compression process preparation or the identical poorly water-soluble in the tablet, and reach larger degree. Compare with the identical active pharmaceutical ingredient that joins by in the particle of conventional method preparation, having the improvement that poorly water-soluble gets active pharmaceutical ingredient dissolution rate in particle of the present invention can determine by the mensuration of carrying out under the condition of following at least strict (stringent): use in the USP of 50rpm oar method, at 37 ℃, use the aqueous solution of 1% the lauryl sodium sulfate of 1000 ml, sampling time is 15,30,45 or 60 minutes, if wherein described active pharmaceutical ingredient is Bicalutamide, detect the burst size of Bicalutamide at 272nm with the UV detector. For example, can will make tablet by the particle of method preparation of the present invention, with the suitable technology dissolution determination of American Pharmacopeia＜711 for example〉measure the dissolution rate of active pharmaceutical ingredient, and compare with the dissolution rate that uses the conventional tablet of producing the particle compacting to measure. When active pharmaceutical ingredient is Bicalutamide, when under following at least strict condition, measure and when by the UV detector when 272nm detects, the pharmaceutical dosage form that comprises particle of the present invention can have following Dissolution behaviours: wherein at least 50% Bicalutamide dissolved in about 15 minutes, preferably dissolve in about 30 minutes at least about 65% Bicalutamide, more preferably at least 75% Bicalutamide dissolved in about 45 minutes, described condition is: use the USP oar method in the 50rpm rotation, under 37 ℃, in 1% the lauryl sodium sulfate aqueous solution of 1000ml. For example, when described active pharmaceutical ingredient is Bicalutamide, when under following at least strict condition, measure and when by the UV detector when 272nm detects, pharmaceutical dosage form of the present invention can discharge about 80% Bicalutamide in about 15 minutes, or the Bicalutamide of release about 95% in about 30 minutes, described condition is: use the USP oar method in the 50rpm rotation, under 37 ℃, in 1% the lauryl sodium sulfate aqueous solution of 1000ml.
In present patent application, term " at least a pharmaceutically acceptable sugar " refers to pharmaceutically acceptable monose, disaccharides or its mixture, and " at least a pharmaceutically acceptable sugar " preferably includes at least a pharmaceutically acceptable disaccharides. The example of described " at least a pharmaceutically acceptable sugar " comprises sweet mellow wine, sorbierite, glucose, fructose, galactolipin, and, preferred disaccharides is such as sucrose, more preferably pyrans glycosyl pyranose (for example maltose, isomaltose, cellobiose, melibiose, gentiobiose, most preferably lactose). Described " at least a pharmaceutically acceptable sugar " that mixes with API is the form of solution, preferred aqueous solutions or water/organic solution, wherein sugar is generally about 0.05: 1 to about 1: 0.05 with the ratio of solvent, preferred about 0.1: 1 to about 1: 0.1, more preferably from about 0.5: 1 to about 1: 0.5,1: 1 (wt/wt most preferably from about; Gross weight based at least a pharmaceutically acceptable sugar: the weight of the solvent in sugar juice). According to API and the intensity that comprises about pharmaceutical dosage form of particle of the present invention, sugar (deriving from granulation solution) and the weight ratio of API in particle with poorly water-soluble can be about 0.1: 1 to about 1000: 1, preferred about 0.1: 1 to about 100: 1, perhaps about 0.1: 1 to about 10: 1, for example about 0.5: 1, about 1: 1, about 2: 1, about 3: 1, about 5: 1, about 10: 1 or about 50: 1. Product (drug particles that for example comprises Bicalutamide) for relative high dose, sugar and have the weight ratio of poorly water-soluble API in particle and be preferably about 0.5: 1 to about 5: 1, for example about 0.5: 1, about 1: 1, about 2: 1 or about 3: 1, more preferably from about 0.7: 1. In one embodiment, the invention provides the tablet that comprises particle of the present invention, wherein the active pharmaceutical ingredient with poorly water-soluble in described particle is Bicalutamide, and wherein the weight ratio of sugar and Bicalutamide can be about 0.7: 1.
It is particularly human that many active pharmaceutical ingredients can be administered to the experimenter who needs treatment, and wherein said active pharmaceutical ingredient is the form of oral dosage form. The compressed tablets of various shapes and filled capsules are the example of oral dosage form. Oral dosage form is seldom by pure active pharmaceutical ingredient preparation. On the contrary, they are usually by the particle manufacturing of the pharmaceutically acceptable excipient preparation of mixed active drug ingedient and one or more. As everyone knows, pharmaceutically acceptable excipient is according to its expectation function rough classification in particle or oral dosage form. The known given excipient of the technical staff of field of pharmaceutical preparations can be carried out more than a kind of function, and the function of excipient can be depending on the kind of other excipient of use and the given activity drug ingedient of consumption and use.
The kind that is different from the pharmaceutically acceptable excipient of described at least a pharmaceutically acceptable sugar comprises diluent, binding agent, lubricant, fluidizer, disintegrating agent, wetting agent and coloring agent and correctives.In many diluent well-known in the art, common diluent is microcrystalline Cellulose (for example Avicel ), lactose and starch.Also binding agent can be added in the tablet formulation to help after compacting, keeping described tablet together.In many binding agents well-known in the art, some typical binding agent is sodium carboxymethyl cellulose, ethyl cellulose, gelatin, hydroxypropyl cellulose (for example Klucel ), hydroxypropyl emthylcellulose (for example Methocel ), polyvidone (for example Kollidon , Plasdone ), sodium alginate and starch.Tablet can further comprise accelerates the disintegrating agent of tablet in the disintegrate of patient's gastric.In many disintegrating agents well-known in the art, disintegrating agent can typically comprise cross-linked carboxymethyl cellulose sodium, crospovidone (for example Kollidon , Polyplasdone ), microcrystalline Cellulose, pregelatinized Starch, primojel (for example Explotab ).The excipient pharmaceutical composition that is used to prepare compressed tablet can further comprise fluidizer, lubricant, correctives, coloring agent and other normally used pharmaceutically acceptable excipient.
Within the scope of the invention, the present invention includes the new method of preparation drug particles, it comprises mixing to have the active pharmaceutical ingredient of poorly water-soluble and the solution of at least a pharmaceutically acceptable sugar (preferred aqueous solutions) and randomly at least a, preferably more than a kind of pharmaceutically acceptable excipient that is different from least a pharmaceutically acceptable sugar; The product of dry this blend step; And pulverize described exsiccant product.Suitable pharmaceutically acceptable excipient comprises for example sodium lauryl sulphate of the polymer of vinyl pyrrolidone or copolymer and wetting agent.Described mixing can be undertaken by any mixing known in the art or dispersing mode.For example, use bivalve mixer, the planetary-type mixer of Glen type or the super mixer (only mentioning) of Henschel, Lodige/Littleford or Baker-Perkins type of Patterson-Kelly type to mix the composition of weighing, it comprises the aqueous solution of at least a sugar.Using high shear/high intensity mixer is preferred hybrid mode.
In an embodiment preferred of method of the present invention, the polymer that is vinyl pyrrolidone with at least a pharmaceutically acceptable excipient adds in the blend step, and adds in the described granule.The suitable polymer blend of vinyl pyrrolidone comprises polyvidone and crospovidone, and it is from BASF Corporation or the Wayne NJ of for example Mt.Olive NJ, and the International SpecialtyProducts of USA obtains.Polyvidone is the example of the polymer of preferred vinyl pyrrolidone.Preferably, microcrystalline Cellulose (for example Avicel  obtains from FMC Corporation) is added the blend step, and add in the described granule.
Behind blend step, for example the product of dry mixed step in tray dryer or fluidized bed dryer randomly sieves, and pulverizes then to obtain granule.Described pulverizing can for example be ground acquisition by any-mode known in the art.Fitzpatrick dismembyator with 0.5mm sieve is applicable to described pulverising step.Usually use those people of the type equipment will know the time and intensity that optimization is pulverized, further do not increase significantly so that other pulverizing can not cause the dissolution speed of the API that joins in the described granule and degree.Preferably measure dissolution rate and degree in method well-known in the art with use from the tablet of granule compacting and that for example American Pharmacopeia, announce.
In a preferred embodiment, before pulverizing, colloidal silica is mixed with exsiccant mix products.Described mixing can be passed through manner known in the art, for example obtains with planetary-type mixer or super mixer.
Can directly use the granule of acquisition, perhaps before use, with itself and one or more other pharmaceutically acceptable mixed with excipients.Preferably, before use, for example before being pressed into tablet, with granule and mix lubricant.
The technical staff of field of pharmaceutical preparations will know according to the dosage form that will prepare and the equipment optimization of obtainable mixing and tabletting or filled capsules to have the active pharmaceutical ingredient (API) of poorly water-soluble and the kind and the consumption of pharmaceutically acceptable excipient.In a preferred blend step, in high shear mixer, mix following compositions:
About 0.3 to about 75wt.-% API with poorly water-soluble,
About diluent of 5 to about 45wt.-%,
About disintegrating agent of 5 to about 15wt.-%,
About binding agent of 0.5 to about 8wt.-%,
About wetting agent of 1 to about 10wt.-%,
The solution of about 1 to about 50wt wt.-% at least a pharmaceutically acceptable sugar (about 1: 1, sugar weight: weight of solvent).
In above-mentioned preferred blend step, use about 10 to about 60wt.-% API sometimes with poorly water-soluble.At least a pharmaceutically acceptable sugar that uses in above-mentioned preferred blend step is preferably lactose.The aqueous solution of lactose is particularly preferred as the solution of the sugar that uses in above-mentioned preferred blend step.The consumption of the lactose aqueous solution that those skilled in the art can optimization use is with denseness that obtains to want and the mixture of pulverizing feature.Dry from the product that mixes mentioned component, with fluidizer (based on from the product weight about 0.5 of combination to 1.5wt.-%) mixes, use for example mixture that obtains of Fitzpatrick impact grinder pulverizing of suitable grinding.The direct mixture (for example, being pressed into label) pulverized of processing, perhaps before processing, can and preferably with itself and mix lubricant.
The present invention sets forth (for example, referring to table 1) by following non-restrictive example.Embodiment 1 and 2 is the purposes that are used for comparison.Embodiment 3 and 4 is processing and implementation examples.
Embodiment 1:
Use direct compression process to prepare tentative batch of material, numbering K-31049 and K-31050.The described exsiccant composition of dry mixed is pressed into tablet in agitator.The dissolution rate of the tablet that obtains is too low, and promptly when under 37 ℃, starch and be 75rpm, when in the SLS aqueous solution of the 0.05M of 1000mL, measuring, the stripping after 45 minutes of the active pharmaceutical ingredient about only 50%.
Embodiment 2:
Prepare tentative batch of material with wet granulation, numbering R-00419 and K-31112.Use high shear mixer and fluidized bed dryer to prepare this batch of material.Extra-granular excipient is joined in the granule of grinding, and in agitator, mix.Compressed cores.Use pure water to prepare batch of material R-00419 as granulation liquid.The dissolution rate of the tablet that obtains is too low, wherein about only active pharmaceutical ingredient stripping after 45 minutes of 58%.Use alcohol 95% to prepare batch of material K-31112 as granulation liquid.The dissolution rate of the tablet that obtains is too low, wherein when under 37 ℃, starches and is 75rpm, when measuring in the SLS aqueous solution of the 0.05M of 1000mL, on average about only active pharmaceutical ingredient stripping after 45 minutes of 55%.
Embodiment 3 (processing and implementation example):
Use the solution of lactose monohydrate in pure water to prepare tentative batch of material K-31557 as granulation solution.Mix preparation composition in super mixer (bicalutamide, microcrystalline Cellulose, polyvidone, cross-linked carboxymethyl cellulose sodium and sodium lauryl sulphate), described super mixer contain the solution of lactose monohydrate in pure water (1: 1, lactose monohydrate wt: water wt).Dry product from blend step mixes with colloidal silica, and grinds in the Fitzpatrick impact grinder.The granule that so obtains is mixed with microcrystalline Cellulose and magnesium stearate, be pressed into label in the usual way, and the described label of coating.
Table 1
Batch of material numbering composition K-31049 directly suppresses K-31050 directly suppresses The R-00419 wet granulation The K-31112 wet granulation The K-31557 wet granulation
Bicalutamide 50.0 50.0 50.0 50.0 50.0
Avicel PH 102 (microcrystalline Cellulose NF) 20.0 20.0 --- 30.0 21.0
Aerosil 200 (colloidal silica NF) 3.0 3.0 --- --- 2.0
Lactose monohydrate NF 200 orders 30.8 30.8 59.8 24.0 35.0
PVP K-30 polyvidone USP 3.0 3.0 4.0 2.0 1.5
Ac-Di-Sol (cross-linking sodium carboxymethyl cellulose NF) --- --- --- --- 12.5
Primojel NF 20.0 20.0 13.0 20.0 ---
Sodium lauryl sulphate NF --- --- --- 2.0 4.0
Magnesium stearate NF 1.2 1.2 1.2 2.0 2.0
The result is presented in the table 2 with stripping.Under 37 ℃, starch and be 75rpm, in the SLS aqueous solution of the 0.05M of 1000ml, measure dissolution rate.
Table 2
15 minutes 30 minutes 45 minutes
K-31049 29％ 40％ 48％
K-31050 31％ 45％ 53％
R-00419 39％ 51％ 58％
K-31112 41％ 50％ 55％
K-31557 (processing and implementation example) 79％ 95％ 97％
The stripping result who occurs in the table 2 is the meansigma methods of several tablets, and therefore, the dissolution rate of individual tablet can be higher or lower than this meansigma methods.
Embodiment 4 (processing and implementation example):
Preparation 1
Prepare the fenofibrate compositions by wet granulation of the present invention, preparation 1.Composition in the wet granulation table 3 is pressed into tablet with it then, the heavy 750mg of each sheet.
The method for preparing preparation 1 is to implement an example of basic conception of the present invention, wherein in method of granulating, use lactose solution (lactose: water, 1: 1, v: v) as binding agent, the granule that dry then this mixture and grinding obtain.All other non-API compositions in granulation mixture can have effect to final result, but inessential for using notion of the present invention, therefore, can or partly be removed by replacement (by the different component of same type).The weight ratio of granulation components and API can be higher or lower than in preparation 1.More preferably, described weight ratio is higher than in preparation 1, so that compare with the stripping of preparation 1, keeps at least or even increase dissolution rate.
The amount and the concentration of the lactose solution that uses are very important.The lactose solution that equals 424mg is used in the preparation of preparation 1, and (lactose: water, 212mg: 212mg), it is 40% of total granulation mixture (solid and water) weight.Usually, the solution of at least a pharmaceutically acceptable sugar can account for total granulation mixture about 15 to about 60% weight, more preferably be about 35 to about 50% of total granulation mixture.The increase of the lactose yield that uses (adding as solution) can further improve final result of the present invention.For example, the total amount of granulation solution increases to 500mg (lactose: water, 250mg: 250mg) keep simultaneously that the amount of other composition is constant improves stripping from 424mg.On the other hand, the total amount of granulation solution is reduced to 500mg (lactose: 125 125mg: 125mg) keep the constant dissolution rate that reduces of amount of other composition simultaneously from 424mg.In embodiment 4, firmly grind described granule with Fitzmill (TM) Communitor that the 0.5mm sieve is housed, generation has the powder of the particle size distribution that is displayed in Table 4, and wherein with use the ATM Sonic filter of 60,80,100,140,170 sieves and Pan or the sound filtering method mensuration particle diameter of GilsonAutosiever GA is housed.
Table 3
Composition Weight (mg/ sheet) Approximate weight percentage ratio
Part I fenofibrate polyvinylpyrrolidone (PVP K-30) primojel cross-linking sodium carboxymethyl cellulose (Ac-di-sol TM) crospovidone microcrystalline Cellulose (Avicel) part II sodium lauryl sulphate (SLS) lactose part III Aerosil 160 60 48 48 48 139.5 15 212 7.5 21.3 8.0 6.4 6.4 6.4 18.6 2.0 28.3 1.0
Part IV Pruv (sodium stearyl fumarate) 12 1.6
Prepare described granule with the method that comprises the steps:
1. the composition of mixing portion fully.
2. the lactose of part II is dissolved in and is heated in about 70 ℃ water.
3. the SLS with part II is dissolved in the water of about 10mg.
4. by the lactose of adding step 2 and 3 and the mixture of SLS solution granulation step 1, form granule.
5. the granule of drying steps 4 (55 ℃ of inlet airs, outlet air are no more than 40 ℃) in fluidized bed dryer (FBD).
6. the Aerosil with part III mixes with the dried granules of step 5, then with the Fitzmill that the 0.5mm hole sizer is housed TMGrind.
7. then, the granule that composition and the step 6 of part IV are ground mixed about 2 minutes, formed final mixture.
8. final mixture is pressed into tablet.
Table 4
Particle size distribution
Screen size (order) Keep % thereon)
Batch of material 1 k-29740 Batch of material 2 k-29738 Batch of material 3 batch of materials numbering F15001 Batch of material 4 batch of materials numbering F15002 Batch of material 5 batch of materials numbering F15003
60 12 9.7 9.9 10.3 10.7
80 15 13.8 11.3 13.3 13.3
100 7.0 6.9 3.4 6.8 6.7
140 14.5 17.9 13.7 11.8 11.1
170 7.1 6.8 3.5 5.2 5.1
PAN 43.3 43.9 57.1 52.7 53.3
Amount to 98.8 99.0 98.9 100.1 100.2
Table 4 has shown granule at least about 72% grinding by 80 mesh sieves, and at least about 66% 100 mesh sieves that pass through.
At 37 ℃, oar is 75rpm (device II), measures the stripping feature of tablet of the batch 1 (K-29740) of preparation 1 in the SLS aqueous solution of the 0.05M of 1000mL.In order to contrast, also measure the stripping feature of commercially available fenofibrate tablet Tricor 160mg by same mode.With the stripping characteristic series that obtains in table 5, and in Fig. 1 with pictorialization.
Table 5
(stripping feature)
Time (branch) K-29740 Tricor 160 mg
0 0.0 0.0
10 68.0 57.0
20 95.0 94.0
30 99.0 99.0
40 100.0 100.0
The active pharmaceutical ingredient that the comprises poorly water-soluble for example drug particles of the present invention of fenofibrate and at least a pharmaceutically acceptable sugar of combining closely can have following particle size distribution, wherein pass through 80 mesh sieves at least about 70%, at least about 60% by 100 mesh sieves, and at least about 50% by 140 mesh sieves.
When measuring under the condition of following at least strictness, solid pharmaceutical preparation of the present invention for example tablet can demonstrate following stripping character, makes after about 10 minutes, at least about 50%, preferably at least about 60% stripping; After about 20 minutes, at least about 70%, more preferably at least about 75% stripping; After about 30 minutes, at least about 80%, more preferably at least about 85% stripping; And after about 40 minutes, at least about 90%, preferably at least about 95%, more preferably from about 98% to about 100% stripping, and described condition is: under 37 ℃, starch and be 75rpm, in the SLS aqueous solution of the 0.05M of 1000mL.

Claims (98)

1. granule that is used for pharmaceutical composition, described pharmaceutical composition comprises active pharmaceutical ingredient with poorly water-soluble and at least a pharmaceutically acceptable sugar of combining closely, the dissolubility that wherein said active pharmaceutical ingredient has in water is less than about 20mg/ml, condition is when described active pharmaceutical ingredient is fenofibrate, and at least a pharmaceutically acceptable sugar is not lactose.
2. the granule of claim 1 further comprises at least a pharmaceutically acceptable excipient that is different from described at least a pharmaceutically acceptable sugar.
3. the granule of claim 2, at least a pharmaceutically acceptable excipient that wherein is different from described at least a pharmaceutically acceptable sugar is selected from diluent, binding agent, disintegrating agent, wetting agent, lubricant, fluidizer, coloring agent and correctives.
4. the granule of claim 3, wherein said diluent is microcrystalline Cellulose, lactose and starch, described binding agent is sodium carboxymethyl cellulose, ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvidone, sodium alginate and starch, and described disintegrating agent is cross-linked carboxymethyl cellulose sodium, crospovidone, microcrystalline Cellulose, pregelatinized Starch and primojel.
5. the granule of claim 3, at least a pharmaceutically acceptable excipient that wherein is different from described at least a pharmaceutically acceptable sugar is selected from the polymer or the copolymer of vinyl pyrrolidone, cross-linked carboxymethyl cellulose sodium, microcrystalline Cellulose and sodium lauryl sulphate.
6. the granule of claim 5 wherein is different from the polymer of vinyl pyrrolidone or at least a pharmaceutically acceptable excipient of copolymer and is selected from polyvidone and crospovidone.
7. the granule of claim 6, at least a pharmaceutically acceptable excipient that wherein is different from least a pharmaceutically acceptable sugar comprises polyvidone, microcrystalline Cellulose and sodium lauryl sulphate.
8. the granule of claim 7, at least a pharmaceutically acceptable excipient that wherein is different from least a pharmaceutically acceptable sugar comprises polyvidone, microcrystalline Cellulose, sodium lauryl sulphate, cross-linked carboxymethyl cellulose sodium and colloidal silica.
9. the granule of claim 1, wherein at least a pharmaceutically acceptable sugar is selected from mannitol, sorbitol, glucose, fructose, galactose, sucrose, maltose, dextrinose, cellobiose, 6-(.alpha.-D-galactosido)-D-glucose., gentiobiose and lactose.
10. the granule of claim 1, wherein at least a pharmaceutically acceptable steamed bun stuffed with sugar is drawn together pharmaceutically acceptable disaccharide.
11. the granule of claim 10, wherein at least a pharmaceutically acceptable steamed bun stuffed with sugar is drawn together pyrans glycosyl pyranose.
12. the granule of claim 11, wherein said pyrans glycosyl pyranose is selected from maltose, dextrinose, cellobiose, lactose, 6-(.alpha.-D-galactosido)-D-glucose. and gentiobiose.
13. the granule of claim 12, wherein said at least a pharmaceutically acceptable sugar is lactose.
14. the granule of claim 1, wherein said active pharmaceutical ingredient is selected from fenofibrate, bicalutamide, atorvastatin, fluvastatin, simvastatin, Candesartan, ezetimibe, oxcarbazepine, meloxicam, celecoxib, rofecoxib, valdecoxib, raloxifene, Aripiprazole and glibenclamide.
15. the granule of claim 14, wherein said active pharmaceutical ingredient are bicalutamide.
16. the granule of claim 15, at least a pharmaceutically acceptable excipient that wherein is different from least a pharmaceutically acceptable sugar comprises polyvidone, coarse-grain cellulose, sodium lauryl sulphate, cross-linked carboxymethyl cellulose sodium and colloidal silica.
17. the granule of claim 16, wherein said at least a pharmaceutically acceptable sugar is lactose or lactose monohydrate, at least a pharmaceutically acceptable excipient that wherein is different from described at least a pharmaceutically acceptable sugar comprises polyvidone, coarse-grain cellulose, sodium lauryl sulphate, cross-linked carboxymethyl cellulose sodium, colloidal silica and magnesium stearate.
18. a pharmaceutical dosage form comprises the granule of claim 1.
19. the pharmaceutical dosage form of claim 18, wherein at least a pharmaceutically acceptable sugar is lactose.
20. the pharmaceutical dosage form of claim 19, wherein said granule further comprise at least a following pharmaceutically acceptable excipient that is selected from: filler, fluidizer, binding agent, disintegrating agent, surfactant and lubricant.
21. the pharmaceutical dosage form of claim 20, wherein said filler are the coarse-grain cellulose, described fluidizer is a silicon dioxide, described binding agent is a polyvidone, described disintegrating agent is cross-linked carboxymethyl cellulose sodium, and described surfactant is a sodium lauryl sulphate, and described lubricant is a magnesium stearate.
22. claim 18 pharmaceutical dosage form, wherein said active pharmaceutical ingredient is a bicalutamide, wherein when under the condition of following at least strictness, measure and when by the UV detector when 272nm detects, at least 50% bicalutamide dissolved in about 15 minutes, described condition is: use the USP oar method in the 50rpm rotation, under 37 ℃, in 1% the lauryl sodium sulfate aqueous solution of 1000ml.
23. claim 18 pharmaceutical dosage form, wherein said active pharmaceutical ingredient is a bicalutamide, wherein when under the condition of following at least strictness, measure and when by the UV detector when 272nm detects, at least 65% bicalutamide dissolved in about 30 minutes, described condition is: use the USP oar method in the 50rpm rotation, under 37 ℃, in 1% the lauryl sodium sulfate aqueous solution of 1000ml.
24. claim 18 pharmaceutical dosage form, wherein said active pharmaceutical ingredient is a bicalutamide, wherein when under the condition of following at least strictness, measure and when by the UV detector when 272nm detects, at least 75% bicalutamide dissolved in about 45 minutes, described condition is: use the USP oar method in the 50rpm rotation, under 37 ℃, in 1% the lauryl sodium sulfate aqueous solution of 1000ml.
25. claim 22 pharmaceutical dosage form, wherein when under the condition of following at least strictness, measure and when by the UV detector when 272nm detects, about 80% bicalutamide dissolved in about 15 minutes, described condition is: use the USP oar method in the 50rpm rotation, under 37 ℃, in 1% the lauryl sodium sulfate aqueous solution of 1000ml.
26. claim 23 pharmaceutical dosage form, wherein when under the condition of following at least strictness, measure and when by the UV detector when 272nm detects, about 95% bicalutamide dissolved in about 30 minutes, described condition is: use the USP oar method in the 50rpm rotation, under 37 ℃, in 1% the lauryl sodium sulfate aqueous solution of 1000ml.
27. the pharmaceutical dosage form of claim 25, it does not comprise primojel.
28. the pharmaceutical dosage form of claim 26, it does not comprise primojel.
29. claim 24 pharmaceutical dosage form, wherein said active pharmaceutical ingredient is a bicalutamide, wherein when under the condition of following at least strictness, measure and when by the UV detector when 272nm detects, about 100% bicalutamide dissolved in about 45 minutes, described condition is: use the USP oar method in the 50rpm rotation, under 37 ℃, in 1% the lauryl sodium sulfate aqueous solution of 1000ml, condition is that described pharmaceutical dosage form does not comprise primojel.
30. be used to prepare the method for drug particles, comprise "
(a) mix active pharmaceutical ingredient with poorly water-soluble, comprise the solution of at least a pharmaceutically acceptable sugar and randomly be different from least a pharmaceutically acceptable excipient of described at least a pharmaceutically acceptable sugar, form mixture, the water solublity that wherein said active pharmaceutical ingredient has is less than the water of the every ml of about 20mg, and wherein said solution comprises at least a pharmaceutically acceptable sugar and at least a solvent;
(b) dry described mixture; With
(c) product of pulverising step (b) obtains drug particles.
31. the method for claim 30, wherein said at least a solvent is a water.
32. the method for claim 30, wherein in step (a), with described active pharmaceutical ingredient and described at least a pharmaceutically acceptable sugar be different from least a pharmaceutically acceptable mixed with excipients of described at least a pharmaceutically acceptable sugar, and at least a pharmaceutically acceptable excipient that is different from described at least a pharmaceutically acceptable sugar is selected from disintegrating agent, wetting agent, diluent, binding agent, lubricant, fluidizer, coloring agent and flavoring agent.
33. the method for claim 32, wherein said diluent is coarse-grain cellulose, lactose and starch, described binding agent is sodium carboxymethyl cellulose, ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvidone, sodium alginate and starch, and described disintegrating agent is cross-linked carboxymethyl cellulose sodium, crospovidone, microcrystalline Cellulose, pregelatinized Starch and primojel.
34. the method for claim 33, at least a pharmaceutically acceptable excipient that wherein is different from described at least a pharmaceutically acceptable sugar is selected from the polymer or the copolymer of vinyl pyrrolidone, cross-linked carboxymethyl cellulose sodium, microcrystalline Cellulose and sodium lauryl sulphate.
35. the method for claim 34, the polymer of wherein said vinyl pyrrolidone or copolymer are selected from polyvidone and crospovidone.
36. the method for claim 35, at least a pharmaceutically acceptable excipient that wherein is different from least a pharmaceutically acceptable sugar comprises polyvidone, microcrystalline Cellulose and sodium lauryl sulphate.
37. the method for claim 36, at least a pharmaceutically acceptable excipient that wherein is different from least a pharmaceutically acceptable sugar comprises polyvidone, microcrystalline Cellulose, sodium lauryl sulphate, cross-linked carboxymethyl cellulose sodium and colloidal silica.
38. the method for claim 30, wherein at least a pharmaceutically acceptable sugar is selected from mannitol, sorbitol, glucose, fructose, galactose, sucrose, maltose, dextrinose, cellobiose, 6-(.alpha.-D-galactosido)-D-glucose., gentiobiose and lactose.
39. the method for claim 30, wherein at least a pharmaceutically acceptable steamed bun stuffed with sugar is drawn together pharmaceutically acceptable disaccharide.
40. the method for claim 39, wherein at least a pharmaceutically acceptable steamed bun stuffed with sugar is drawn together pyrans glycosyl pyranose.
41. the method for claim 40, wherein said pyrans glycosyl pyranose is selected from maltose, dextrinose, cellobiose, lactose, 6-(.alpha.-D-galactosido)-D-glucose. and gentiobiose.
42. the method for claim 41, wherein said at least a solvent is a water, and described at least a pharmaceutically acceptable sugar is lactose.
43. the method for claim 30, wherein said at least a solvent is a water, and comprises about 0.05: 1 at least a pharmaceutically acceptable sugar of about 1: 0.05 weight with the aqueous solution of the blended at least a pharmaceutically acceptable sugar of active pharmaceutical ingredient in step (a): the water of weight.
44. the method for claim 43 wherein comprises at least a pharmaceutically acceptable sugar of about 0.1: 1 to about 1: 0.1 weight: the water of weight with the aqueous solution of the blended at least a pharmaceutically acceptable sugar of active pharmaceutical ingredient in step (a).
45. the method for claim 44 wherein comprises at least a pharmaceutically acceptable sugar of about 0.5: 1 to about 1: 0.5 weight: the water of weight with the aqueous solution of the blended at least a pharmaceutically acceptable sugar of active pharmaceutical ingredient in step (a).
46. the method for claim 42 wherein comprises at least a pharmaceutically acceptable sugar of about 1: 1 weight: the water of weight with the aqueous solution of the blended at least a pharmaceutically acceptable sugar of active pharmaceutical ingredient in step (a).
47. the method for claim 30 is wherein mixed following substances in step (a):
About 0.3 to about 75wt.-% active pharmaceutical ingredient,
About diluent of 5 to about 45wt.-%,
About disintegrating agent of 5 to about 15wt.-%,
About binding agent of 0.5 to about 8wt.-%,
About wetting agent of 1 to about 10wt.-% and
The solution of about at least a pharmaceutically acceptable sugar of 1 to about 50wt.-% (sugar+solvent) (about 1: 1, sugar weight: weight of solvent).
48. the method for claim 47, wherein said at least a pharmaceutically acceptable sugar is lactose, and described solvent is a water.
49. the method for claim 47, wherein the mixing of step (a) is carried out in high shear mixer.
50. the method for claim 30 further is included in step (c) product and the colloidal silica of blend step (b) before.
51. the method for claim 30, wherein said active pharmaceutical ingredient is selected from fenofibrate, bicalutamide, atorvastatin, fluvastatin, simvastatin, Candesartan, ezetimibe, oxcarbazepine, meloxicam, celecoxib, rofecoxib, valdecoxib, raloxifene, Aripiprazole and glibenclamide.
52. the method for claim 51, wherein said active pharmaceutical ingredient are bicalutamide.
53. the method for claim 52, wherein said pharmaceutically acceptable steamed bun stuffed with sugar is drawn together lactose monohydrate, and the described at least a pharmaceutically acceptable excipient that is different from least a pharmaceutically acceptable sugar comprises microcrystalline Cellulose, colloidal silica, polyvidone, cross-linked carboxymethyl cellulose sodium, sodium lauryl sulphate and magnesium stearate.
54. the method for claim 52, wherein the aqueous solution of mixing bicalutamide, microcrystalline Cellulose, polyvidone, cross-linked carboxymethyl cellulose sodium, sodium lauryl sulphate and lactose monohydrate in step (a) forms mixture.
55. the method for claim 54 further is included in step (c) product and the colloidal silica of blend step (b) before, obtains mixture.
56. the method for claim 55, wherein step (c) is that mixture by grinding steps (b) carries out.
57. the method for claim 56 further comprises mixture and the microcrystalline Cellulose and the magnesium stearate of mixing described grinding, obtains blended granule, and this blended granule of compacting is to form label.
58. the method for claim 47 is wherein used 10 to 60wt.-% active pharmaceutical ingredient in step (a).
59. drug particles by the method preparation of claim 30.
60. drug particles by the method preparation of claim 42.
61. drug particles by the method preparation of claim 46.
62. drug particles by the method preparation of claim 47.
63. a method that is used to prepare medicinal tablet comprises the granule that is used for pharmaceutical composition of suppressing claim 1, forms tablet.
64. an optional method for preparing medicament capsule comprises with the granule that is used for pharmaceutical composition of claim 1 and the inclusion filled capsules shell of one or more pharmaceutically acceptable excipient of choosing wantonly, obtains capsule,
65. medicinal tablet by the method preparation of claim 63.
66. medicament capsule by the method preparation of claim 64.
67. the granule of claim 1, wherein said at least a pharmaceutically acceptable sugar and the described weight ratio of active pharmaceutical ingredient in described granule with poorly water-soluble are about 0.1: 1 to about 1000: 1.
68. the granule of claim 67, wherein said at least a pharmaceutically acceptable sugar and the described weight ratio of active pharmaceutical ingredient in described granule with poorly water-soluble are about 0.1: 1 to about 100: 1.
69. the granule of claim 68, wherein said at least a pharmaceutically acceptable sugar and the described weight ratio of active pharmaceutical ingredient in described granule with poorly water-soluble are about 0.1: 1 to about 10: 1.
70. the granule of claim 69, wherein said active pharmaceutical ingredient with poorly water-soluble is a bicalutamide.
71. the method for claim 30, wherein said at least a pharmaceutically acceptable sugar and described active pharmaceutical ingredient with poorly water-soluble were mixed to about 1000: 1 weight ratio with about 0.1: 1 in step (a).
72. the method for claim 71, wherein said at least a pharmaceutically acceptable sugar and described active pharmaceutical ingredient with poorly water-soluble were mixed to about 100: 1 weight ratio with about 0.1: 1 in step (a).
73. the method for claim 72, wherein said at least a pharmaceutically acceptable sugar and described active pharmaceutical ingredient with poorly water-soluble were mixed to about 10: 1 weight ratio with about 0.1: 1 in step (a).
74. the method for claim 30, wherein said active pharmaceutical ingredient with poorly water-soluble is a bicalutamide.
75. the method for claim 30, wherein said active pharmaceutical ingredient with poorly water-soluble is a fenofibrate.
76. the method for claim 30, wherein the described at least a pharmaceutically acceptable sugar that the solution of use has in step (a) and the weight ratio of solvent are about 0.05: 1 to about 1: 0.05.
77. the method for claim 30, wherein said active pharmaceutical ingredient is a fenofibrate, wherein when under the condition of following at least strictness, measuring described drug particles, fenofibrate at least about 50% dissolved in about 10 minutes, described condition is: use the USP oar method in the 75rpm rotation, under 37 ℃, in the lauryl sodium sulfate aqueous solution of the 0.05M of 1000ml.
78. the method for claim 77, wherein when under the condition of following at least strictness, measuring described drug particles, fenofibrate at least about 60% dissolved in about 10 minutes, described condition is: use the USP oar method in the 75rpm rotation, under 37 ℃, in the lauryl sodium sulfate aqueous solution of the 0.05M of 1000ml.
79. the method for claim 78, wherein when under the condition of following at least strictness, measuring described drug particles, fenofibrate at least about 70% dissolved in about 20 minutes, described condition is: use the USP oar method in the 75rpm rotation, under 37 ℃, in the lauryl sodium sulfate aqueous solution of the 0.05M of 1000ml.
80. the method for claim 79, wherein when under the condition of following at least strictness, measuring described drug particles, fenofibrate at least about 80% dissolved in about 30 minutes, described condition is: use the USP oar method in the 75rpm rotation, under 37 ℃, in the lauryl sodium sulfate aqueous solution of the 0.05M of 1000ml.
81. the method for claim 80, wherein when under the condition of following at least strictness, measuring described drug particles, fenofibrate at least about 90% dissolved in about 40 minutes, described condition is: use the USP oar method in the 75rpm rotation, under 37 ℃, in the lauryl sodium sulfate aqueous solution of the 0.05M of 1000ml.
82. the method for claim 81, wherein when under the condition of following at least strictness, measuring described drug particles, fenofibrate at least about 95% dissolved in about 40 minutes, described condition is: use the USP oar method in the 75rpm. rotation, under 37 ℃, in the lauryl sodium sulfate aqueous solution of the 0.05M of 1000ml.
83. the method for claim 51, wherein in step (a), mix the aqueous solution of fenofibrate, polyvinylpyrrolidone, primojel, cross-linked carboxymethyl cellulose sodium, crospovidone, microcrystalline Cellulose, sodium lauryl sulphate and lactose, form mixture.
84. the method for claim 83 further comprises the product that mixes Aerosil and step (b).
85. the method for claim 84 further comprises the product of the method for mixing sodium stearyl fumarate and claim 83.
86. the granule of claim 14, wherein said active pharmaceutical ingredient are fenofibrate.
87. granule that is used for pharmaceutical composition, comprise active pharmaceutical ingredient with poorly water-soluble and at least a pharmaceutically acceptable sugar of combining closely, described ingredient comprises fenofibrate, and described particle grain size distribution is passed through 80 mesh sieves for feasible granule at least about 75%.
88. the granule of claim 87, wherein at least about 66% granule by 100 mesh sieves.
89. the method for claim 30, wherein said at least a pharmaceutically acceptable sugar comprises lactose at least, the wherein said solution that comprises at least a pharmaceutically acceptable sugar for the mixture of formation in blend step (a) at least about 15% to about 60% weight.
90. the method for claim 89, wherein said solution be the mixture that in blend step (a), forms weight at least about 35% to about 50%.
91. the method for claim 90, wherein said solution be the mixture that in blend step (a), forms weight at least about 40%.
92. the method for claim 30, wherein said at least a pharmaceutically acceptable sugar comprises lactose at least, and the wherein said solution that comprises at least a pharmaceutically acceptable sugar is for the mixture preparation by heating lactose and water under about 70 ℃ temperature.
93. the pharmaceutical dosage form of claim 18, wherein when under the condition of following at least strictness, measuring described pharmaceutical dosage form, active pharmaceutical ingredient at least about 50% dissolved in about 10 minutes, described condition is: use the USP oar method in the 75rpm rotation, under 37 ℃, in the lauryl sodium sulfate aqueous solution of the 0.05M of 1000ml.
94. the pharmaceutical dosage form of claim 93, wherein when under the condition of following at least strictness, measuring described pharmaceutical dosage form, active pharmaceutical ingredient at least about 70% dissolved in about 20 minutes, described condition is: use the USP oar method in the 75rpm rotation, under 37 ℃, in the lauryl sodium sulfate aqueous solution of the 0.05M of 1000ml.
95. the pharmaceutical dosage form of claim 94, wherein when under the condition of following at least strictness, measuring described pharmaceutical dosage form, active pharmaceutical ingredient at least about 80% dissolved in about 30 minutes, described condition is: use the USP oar method in the 75rpm rotation, under 37 ℃, in the lauryl sodium sulfate aqueous solution of the 0.05M of 1000ml.
96. the pharmaceutical dosage form of claim 95, wherein when under the condition of following at least strictness, measuring described pharmaceutical dosage form, active pharmaceutical ingredient at least about 90% dissolved in about 40 minutes, described condition is: use the USP oar method in the 75rpm rotation, under 37 ℃, in the lauryl sodium sulfate aqueous solution of the 0.05M of 1000ml.
97. a pharmaceutical dosage form comprises the granule of claim 87.
98. a pharmaceutical dosage form comprises the granule of claim 88.
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* Cited by examiner, † Cited by third party
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CN102238941A (en) * 2008-09-17 2011-11-09 迈兰实验室公司 Granulates, process for preparing them and pharmaceutical products containing them
CN114177157A (en) * 2015-06-30 2022-03-15 基因泰克公司 Immediate release tablet containing drug and method for forming tablet
CN108524527A (en) * 2017-03-02 2018-09-14 北京德立福瑞医药科技有限公司 Celecoxib pharmaceutical composition and preparation method thereof
CN108524527B (en) * 2017-03-02 2020-08-04 北京德立福瑞医药科技有限公司 Celecoxib pharmaceutical composition and preparation method thereof

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WO2007011349A1 (en) 2007-01-25

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