WO2010143199A1 - Dispersion lipidique solide destinée à améliorer la solubilité aqueuse de médicaments peu solubles dans l'eau - Google Patents

Dispersion lipidique solide destinée à améliorer la solubilité aqueuse de médicaments peu solubles dans l'eau Download PDF

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WO2010143199A1
WO2010143199A1 PCT/IN2010/000346 IN2010000346W WO2010143199A1 WO 2010143199 A1 WO2010143199 A1 WO 2010143199A1 IN 2010000346 W IN2010000346 W IN 2010000346W WO 2010143199 A1 WO2010143199 A1 WO 2010143199A1
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agents
lipid
dispersion
solid dispersion
water soluble
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PCT/IN2010/000346
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English (en)
Inventor
Ravula Sayisiva Prasad
Yandrapu Sarath Kumar
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Suven Nishtaa Pharma Private Limited
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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
    • 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
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin

Definitions

  • the present invention relates to drug delivery systems, in particular to the solid dispersions for the improved delivery of poorly water-soluble compounds, and/or a pharmaceutical salt thereof. Also provided are methods for the preparation of these solid dispersions. 0 BACKGROUND ART
  • a solid dispersion has traditionally been defined as "the dispersion of one or more active ingredients in an inert excipient or matrix" where the active ingredients could exist in finely crystalline, solubilized or amorphous states.
  • Pharmaceutical solid dispersions have been studied for close to half a century as a means for increasing the dissolution rate and oral bioavailability of poorly water soluble drugs (Chiou, W. L.; Riegelman, S. Pharmaceutical applications of solid dispersion systems. J. Pharm. ScL (1971) 60, 1281-1302).
  • a portion of the drug contained in a solid dispersion dissolves immediately upon contact with the gastrointestinal (GI) fluid, resulting in a saturated or supersaturated solution for rapid absorption, and the excess drug precipitates in the GI fluid forming amorphous or crystalline particles in the sub micron size range with high surface area and a correspondingly high dissolution and absorption rate.
  • GI gastrointestinal
  • the commercial application of solid dispersion formulations has been limited. The reasons include (i) inability to scale up to manufacturing level (ii) difficulty to control physiochemical properties (iii) difficulty in delivering solid dispersion formulations as tablet or capsule dosage forms (iv) physical and chemical instability of the drug/formulation.
  • the polymeric solid dispersions are often limited by the relatively rapid dissolution rate of the water soluble excipient matrix as compared to that of the dispersed drug substance. This results in the formation of a highly concentrated solution of drug which precipitates on the surface of the excipient.
  • the solid dispersions prepared with polymers require milling but the dispersions prepared with PEGs and other polymers are usually soft and tacky and may not be readily milled (Ford, J. L. The current status of solid dispersions. Pharm. Acta HeIv. ( 1986) 61, 69-88).
  • the powders thus produced often have poor flow and mixing properties and are difficult to fill into capsules or compress into tablets.
  • lipid mediated solid dispersions involve the dispersion of drug in the molten lipid and filled into hard gelatin or soft gelatin capsule, by twin screw extrusion, by melt fusion, by mechanical admixture such as by ball milling and by mechanical admixture at an elevated but non-melting temperature.
  • a melt extrusion process a compound is co-extruded with a carrier which forms a solid solution upon cooling and solidifying.
  • the extrudates are then milled and sieved to produce particles of a desired size range to ensure good dissolution (US 6342245).
  • This method suffers from many disadvantages, including: compound loading, down stream product handling (for e.g., pulverization of solid dispersion extrudates into particles is often difficult because carriers are tacky), lengthy cleaning time and, high capital investment.
  • the structure of the solid dispersion and final state of drug in the formulation mainly depends on intrinsic drug crystallization tendency, drug loading, drug carrier interaction, crystanlility of the carrier and cooling rate of the molten formulation.
  • the present invention provides a pharmaceutical composition in the form of a solid dispersion wherein a poorly soluble drug is dissolved in a lipid carrier medium without heating the material to its high fusion temperature.
  • the drug dispersed in the lipid dispersion is dried into free flowing powders by spray drying.
  • the solid dispersions of this invention provide a high bioavailability of drug substance, are convenient to administer, and are stable.
  • the invention relates to a method of manufacturing the solid dispersion or the pharmaceutical composition.
  • FIG. 1 illustrates the rate of dissolution of a unit dose of entacapone, alone, and as formulated in two water-dispersible lipidic carriers, composed of diglyceroyl polyacyladipate and linoeleoyl polyoxyglyceride.
  • FIG. 2 illustrates the rate of dissolution of a unit dose of entacapone, alone, and as formulated in two water-dispersible lipidic carriers, composed of diglyceroyl polyacyladipate and diethylene glycol monoethyl ether.
  • FIG. 3 illustrates the rate of dissolution of a unit dose of itraconazole, alone, and as formulated in two water-dispersible lipidic carriers, composed of glyceroyl trimyristate and diglyceroyl polyacyladipate
  • FIG. 4 illustrates the rate of dissolution of a unit dose of itraconazole, alone, and as formulated in two water-dispersible lipidic carriers, composed of glyceryl monooleate and caprylocaproyl macroglyceride.
  • FIG. 5 illustrates the rate of dissolution of a unit dose of carvedilol, alone, and as formulated in two water-dispersible lipidic carriers, composed of glyceroyl di stearate and mono di glyceride of edible fatty acids.
  • FIG. 6 illustrates the rate of dissolution of a unit dose of carvedilol, alone, and as formulated in two water-dispersible lipidic carriers, composed of glyceroyl trimyristate and diglyceroyl polyacyladipate.
  • FIG. 7 shows the mean plasma concentration data of entacapone, as a function of time lipid solid dispersions of entacapone (pH 3.0) according to example 2 of the present invention and entacapone suspension in potassium bipthalate buffer (pH 3.0)
  • FIG. 8 shows the mean plasma concentration data of carvedilol, as a function of time for lipid solid dispersions of carvedilol (pH 7.4) according to example 11 of the present invention and carvedilol suspension in potassium bipthalate buffer (pH 7.4)
  • the present invention provides pharmaceutical compositions in the form of solid lipid dispersions for improved delivery of a wide variety of poorly soluble pharmaceutically active ingredients, methods for their preparation and their use in dosage form.
  • One embodiment of this invention is directed to a pharmaceutical composition comprising lipid solid dispersion of poorly water soluble therapeutic agents and inactive lipid excipients, useful for the oral delivery of poorly water soluble therapeutic agents.
  • the present invention provides a process for the preparation of these lipid solid dispersions by spray drying a dispersion of poorly water soluble therapeutic agent and lipid excipient.
  • the lipid solid dispersions obtained by the said process shows enhanced aqueous solubility by virtue of amorphous structure of active ingredient and reduced particle size.
  • the solid particulate dispersions obtained has suitable properties with respect to flowability, compressibility, non-cohesiveness, density and particle size, which enables it to be further, processed into a solid dosage forms such as tablets, capsules etc.
  • the solid dispersions enhance the dissolution of poorly water soluble therapeutic agent by virtue of i) reduced particle size, relative to the bulk drug substance used in preparation of the formulation; ii) metastable crystalline form; iii) partial or complete conversion of the drug into an amorphous form; iv) full or partial solubilization of the drug in the carrier matrix.
  • the poorly water soluble therapeutic agent is present in the lipid solid dispersion in an amount of about 1% to about 50% of the total weight of the dispersion.
  • Such therapeutic agents have poor oral bioavailability and include lipophillic drugs, vitamins, and hormones.
  • -blockers cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2 inhibitors, leucotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids, and mixtures thereof.
  • the preferred therapeutic agents are amantadine hydrochloride; amphotericin B, acebutolol, atenolol, bisoprolol, carvedilol, clindamycin and clindamycin derivatives, esmolol, entacapone, fluconazole, ketoconazole, itraconazole, isavuconazole, metoprolol, miconazole, posaconazole, ravuconazole, sotalol, terconazole, tolcapone, vinblastine; vincristine, voriconazole.
  • This invention provides a way to increase the oral bioavailability of these poorly water soluble therapeutic agent compounds.
  • the concentration of the lipids in the lipid solid dispersion of this invention is in the range of about 20 to 80% of the total weight of the dispersion, preferably in the range of about 40% to about 60% of the total weight of the dispersion.
  • examples of some of the lipids used in the dispersion are glycerol fatty acid esters, polyethylene glycol fatty acids esters, polyethylene glycol glycerol fatty acid esters, polyoxyethylene glycerides, lauryl macrogolglycerides, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene vegetable oils, polyoxyethylene hydrogenated vegetable oils; fatty acids, glycerides, tocopherol polyethylene glycol succinates, a triglyceride selected from the group consisting of vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, synthetic triglycerides, modified triglycerides, fractionated triglycerides.
  • the preferred lipids are glyceryl trimyristate, glyceryl dibehanate, diglyceroyl polyacyladipate, linoeleoyl polyoxyglyceride, glyceryl monooleate, caprylocaproyl macroglyceride, caprylic/capric triglyceride, glyceroyl trimyristate, glyceroyl distearate, mono di glyceride of edible fatty acids, glyceryl monooleate.
  • the lipids present in the prepared dispersions may be used to control the release of poorly water soluble therapeutic agent by modulating the hydrophilicity or hydrophobicity of the dispersion.
  • lipids enhance the active ingredient absorption by alternative pathways and prevent the drug precipitation in the intestine. Moreover, the lipid excipients will minimize the food effects on the drug absorption and also prevents the pre- systemic metabolism and thus resulting in enhancement of the bioavailability of poorly water soluble therapeutic agent.
  • the lipid solid dispersion formulation of this invention may further comprise one or more pharmaceutical excipients such as one or more fillers, diluents, disintegrants, binders, lubricants etc or mixture thereof.
  • suitable fillers, diluents include calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, hydroxypropyl cellulose, dextrans, dextrin, dextrose, fructose, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar etc.
  • disintegrants examples include alginic acid or alginates, microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives, croscarmellose sodium, crospovidone, polacrillin potassium, sodium starch glycolate, starch, pregelatinized starch, carboxymethyl starch
  • binders are acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, povidone, pregelatinized starch. Glidants and lubricants may also be included in the composition.
  • Examples include stearic acid, magnesium stearate, calcium stearate or other metallic stearate, talc, silica acid and derivatives or salts thereof including silicates, colloidal silicon dioxide, soft silic anhydride, kaolin, titanium dioxide waxes and glycerides, light mineral oil, PEG, glyceryl behenate, colloidal silica, hydrogenated vegetable oils, com starch, sodium stearyl fumarate, polyethylene glycols, alkyl sulfates, sodium benzoate, sodium acetate.
  • silica acid and derivatives or salts thereof including silicates, colloidal silicon dioxide, soft silic anhydride, kaolin, titanium dioxide waxes and glycerides, light mineral oil, PEG, glyceryl behenate, colloidal silica, hydrogenated vegetable oils, com starch, sodium stearyl fumarate, polyethylene glycols, alkyl sulfates, sodium benzoate, sodium acetate.
  • a lipid solid dispersion can be processed to prepare a capsule, a tablet, a chewable tablet, a buccal tablet, a sublingual tablet, a orally disintegrating tablet, an effervescent tablet, a granule, a sachet, a film, a dry syrup, a reconstitutable solid, a suspension and/or a solution.
  • the solid molecular dispersion is formulated into a tablet or pill, the tablet or pill may be further coated or otherwise compounded with pharmaceutically acceptable materials known in the art to provide a dosage form affording prolonged action or delayed or extended or sustained release.
  • the present invention provides a process for the preparation of these lipid solid dispersions by spray drying a dispersion of poorly water soluble therapeutic agent and lipid excipient.
  • the said process comprises steps of a) preparing a dispersion comprising of one or more poorly water soluble therapeutic agent; one or more lipids; non-aqueous solvent and optionally one or more pharmaceutically acceptable excipients; b) optionally, heating the prepared dispersion; c) homogenizing the optionally heated dispersion; d) optionally, adding one or more pharmaceutically acceptable excipients to obtain a feed composition e) feeding the feed composition into a spray drier; f) drying the feed composition, and g) collecting the dried particulate material.
  • non aqueous solvents used in the preparation of solid lipid dispersion include isopropyl alcohol, dichloromethane, ethanol, chloroform, ether, acetonitrile.
  • the particulate material obtained have lipid materials which are in liquid or solid form at room temperature and normally has an oily, sticky or waxy character.
  • the particulate material obtained by the novel process has suitable properties with respect to bulk density and particle size. Thus, by use of the present method it is possible to obtain powders that are suitable for further processing into tablets or the like. Due to the possibility of incorporating a lipid a high load of poorly water soluble active substance can be incorporated into the formulation.
  • the dispersed drug is converted to stabilized amorphous form and the particulate material obtained has reduced particle size which enhances the aqueous solubility by increased surface area.
  • the dispersion employed comprises a nonaqueous solvent and a lipid phase. It may be in the form of a dispersion comprising a lipid and a non-aqueous phase.
  • the dispersion is normally prepared in a process step before the step of spray-drying. And during spray drying the particles are separated depends on the particle size by using cyclones.
  • the solid dispersion particles obtained by the said process possess porous structure which results in enhancement of the solubility of poorly water soluble agent. Further, these dispersions enhance the oral absorption of poorly water soluble compounds by attaining and sustaining a supersaturated concentration of drug in the gastrointestinal (GI) fluid.
  • GI gastrointestinal
  • the said process also provides a physically stable form of drug by preventing crystallization or phase separation of amorphous drug and thus enables easy processing of the dispersion into solid dosage forms for shipment and usage.
  • a further advantage of the said process is that (i) it provides a solid drug form that can be manufactured via a reproducible, controllable, and scalable process; (ii) controlled particle size and size distribution of the dispersed particles; (iii) spray drying technology is applicable to structurally diverse insoluble compounds across a wide range of physicochemical properties
  • the atomization of dispersion was performed with a nozzle operating at about 2-2.5 Kg/cm in co-current mode.
  • the prepared dispersions were duly characterized for their physical behavior and their in vitro dissolution. In vivo bioavailability was evaluated after administering the dose to the rats.
  • caprylic/capric triglyceride and 10.0g of caprylocaproyl macroglyceride were dissolved in 500ml of Isopropyl alcohol and was subjected to heating to give a clear solution.
  • 6g of poorly water soluble drug substance, entacapone was slowly added to the above solution while stirring and then the solution was heated till whole drug was dissolved and 4g of colloidal silicone dioxide was added to the dispersion and homogenized. Then the dispersion was fed to the spray dryer.
  • the inlet temperature of the spray drying technique was approximately 40 0 C and spray rate was adjusted in such a manner that outlet temperature was maintained at 35°C.
  • the atomization of dispersion was performed with a nozzle operating at about 2-2.5 Kg/cm in co-current mode.
  • lipid solid pharmaceutical particulate material Preparation of a lipid solid pharmaceutical particulate material according to the invention 11.25g of glyceryl trimyristate and 3.75g of diglyceroyl polyacyladipate were dissolved in 500ml of dichloromethane and was subjected to heating to give a clear solution. 4.5g of poorly water soluble drug substance, entacapone, was slowly added to the above solution while stirring and then the solution was heated till whole drug was dissolved and dispersion was fed to the spray dryer. The inlet temperature of the spray drying technique was approximately 40 0 C and spray rate was adjusted in such a manner that outlet temperature was maintained at 35°C. The atomization of dispersion was performed with a nozzle operating at about 2- 2.5 Kg/cm 2 in co-current mode.
  • a lipid solid pharmaceutical particulate material according to the invention 1Og of glyceroyl distearate was dissolved in 300ml of isopropyl alcohol and was dissolved by heating to give a clear solution. 4g of poorly water soluble drug substance, itraconazole, was slowly added to the above solution while stirring and then the solution was heated till whole drug was dissolved and dispersion was fed to the spray dryer. The inlet temperature of the spray drying technique was approximately 40 0 C and spray rate was adjusted in such a manner that outlet temperature was maintained at 35°C. The atomization of dispersion was performed with a nozzle operating at about 2-2.5 Kg/cm 2 in co-current mode. The prepared dispersions were duly characterized for their physical behavior and their in vitro dissolution.
  • caprylic/capric triglyceride and 3g caprylocaproyl macroglyceride were dissolved in 300ml of Isopropyl alcohol and was subjected to heating to give a clear solution.
  • 4g of poorly water soluble drug substance, Itraconazole was slowly added to the above solution while stirring and then the solution was heated till whole drug was dissolved and 2g of colloidal silicone dioxide was added to the dispersion and homogenized. Then the dispersion was fed to the spray dryer.
  • the inlet temperature of the spray drying technique was approximately 4O 0 C and spray rate was adjusted in such a manner that outlet temperature was maintained at 35 0 C.
  • the atomization of dispersion was performed with a nozzle operating at about 2-2.5 Kg/cm in co-current mode.
  • lipid solid pharmaceutical particulate material 8.3g of glyceroyl distearate and 16.6g of mono di glyceride of edible fatty acids were dissolved in 300ml of dichloromethane and was subjected to heating to give a clear solution. 5g of poorly water soluble drug substance, carvedilol, was slowly added to the above solution while stirring and then the solution was heated till whole drug was dissolved and dispersion was fed to the spray dryer. The inlet temperature of the spray drying technique was approximately 40 0 C and spray rate was adjusted in such a manner that outlet temperature was maintained at 35°C.
  • the atomization of dispersion was performed with a nozzle operating at about 2- 2.5 Kg/cm 2 in co-current mode.
  • the prepared dispersions were duly characterized for their physical behavior and their in vitro dissolution.
  • the in-vivo bioavailability was evaluated in rats after administering orally
  • lipid solid pharmaceutical particulate material Preparation of a lipid solid pharmaceutical particulate material according to the invention 11.25g of caprylic/capric triglyceride and 3.75g of caprylocaproyl macroglyceride were dissolved in 300ml of Isopropyl alcohol and was subjected to heating to give a clear solution. 4g of poorly water soluble drug substance, Carvedilol, was slowly added to the above solution while stirring and then the solution was heated till whole drug was dissolved and 2g of colloidal silicone dioxide was added to the dispersion and homogenized. Then the dispersion was fed to the spray dryer. The inlet temperature of the spray drying technique was approximately 4O 0 C and spray rate was adjusted in such a manner that outlet temperature was maintained at 35°C. The atom ⁇ zation of dispersion was performed with a nozzle operating at about 2-2.5 Kg/cm in co-current mode.
  • Example 15 In vivo study i) Male S.D rats weighing 250gm were used and kept on fasting for overnight before the experiment. The rats were randomized into 3 groups each group containing 3 animals. On the test day 5.7mg/kg of entacapone in different dosage forms were administered orally. Blood samples were collected after 15, 30,
  • the plasma concentration for the unformulated test compound, [Entacapone suspension in potassium bipthalate buffer (pH 3.0)] and the solid dispersion compositions of entacapone in potassium bipthalate buffer (pH 3.0) is shown in FIG 7.
  • the plasma concentration of test compound (entacapone) was higher for the lipid solid dispersion compositions as compared the unformulated test compound.
  • the plasma concentration for the unformulated test compound, [Carvedilol suspension in phosphate buffer (pH 7.4)] and the solid dispersion compositions of carvedilol in phosphate buffer (pH 7.4) is shown in FIG 8.
  • the plasma concentration of test compound (carvedilol) was higher for the lipid solid dispersion compositions as compared the unformulated test compound.

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Abstract

La présente invention concerne une composition pharmaceutique sous forme de dispersions lipidiques solides comprenant un médicament peu soluble dans l'eau et une matière lipidique, et leur utilisation en forme posologique. Ces dispersions solides améliorent la biodisponibilité des agents actifs, sont pratiques à administrer et stables. L’invention concerne également une méthode de préparation de ces dispersions solides lipidiques par séchage par pulvérisation d'une dispersion de médicament peu soluble dans l'eau et d'excipient lipide.
PCT/IN2010/000346 2009-06-11 2010-05-21 Dispersion lipidique solide destinée à améliorer la solubilité aqueuse de médicaments peu solubles dans l'eau WO2010143199A1 (fr)

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US20170112762A1 (en) * 2014-06-10 2017-04-27 Capsugel Belgium Nv Orally disintegrating tablet containing solid lipid particles and methods for their preparation and use
US10722527B2 (en) 2015-04-10 2020-07-28 Capsugel Belgium Nv Abiraterone acetate lipid formulations
CN112165958A (zh) * 2017-10-27 2021-01-01 普莱希科公司 调制激酶的化合物的制剂
US11324699B2 (en) 2014-12-04 2022-05-10 Capsugel Belgium Nv Lipid multiparticulate formulations

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US20170112762A1 (en) * 2014-06-10 2017-04-27 Capsugel Belgium Nv Orally disintegrating tablet containing solid lipid particles and methods for their preparation and use
US11324699B2 (en) 2014-12-04 2022-05-10 Capsugel Belgium Nv Lipid multiparticulate formulations
US10722527B2 (en) 2015-04-10 2020-07-28 Capsugel Belgium Nv Abiraterone acetate lipid formulations
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