CN111617257A - Abiraterone or derivative pharmaceutical composition thereof and application thereof - Google Patents
Abiraterone or derivative pharmaceutical composition thereof and application thereof Download PDFInfo
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- CN111617257A CN111617257A CN202010122422.1A CN202010122422A CN111617257A CN 111617257 A CN111617257 A CN 111617257A CN 202010122422 A CN202010122422 A CN 202010122422A CN 111617257 A CN111617257 A CN 111617257A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The disclosure relates to an abiraterone or derivative pharmaceutical composition thereof and application thereof. Specifically, the pharmaceutical composition contains abiraterone or a derivative thereof, an absorption enhancer and lactose, wherein the lactose accounts for 15-80% of the total weight of the pharmaceutical composition. Compared with the commercial preparation, the bioavailability is improved, and the individual difference of administration patients is improved.
Description
Technical Field
The disclosure belongs to the field of pharmaceutical preparations, and particularly relates to an abiraterone or derivative pharmaceutical composition and application thereof.
Background
Abiraterone is a CYP17 inhibitor used to inhibit androgen and estrogen biosynthesis. TheThe acetate esters of the compounds are approved in the united states for the treatment of castration-resistant prostate cancer. However, in clinical curative effect, the commercial zeke is sold on the market
Exhibit poor bioavailability and a large degree of inter-individual variation. Meanwhile, abiraterone acetate belongs to a class of compounds with poor water solubility. Therefore, there is an urgent need for pharmaceutical formulation researchers to develop pharmaceutical formulations with higher bioavailability and lower individual variation.
Two approaches are mainly used for improving the oral bioavailability of the drug, one is to change the physicochemical property of the drug, improve the membrane permeability or improve the dissolution property of the drug, such as micronization technology, solid dispersion technology, inclusion technology and the like, for example, CN103813794A disperses 17- (3-pyridyl) androstane-5, 16-diene-3 beta-acetate analogues in a water-soluble polymer carrier material to prepare a solid dispersion so as to solve the dissolution problem after the drug is prepared; CN103070828B discloses the preparation of solid dispersion with povidone as carrier material, solving similar problems. Another approach is to improve the membrane properties to increase the membrane permeability of the drug, or the inhibition of efflux pumps to prevent the efflux of the absorbed drug from the body, i.e., the use of oral absorption enhancers. For example, CN102123697A addresses the bioavailability of GLP-1 analogs in compositions by enhancing the absorption of proteins, protease inhibitors through the intestinal mucosal barrier by adding absorption enhancers sodium N- (8- (2-hydroxybenzoyl) amino) caprylate (SNAC) or sodium N- (8- (2-hydroxybenzoyl) amino) caprate (SNAD) or combinations thereof.
In addition, there is no literature report on the utilization of absorption enhancers to solve the problem of bioavailability of small molecule compounds and the use of absorption enhancers to improve the individual variability of a drug among different patients.
Disclosure of Invention
The present disclosure provides a pharmaceutical composition comprising abiraterone or a derivative thereof, an absorption enhancer and lactose, preferably the filler is present in an amount of 15 to 80% by weight, based on the total weight of the pharmaceutical composition, and may be 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80% or any value in between, more preferably 25 to 75%, e.g. 36%, 36.5%, 37%, 37.5% or 38%.
In some embodiments, the absorption enhancer in the pharmaceutical composition is a natural or synthetic adjuvant that can enhance the different physicochemical properties of the drug absorption in the intestinal tract.
The absorption enhancers in the present disclosure include, but are not limited to, one or more selected from capric acid, sodium or potassium caprate, N- (10- [ 2-hydroxybenzoyl ] amino) capric acid (SNAD), caprylic acid, sodium or potassium caprylate, N- (8- (2-hydroxybenzoyl) amino) caprylic acid (NAC), N- (5-chlorosalicyloyl) -8-aminocaprylic acid (5-CNAC), sodium 8- (salicylamido) caprylate (SNAC), preferably one or more of sodium 8- (salicylamido) caprylate or N- (8- (2-hydroxybenzoyl) amino) caprylic acid.
Further, in some embodiments, the weight ratio of the absorption enhancer to abiraterone or derivative thereof is 1:100 to 100:1, and may be 1:100, 1:99, 1:98, 1:97, 1:96, 1:95, 1:94, 1:93, 1:92, 1:91, 1:90, 1:89, 1:88, 1:87, 1:86, 1:85, 1:84, 1:83, 1:82, 1:81, 1:80, 1:79, 1:78, 1:77, 1:76, 1:75, 1:74, 1:73, 1:72, 1:71, 1:70, 1:69, 1:68, 1:67, 1:66, 1:65, 1:64, 1:63, 1:62, 1:61, 1:60, 1:59, 1:58, 1:57, 1:56, 1:55, 1:54, 1:52, 1:53, 1:48, 1:49, 1:48, 1:51, 1:49, 1:48, 1:54, 1:48, 1:49, 1:58, 1:75, 1:74, 1:72, 1:71, 1:69, 11: 47, 1:46, 1:45, 1:44, 1:43, 1:42, 1:41, 1:40, 1:39, 1:38, 1:37, 1:36, 1:35, 1:34, 1:33, 1:32, 1:31, 1:30, 1:29, 1:28, 1:27, 1:26, 1:25, 1:24, 1:23, 1:22, 1:21, 1:20, 1:19, 1:18, 1:17, 1:16, 1:15, 1:14, 1:13, 1:12, 1:11, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9, 1:1, 1:11, 1:13, 1:1, 6:1, 1:1, 6:1, 1:1, 6:1, 1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1, 60:1, 61:1, 62:1, 63:1, 64:1, 65:1, 66:1, 67:1, 68:1, 69:1, 70:1, 71:1, 72:1, 73:1, 74:1, 84:1, 77:1, 83:1, 84:1, 78:1, 83:1, 70:1, 71:1, 7:1, 72:1, 7:1, 1, 85:1, 86:1, 87:1, 88:1, 89:1, 90:1, 91:1, 92:1, 93:1, 94:1, 95:1, 96:1, 97:1, 98:1, 99:1, 100:1 or any value in between, further preferably 1:10 to 20:1, more preferably 1:10 to 10: 1. Some embodiments provide the pharmaceutical composition wherein the weight ratio of the absorption enhancer to abiraterone or derivative thereof is 1: 2. Some embodiments provide the pharmaceutical composition wherein the weight ratio of the absorption enhancer to abiraterone or derivative thereof is 1: 1. Some embodiments provide the pharmaceutical composition wherein the weight ratio of the absorption enhancer to abiraterone or derivative thereof is 2: 1.
Further, the pharmaceutical composition is a solid preparation, and the pharmaceutical composition further comprises at least one disintegrating agent selected from croscarmellose sodium, crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch and alginic acid. Preferably, the disintegrant is used in an amount of 0.5 to 20% of the total weight of the pharmaceutical composition, and may be 0.5%, 06%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.3%, 1.5%, 1.7%, 1.9%, 2.1%, 2.3%, 2.5%, 2.7%, 2.9%, 3.1%, 3.3%, 3.5%, 3.7%, 3.9%, 4.1%, 4.3%, 4.5%, 4.7%, 4.9%, 5.1%, 5.3%, 5.5%, 5.7%, 5.9%, 6.1%, 6.3%, 6.5%, 6.7%, 6.9%, 7.1%, 7.3%, 7.5%, 7.7%, 7.9%, 8.1%, 8.3%, 8.5%, 8.7%, 8.9%, 9.1%, 9.3%, 9.5%, 9.9%, 10.9%, 10.5%, 10.12%, 11.12%, 14.9%, 10%, 14.9%, 10.9%, 10%, 10.9%, 7%, 14.9%, 3%, 7.9.9%, 10.9%, 10%, 7%, 10.1%, 14.9%, 10.9%, 3%, 7%, 15.1%, 15.3%, 15.5%, 15.7%, 15.9%, 16.1%, 16.3%, 16.5%, 16.7%, 16.9%, 17.1%, 17.3%, 17.5%, 17.7%, 17.9%, 18.1%, 18.3%, 18.5%, 18.7%, 18.9%, 19.1%, 19.3%, 19.5%, 19.7%, 19.9%, 20% or any value in between, preferably 2 to 10%, e.g. 7%, 7.5%, 8% or 8.5%.
Further, the particle size D90 value of the abiraterone or the derivative thereof in the pharmaceutical composition is less than 1000nm, less than 900nm, less than 800nm, less than 700nm, less than 600nm, less than 500nm, less than 400nm, less than 300nm, less than 200nm, less than 100nm, less than 50nm or less, preferably 400-600 nm.
It was found that the pharmaceutical compositions of the present disclosure, having a D90 of less than 1000nm, facilitate increased solubility and dissolution rate of abiraterone acetate as compared to conventional compositions or micronized compositions. Furthermore, reduced food effect is also advantageously manifested. In particular, the increased solubility and dissolution rate of abiraterone acetate results in improved bioavailability and pharmacokinetic profile of the drug, which in turn reduces the required daily dose of abiraterone acetate.
In some embodiments, the required daily dosage of abiraterone acetate is reduced by 10 wt%, preferably 20 wt%, 25 wt%, 30 wt%, 35 wt%, more preferably up to 40 wt%.
Further, the particle size of the active ingredient in the pharmaceutical composition has a value of D50 of less than 1 μm, preferably the value of D50 is selected from the group consisting of less than 1 μm, less than 900nm, less than 800nm, less than 700nm, less than 600nm, less than 500nm, less than 450nm, less than 400nm, less than 350nm, less than 300nm, less than 250nm, less than 200nm, less than 150nm, less than 100nm or less, preferably less than 800nm, more preferably less than 700nm, most preferably less than 600 nm.
Still further, the particle size of the active ingredient in the pharmaceutical composition has a D10 value of less than 300nm, preferably a D50 value of from less than 300nm, less than 280nm, less than 250nm, less than 220nm, less than 200nm, less than 180nm, less than 150nm, less than 120nm, less than 100nm, less than 90nm, less than 80nm, less than 70nm, less than 60nm, less than 50nm, less than 40nm, less than 30nm, less than 20nm, less than 10nm, less than 5nm or less, preferably less than 200nm, most preferably less than 100 nm.
In some embodiments, the steps of the present disclosure to prepare abiraterone or derivative thereof nanosuspensions include the following steps or refer to the preparation process in WO2014009436, and the relevant contents are incorporated herein:
(a) preparing a suspension of abiraterone or a derivative thereof in a liquid solvent selected from water, polyethylene glycol, glycerol, propylene glycol or any combination thereof, preferably water;
(b) adding grinding balls to the suspension of step (a) to obtain a slurry for grinding,
(c) grinding to obtain the nano suspension with the particle size D90 value less than 1000 nm.
Further, the nanosuspension is further processed to convert into a concentrated nanosuspension.
In some embodiments, at least a portion of the solvent is removed by conventional drying methods, such as freeze drying or spray drying, to obtain a concentrated nanosuspension.
In another aspect, the present disclosure also provides a method of preparing the aforementioned pharmaceutical composition, comprising: a) preparing a nanosuspension of abiraterone or a derivative thereof as described above, b) adding an absorption enhancer and optionally at least one excipient such as lactose.
Further, step b) is optionally preceded by a step of removing liquid agent from the nanosuspension to obtain a concentrated nanosuspension.
Further, the method for preparing the aforementioned pharmaceutical composition further comprises the step of removing the solvent from the nanosuspension using fluidized bed granulation to obtain a concentrated nanosuspension.
In a preferred embodiment, a method of making the aforementioned pharmaceutical composition comprises:
a) a nanosuspension of the active ingredient was prepared as described above,
b) adding absorption enhancer and optionally at least one excipient such as lactose,
c) and c, granulating the nano suspension obtained in the step b through a fluidized bed.
On the other hand, the active ingredient abiraterone or derivative thereof used in the present disclosure preferably (but not necessarily) has a particle size of less than 100 μm as measured by a sieve method if the active ingredient drug substance particle size is greater than 100 μm, then it is preferable to reduce the particle size below 100 μm by a conventional grinding method such as an air jet mill or a crushing mill.
The selected active ingredient drug substance may be added to a liquid medium, preferably water, which is substantially insoluble in it, to form a primary mixture. The concentration of the active ingredient in the liquid medium is from 0.1 to 60% (W/W), preferably from 5 to 30% (W/W), and may be 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30% (W/W). It is preferred, but not necessary, that the stabilizer be present in the initial mixture. The initial mixture suspension preferably has an apparent viscosity of less than 2000 centipoise.
The initial mixture can be reduced to below 5000nrn in the dispersed phase by mechanical means. The initial mixture is preferably applied directly when grinding with a ball mill. Alternatively, the active ingredient and any surface stabilizer may be dispersed in a liquid medium by any suitable means, such as a roller mill or a Cowles-type mixer, until a uniform dispersion of large agglomerates is formed which is not visible to the naked eye. If a circulating media mill is used for milling, it is preferred to subject the initial mixture to this pre-milling dispersion step.
The conventional mechanical means for preparing the active ingredient in a nano-sized particle size may be a dispersion mill including a ball mill, a attrition mill, a vibration mill, a planetary mill, a media mill (e.g., a sand mill and a bead mill) in a form suitable for the dispersion mill.
The grinding media used in the step of grinding the particles may be selected from rigid media, preferably spherical or granular, having an average particle size of less than 3mm, more preferably less than 1 mm. Such media have shorter processing times and less wear on the grinding equipment while providing the particles of the present disclosure. The choice of raw materials for the grinding media is not critical. Such as zirconiaMagnesium stabilized 95% ZrO, zirconium silicate, glass milling media can provide particles within the allowable impurity content range for the preparation of pharmaceutical complexes. Also, other media such as stainless steel, titanium dioxide, alumina can be used. Preferably the specific gravity of the medium is greater than 2.5g/cm3。
The time of milling varies greatly, depending primarily on the particular mechanical method and processing conditions. For a ball mill, the processing time may need 1 day or more. On the other hand, milling with high shear media for processing times of less than one day (retention times ranging from one minute to several hours) has provided desirable results.
The process of pulverizing particles must be carried out at a temperature at which the active ingredient is not significantly degraded. It is generally preferred to process at a temperature below 50 ℃. The processing equipment may be cooled using conventional cooling equipment, if desired. Such particle generation techniques are well known to those skilled in the art and details of milling, wet milling, homogenisation, precipitation or supercritical fluid particle generation techniques and the like are described in CN1063630C, CN101175481A or CN1515244A and are specifically incorporated herein.
Further, the pharmaceutical composition also comprises at least one stabilizer.
The stabilizer in the present disclosure is selected from a cellulose derivative, preferably hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose or sodium carboxymethyl cellulose, or a surfactant; the surfactant is preferably polyoxyethylene ether, poloxamer, polyglycolyzed glyceride, polyethoxylated hydrogenated castor oil, sodium lauryl sulfate or sodium cholate.
In some embodiments, the stabilizing agent is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium lauryl sulfate, or a poloxamer.
Further, at least two or more stabilizers are included in the pharmaceutical composition.
In some embodiments, the stabilizing agent is preferably hydroxypropyl methylcellulose and sodium lauryl sulfate.
Further, the abiraterone or derivative thereof content in the aforementioned step (a) is 40 to 95 wt%, including 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95% or any value therebetween, preferably 60 to 85% by weight, for example 79%, 79.5%, 80%, 80.5% or 81%.
Further, the step (a) for preparing the abiraterone or derivative nano suspension also comprises at least one stabilizer.
In some embodiments, the stabilizing agent is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium lauryl sulfate, or a poloxamer.
Further, at least two or more stabilizers, preferably hydroxypropyl methylcellulose and sodium lauryl sulfate, are included in step (a) of the present disclosure.
In another aspect, the present disclosure also provides a method of preparing a pharmaceutical composition comprising: mixing the nano suspension containing the abiraterone or the derivative thereof with an absorption enhancer and at least one optional excipient, and granulating by a fluidized bed.
Wherein the particle size D90 value of the abiraterone or the derivative thereof is less than 1000nm, less than 900nm, less than 800nm, less than 700nm, less than 600nm, less than 500nm, less than 400nm, less than 300nm, less than 200nm, less than 100nm, less than 50nm or less, preferably 400-600 nm.
Further, the particle size of the active ingredient in the pharmaceutical composition has a value of D50 of less than 1 μm, preferably the value of D50 is selected from the group consisting of less than 1 μm, less than 900nm, less than 800nm, less than 700nm, less than 600nm, less than 500nm, less than 450nm, less than 400nm, less than 350nm, less than 300nm, less than 250nm, less than 200nm, less than 150nm, less than 100nm or less, preferably less than 800nm, more preferably less than 700nm, most preferably less than 600 nm.
Still further, the particle size of the active ingredient in the pharmaceutical composition has a D10 value of less than 300nm, preferably a D50 value of from less than 300nm, less than 280nm, less than 250nm, less than 220nm, less than 200nm, less than 180nm, less than 150nm, less than 120nm, less than 100nm, less than 90nm, less than 80nm, less than 70nm, less than 60nm, less than 50nm, less than 40nm, less than 30nm, less than 20nm, less than 10nm, less than 5nm or less, preferably less than 200nm, most preferably less than 100 nm.
In some embodiments, the step of preparing a nanosuspension of abiraterone or derivative thereof in the process is as described previously, i.e.:
(a) preparing a suspension of abiraterone or a derivative thereof in a liquid solvent selected from water, polyethylene glycol, glycerol, propylene glycol or any combination thereof, preferably water;
(b) adding grinding balls to the suspension of step (a) to obtain a slurry for grinding,
(c) grinding to obtain the nano suspension with the particle size D90 value less than 1000 nm.
Further, the nanosuspension is further processed to convert into a concentrated nanosuspension.
In some preferred embodiments, at least a portion of the solvent is removed by conventional drying methods, such as freeze drying or spray drying, to obtain a concentrated nanosuspension.
In some embodiments, a method of preparing a pharmaceutical composition comprises: a) preparing a nanosuspension of abiraterone or a derivative thereof as described above, b) adding an absorption enhancer and optionally at least one excipient.
Further, step b) is optionally preceded by a step of removing liquid agent from the nanosuspension to obtain a concentrated nanosuspension.
Further, the method of preparing the pharmaceutical composition further comprises the step of removing the solvent from the nanosuspension using fluid bed granulation to obtain a concentrated nanosuspension.
In some embodiments, a method of preparing a pharmaceutical composition, comprises:
a) a nanosuspension of the active ingredient was prepared as described above,
b) adding an absorption enhancer and optionally at least one excipient,
c) and c, granulating the nano suspension obtained in the step b through a fluidized bed.
In other embodiments, the absorption enhancer in the pharmaceutical composition is selected from one or more of sodium 8- (salicyloylamino) caprylate or N- (8- (2-hydroxybenzoyl) amino) caprylic acid.
Further, in some embodiments, the weight ratio of the absorption enhancer to abiraterone or derivative thereof is 1:100 to 100:1, and may be 1:100, 1:99, 1:98, 1:97, 1:96, 1:95, 1:94, 1:93, 1:92, 1:91, 1:90, 1:89, 1:88, 1:87, 1:86, 1:85, 1:84, 1:83, 1:82, 1:81, 1:80, 1:79, 1:78, 1:77, 1:76, 1:75, 1:74, 1:73, 1:72, 1:71, 1:70, 1:69, 1:68, 1:67, 1:66, 1:65, 1:64, 1:63, 1:62, 1:61, 1:60, 1:59, 1:58, 1:57, 1:56, 1:55, 1:54, 1:52, 1:53, 1:48, 1:49, 1:48, 1:51, 1:49, 1:48, 1:54, 1:48, 1:49, 1:58, 1:75, 1:74, 1:72, 1:71, 1:69, 11: 47, 1:46, 1:45, 1:44, 1:43, 1:42, 1:41, 1:40, 1:39, 1:38, 1:37, 1:36, 1:35, 1:34, 1:33, 1:32, 1:31, 1:30, 1:29, 1:28, 1:27, 1:26, 1:25, 1:24, 1:23, 1:22, 1:21, 1:20, 1:19, 1:18, 1:17, 1:16, 1:15, 1:14, 1:13, 1:12, 1:11, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9, 1:1, 1:11, 1:13, 1:1, 6:1, 1:1, 6:1, 1:1, 6:1, 1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39:1, 40:1, 41:1, 42:1, 43:1, 44:1, 45:1, 46:1, 47:1, 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 57:1, 58:1, 59:1, 60:1, 61:1, 62:1, 63:1, 64:1, 65:1, 66:1, 67:1, 68:1, 69:1, 70:1, 71:1, 72:1, 73:1, 74:1, 84:1, 77:1, 83:1, 84:1, 78:1, 83:1, 70:1, 71:1, 7:1, 72:1, 7:1, 1, 85:1, 86:1, 87:1, 88:1, 89:1, 90:1, 91:1, 92:1, 93:1, 94:1, 95:1, 96:1, 97:1, 98:1, 99:1, 100:1 or any value in between, further preferably 1:10 to 20:1, more preferably 1:10 to 10: 1.
Further, the pharmaceutical composition is a solid preparation.
Further, the excipient in the aforementioned preparation method is well known or can be determined by those skilled in the art, and is selected from at least one of, but not limited to, a disintegrant, a filler, a binder, and a lubricant.
The filler provides bulk, making the tablet the actual size that it can handle, and may also aid in handling, improving physical properties of the solid formulation such as flowability, compressibility, and hardness of the solid formulation. The filler of the present disclosure is known or ascertainable to those skilled in the art and is selected from, but not limited to, at least one of dextrin, lactose, sucrose, dibasic calcium phosphate, calcium sulfate, starch, anhydrous dibasic calcium phosphate, mannitol; preferably, the filler is used in an amount of 15 to 80% by weight, based on the total weight of the pharmaceutical composition, and may be 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80% or any value therebetween, more preferably 25 to 75%, e.g., 36%, 36.5%, 37%, 37.5% or 38%.
Further, in some embodiments, the filler is not microcrystalline cellulose.
Further, in some embodiments, the filler is selected from lactose.
In another aspect, the disintegrant is known or identifiable to those skilled in the art and is selected from, but not limited to, at least one of croscarmellose sodium, crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, starch, pregelatinized starch, alginic acid; preferably, the disintegrant is used in an amount of 0.5 to 20% of the total weight of the pharmaceutical composition, and may be 0.5%, 06%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.3%, 1.5%, 1.7%, 1.9%, 2.1%, 2.3%, 2.5%, 2.7%, 2.9%, 3.1%, 3.3%, 3.5%, 3.7%, 3.9%, 4.1%, 4.3%, 4.5%, 4.7%, 4.9%, 5.1%, 5.3%, 5.5%, 5.7%, 5.9%, 6.1%, 6.3%, 6.5%, 6.7%, 6.9%, 7.1%, 7.3%, 7.5%, 7.7%, 7.9%, 8.1%, 8.3%, 8.5%, 8.7%, 8.9%, 9.1%, 9.3%, 9.5%, 9.9%, 10.9%, 10.5%, 10.12%, 11.12%, 14.9%, 10%, 14.9%, 10.9%, 10%, 10.9%, 7%, 14.9%, 3%, 7.9.9%, 10.9%, 10%, 7%, 10.1%, 14.9%, 10.9%, 3%, 7%, 15.1%, 15.3%, 15.5%, 15.7%, 15.9%, 16.1%, 16.3%, 16.5%, 16.7%, 16.9%, 17.1%, 17.3%, 17.5%, 17.7%, 17.9%, 18.1%, 18.3%, 18.5%, 18.7%, 18.9%, 19.1%, 19.3%, 19.5%, 19.7%, 19.9%, 20% or any value in between, preferably 2 to 10%, e.g. 7%, 7.5%, 8% or 8.5%.
In some embodiments, the disintegrant is selected from crospovidone.
Further, the binder is known or identifiable to those skilled in the art, and is selected from but not limited to at least one of polyvinylpyrrolidone, starch, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and alginate, preferably at least one of polyvinylpyrrolidone and hydroxypropylcellulose, more preferably the binder is used in an amount of 0.5 to 10% by weight, and may be 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.3%, 1.5%, 1.7%, 1.9%, 2.1%, 2.3%, 2.5%, 2.7%, 2.9%, 3.1%, 3.3%, 3.5%, 3.7%, 3.9%, 4.1%, 4.3%, 4.5%, 4.7%, 4.9%, 5.1%, 5.3%, 5.5%, 5.7%, 5.9%, 6.1%, 6.3%, 6.5%, 6.7%, 7.7%, 7%, 7.9%, 7%, 7.7%, 7%, 7.9%, 7%, 7.7%, 7%, 8.1%, 8.3%, 8.5%, 8.7%, 8.9%, 9.1%, 9.3%, 9.5%, 9.7%, 9.9%, 10.0%, or any value in between.
Further, the lubricant is known or can be identified by those skilled in the art, and is selected from at least one of magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, colloidal silicon dioxide, carnauba wax, sodium stearyl fumarate; preferably, the lubricant of the present disclosure is used in an amount of 0.1 to 5% by weight, and may be 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.3%, 1.5%, 1.7%, 1.9%, 2.1%, 2.3%, 2.5%, 2.7%, 2.9%, 3.1%, 3.3%, 3.5%, 3.7%, 3.9%, 4.1%, 4.3%, 4.5%, 4.7%, 4.9%, 5.0% or any value therebetween, preferably 0.1 to 2.0% by weight of the total weight of the pharmaceutical composition.
Still further, the method of the present disclosure further comprises the step of granulating, tabletting, or encapsulating.
In some embodiments, the method of preparing a pharmaceutical composition according to the present disclosure further comprises the step of direct compression or direct encapsulation.
On the other hand, the pharmaceutical composition of the present disclosure may further be coated if necessary, and the coating agent is selected from but not limited to water-soluble polymers, water-insoluble polymers, gastric-soluble polymers, and enteric-soluble polymers. Water-soluble polymers such as natural polymers or polysaccharides and derivatives thereof, e.g., acacia powder, gelatin, pullulan, dextrin, sodium carboxymethyl starch, sodium alginate, cellulose derivatives such as sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, methyl cellulose, and carboxymethyl cellulose (carboxymethyl cellulose), and water-soluble vinyl derivatives such as polyvinylpyrrolidone and polyvinyl alcohol; water-insoluble polymers such as ethyl cellulose (an aqueous dispersion of ethyl cellulose (e.g., trade name: AQUACOAT, manufactured by FMC Co.), vinyl acetate polymer (e.g., trade name: Kollicoat SR30D, manufactured by BASF Co.), aminoalkyl methacrylate copolymer (particularly an aqueous dispersion thereof (e.g., trade name: EUDRAGITRL30D, EUDRAGITRS30D, manufactured by EVONIC Co.), ethyl acrylate-methyl methacrylate copolymer dispersion (e.g., trade name: EUDRAGITNE30D, manufactured by EVONIC Co.), gastric-soluble polymers such as polyvinylacetal-diethylaminoacetate (e.g., trade name: AEA, Mitsubishi-KagakuFoods Corporation), aminoalkyl methacrylate copolymer E (e.g., trade name: EUDRAGITE, manufactured by EVONIC Co.), and mixtures thereof Enteric acrylic copolymers such as hydroxypropylmethylcellulose phthalate (hypromellose phthalate), hydroxymethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate, phthalate, etc., methacrylic acid copolymer LD (for example, trade name: EUDRAGITL30D-55, manufactured by EVONIC, trade name: POLYQUIDPA30, manufactured by Sanyo chemical Co., Ltd.; trade name: KollicoatMAE30DP, manufactured by BASF, trade name: Acryl-Eze (Acryk, batch No. 93O18508), Carlekang), methacrylic acid copolymer L (for example, trade name: EUDRAGITL, manufactured by EVONIC), methacrylic acid copolymer S (for example, trade name: EUDRAGITS100, EUDRAGITS 30D, manufactured by EVONIC), etc.
In some embodiments, the coating layer in the pharmaceutical composition of the present disclosure is at least one layer, and may be one, two, three, or even four layers.
Correspondingly, the preparation method disclosed by the disclosure further comprises a coating step.
The total weight of the pharmaceutical composition is the numerical range of the usage amount of the active ingredients or other types of pharmaceutical excipients calculated by the weight of the tablet core without the coating agent.
The present disclosure also provides a pharmaceutical composition obtained by the aforementioned preparation method, comprising abiraterone having a particle size D90 value of less than 1000nm or a derivative thereof, and an absorption enhancer.
In other embodiments, the pharmaceutical composition comprises: abiraterone or a derivative thereof, an absorption enhancer such as sodium 8- (salicylamido) caprylate or N- (8- (2-hydroxybenzoyl) amino) caprylic acid, at least two stabilizers selected from cellulose derivatives or surfactants, preferably at least two of hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium lauryl sulfate or poloxamer,
wherein the particle size D90 value of the active ingredient is less than 1000nm, preferably less than 800nm, more preferably 400-600 nm, such as 500 nm.
Further, the weight ratio of the abiraterone or the derivative thereof to the absorption enhancer is 1:10 to 20:1, more preferably 1:10 to 10:1, and may be 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10: 1.
Further, the pharmaceutical composition further comprises at least one excipient.
In some embodiments, the pharmaceutical compositions of the present disclosure comprise: the active ingredient abiraterone or a derivative thereof, an absorption enhancer such as sodium 8- (salicylamido) caprylate or N- (8- (2-hydroxybenzoyl) amino) caprylic acid, and lactose in an amount of 15 to 80%, more preferably 25 to 75%, for example 36%, 36.5%, 37%, 37.5% or 38% by weight of the total pharmaceutical composition.
Further, the pharmaceutical composition does not contain microcrystalline cellulose.
Further, the pharmaceutical composition also contains a disintegrant, and the disintegrant is selected from crospovidone.
Further, the active ingredient particle size D90 value is less than 1000nm, preferably less than 800nm, more preferably 400-600 nm, for example 500 nm.
Further, the pharmaceutical composition also comprises at least two stabilizers, wherein the stabilizers are selected from cellulose derivatives or surfactants, and the stabilizers are preferably at least two of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, sodium dodecyl sulfate or poloxamer.
In another preferred embodiment, the pharmaceutical composition of the present disclosure comprises:
a) the active ingredient of abiraterone or a derivative thereof,
b) absorption enhancers such as sodium 8- (salicyloylamino) caprylate or N- (8- (2-hydroxybenzoyl) amino) caprylic acid,
c) at least two stabilizers selected from cellulose derivatives or surfactants, preferably at least two of hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium lauryl sulfate or poloxamer,
d) a disintegrating agent selected from at least one of croscarmellose sodium, crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, starch, pregelatinized starch and alginic acid, preferably the disintegrating agent is used in an amount of 0.5 to 20% by weight of the solid preparation,
e) a filler selected from at least one of dextrin, lactose, sucrose, calcium hydrogen phosphate, starch, anhydrous calcium hydrogen phosphate, calcium sulfate, mannitol, preferably in an amount of 15 to 80%, more preferably 25 to 75% by weight of the solid formulation,
wherein the particle size D90 value of the active ingredient is less than 1000nm, preferably less than 800nm, and more preferably 400-600 nm.
Further, in some embodiments, the pharmaceutical composition comprises: the active ingredients are 17- (3-pyridyl) androstane-5, 16-diene-3 beta-ol or derivatives thereof, 8- (salicyloylamino) sodium caprylate, hydroxypropyl methylcellulose and sodium lauryl sulfate, and lactose and crospovidone, wherein the particle size D90 value of the active ingredients is less than 1000nm, preferably less than 800nm, more preferably 400-600 nm.
Some embodiments provide pharmaceutical compositions comprising:
a)10 to 40% of abiraterone or a derivative thereof,
b)10 to 40% of an absorption enhancer, preferably sodium 8- (salicyloylamino) caprylate or N- (8- (2-hydroxybenzoyl) amino) caprylic acid,
c)0.5 to 20% of a stabilizer, preferably at least one of hydroxypropyl methylcellulose or sodium lauryl sulfate,
d)25 to 75% of a filler.
Some embodiments provide pharmaceutical compositions comprising:
a)10 to 40% of abiraterone or a derivative thereof,
b)10 to 40% of an absorption enhancer, preferably sodium 8- (salicyloylamino) caprylate or N- (8- (2-hydroxybenzoyl) amino) caprylic acid,
c)0.5 to 20% of a stabilizer, preferably at least one of hydroxypropyl methylcellulose or sodium lauryl sulfate,
d)25 to 75% of a filler, preferably lactose,
e)0.5 to 20% of a disintegrant,
further, the pharmaceutical composition preferably further comprises 0.1 to 2.0% of a lubricant.
Some embodiments provide pharmaceutical compositions comprising:
a)10 to 40% of abiraterone or a derivative thereof,
b)10 to 40% of an absorption enhancer, preferably sodium 8- (salicyloylamino) caprylate or N- (8- (2-hydroxybenzoyl) amino) caprylic acid,
c)0.5 to 20% of a stabilizer, preferably at least one of hydroxypropyl methylcellulose or sodium lauryl sulfate,
d)25 to 75% of a filler, preferably lactose,
e)0.5 to 20% of a disintegrant,
further, the pharmaceutical composition further comprises 0.1 to 2.0% of a lubricant, wherein the particle size D90 value of the abiraterone or the derivative thereof is less than 1000nm, such as 500 nm. In another aspect, the daily dose of the active ingredient of the pharmaceutical composition of the present disclosure is 50 to 800mg, and may be 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, preferably 300 to 600mg, more preferably 400 to 550mg, and most preferably 500 mg.
In terms of efficacy, the pharmaceutical compositions described in this disclosure improve the individual variability of the patient taking the drug relative to the common tablet of commercially available 17- (3-pyridyl) androsta-5, 16-diene-3 β -acetate.
Further, in some embodiments, the unit dosage forms of abiraterone or derivatives thereof described in this disclosure at a dose of 50-800mg with a dose of 1000mg of zecade
The formulation is bioequivalent in healthy male subjects in the fasted state.
In some embodiments, the unit dosage form of abiraterone or derivative thereof at the dosage of 200-450mg and zecade at the dosage of 1000mg as described in this disclosure
The formulation is bioequivalent in healthy male subjects in the fasted state, wherein the dose of 17- (3-pyridyl) androsta-5, 16-diene-3 β -acetate can be 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 385mg, 390mg, 395mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440mg, 420mg, 450mg, or any value in between.
In another aspect, the present disclosure also provides the use of the aforementioned pharmaceutical composition for the manufacture of a medicament for improving the individual variability of patients taking the medicament, relative to zecade, a commercially available abiraterone acetate plain tablet
The present disclosure also provides a use of the aforementioned pharmaceutical composition for the preparation of a medicament for the treatment of prostate cancer. The present disclosure also provides a method of treating prostate cancer comprising administering to a patient in need of treatment the aforementioned pharmaceutical composition.
In another aspect of the disclosure, there is provided a method of improving individual variability in a patient taking a drug comprising administering to a patient in need thereof the foregoing pharmaceutical composition, the improvement being zecade relative to a commercially available abiraterone acetate plain tablet
In a set control group experiment, the medicinal composition is mixed with a reference preparation zeke
The healthy male subjects in the fasting state were administered, respectively, and blood was collected from the patients within a prescribed time and the corresponding drug concentrations were measured. The study found that the unit dosage form of abiraterone or derivatives thereof at a dose of 50-800mg and zecade at a dose of 1000mg
The AUC of the formulation in healthy male subjects in the fasted state is comparable, and the area under the curve (AUC) at drug time represents the bioavailability of the drug (the extent to which the drug is absorbed and utilized in humans). To some extent, it can be deduced that both are bioequivalent in healthy male subjects in the fasted state.
In some embodiments, the unit dosage form of abiraterone or derivative thereof described in this disclosure at a dose of 50-800mg with a dose of 1000mg of zecade
The formulation is bioequivalent in healthy male subjects in the fasted state.
In some embodiments, the unit dosage form of abiraterone or derivative thereof at the dosage of 200-450mg and zecade at the dosage of 1000mg as described in this disclosure
Healthy male with preparation in fasting stateBioequivalent in a subject wherein the dose of 17- (3-pyridyl) androsta-5, 16-diene-3 β -acetate can be 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 385mg, 390mg, 395mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440mg, 445mg, 450mg, or any value therebetween.
In some embodiments, the unit dosage form of abiraterone or derivative thereof described in this disclosure at a dose of 300mg and zecade at a dose of 1000mg
The formulation is bioequivalent in healthy male subjects in the fasted state. Further, in an alternative embodiment, the unit dosage form of abiraterone or derivatives thereof described in the disclosure at a dose of 200-450mg is combined with zecade at a dose of 1000mg
The formulation is bioequivalent in healthy male subjects in the fasted state, while having the effect of reducing the inter-individual variability among the subjects.
The unit dosage form of the present disclosure comprises a dose of 50-800mg of abiraterone or derivative thereof.
In other embodiments, the unit dosage form comprises the aforementioned pharmaceutical composition.
The total weight of the pharmaceutical composition is the numerical range of the usage amount of the active ingredients or other types of pharmaceutical excipients calculated by the weight of the tablet core without the coating agent.
When the pharmaceutical composition described in the present disclosure employs a tablet, the preparation of the granules obtained as described above can be compressed. The compressible pressure is determined within a suitable range. Further, the tablet shape is not particularly limited, and is preferably a lenticular shape, a disc shape, a circular shape, an oval shape (e.g., a caplet), a teardrop shape or a polygonal shape (e.g., a triangle or a diamond shape).
As used herein, "D10" refers to the particle size corresponding to a cumulative percent particle size distribution of 10% for a sample. "D50" refers to the particle size corresponding to the cumulative percent particle size distribution of a sample at 50%. "D90" refers to the particle size corresponding to 90% of the cumulative percent particle size distribution for a sample. D4, 3 represents the "quartic/volume" mean diameter, also called the volume (or weight) mean diameter.
The measurement data in the present disclosure have a certain degree of error, and generally, plus or minus 10% falls within a reasonable error range. The error change is within plus or minus 10%, which can be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2% or plus or minus 1%, preferably plus or minus 5% ". For example, some embodiments provide that the amount of lactose in the pharmaceutical composition varies to some extent, typically plus or minus 10%, due to the presence of errors. Some embodiments provide that there is also some measured variation, typically plus or minus 10%, in the particle size D90 of abiraterone or a derivative thereof in the medicament.
The derivative disclosed by the invention is a compound which forms an ester or ether structure by 17- (3-pyridyl) androstane-5, 16-diene-3 beta-alcohol and acyl, alkyl and the like, and can be metabolized into 17- (3-pyridyl) androstane-5, 16-diene-3 beta-alcohol in vivo, wherein the derivative is selected from but not limited to 17- (3-pyridyl) androstane-5, 16-diene-3 beta-acetate.
The reference formulation R of this disclosure was a commercial abiraterone acetate plain tablet (trade name zecade,
)。
the pharmaceutical excipients or agents of the present disclosure are all commercially available, e.g., hydroxypropyl methylcellulose is commercially available; 17- (3-pyridyl) androsta-5, 16-diene-3 β -acetate can be prepared according to the method described in example CN 101528308.
The technical scheme of the disclosure is summarized as follows:
1. a pharmaceutical composition comprising abiraterone or a derivative thereof, an absorption enhancer and lactose, preferably in an amount of from 15 to 80%, more preferably from 25 to 75% by weight of the total pharmaceutical composition.
2. The pharmaceutical composition of item 1, wherein the absorption enhancer is selected from one or more of capric acid, sodium or potassium caprate, N- (10- [ 2-hydroxybenzoyl ] amino) capric acid, caprylic acid, sodium or potassium caprylate, N- (8- (2-hydroxybenzoyl) amino) caprylic acid, N- (5-chlorosalicyloyl) -8-aminocaprylic acid, sodium 8- (salicylamido) caprylate, preferably one or more of sodium 8- (salicylamido) caprylate or N- (8- (2-hydroxybenzoyl) amino) caprylate.
3. The pharmaceutical composition according to item 1 or 2, wherein the weight ratio of the absorption enhancer to abiraterone or a derivative thereof is not less than 1:100, preferably 1:10 to 20:1, more preferably 1:10 to 10: 1.
4. The pharmaceutical composition according to any one of items 1 to 3, further comprising at least one disintegrant selected from the group consisting of croscarmellose sodium, crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, starch, pregelatinized starch, and alginic acid, preferably in an amount of 0.5 to 20% by weight based on the total weight of the pharmaceutical composition.
5. The pharmaceutical composition according to any one of claims 1 to 4, further comprising at least one stabilizer selected from a cellulose derivative, preferably hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose or sodium carboxymethylcellulose, or a surfactant; the surfactant is preferably polyoxyethylene ether, poloxamer, polyglycolyzed glyceride, polyethoxylated hydrogenated castor oil, sodium lauryl sulfate or sodium cholate.
6. The pharmaceutical composition of clause 5, wherein the stabilizer is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium lauryl sulfate, or poloxamer, preferably hydroxypropyl methylcellulose and sodium lauryl sulfate.
7. The pharmaceutical composition according to item 5 or 6, wherein the abiraterone or derivative thereof is present in an amount of 40 to 95 wt%, preferably 60 to 85 wt%, based on the total dry weight of the active ingredient and the surface stabilizer.
8. The pharmaceutical composition according to any one of items 1 to 7, wherein the derivative is 17- (3-pyridyl) androsta-5, 16-diene-3 β -acetate.
9. The pharmaceutical composition according to any one of items 1 to 8, wherein the abiraterone or derivative thereof has a particle size D90 value of less than 1000nm, preferably 400 to 600 nm.
10. The pharmaceutical composition according to any one of claims 1 to 9, wherein microcrystalline cellulose is absent.
11. A pharmaceutical composition comprises abiraterone or a derivative thereof, an absorption enhancer, and no microcrystalline cellulose.
12. The pharmaceutical composition of item 11, wherein the absorption enhancer is selected from one or more of capric acid, sodium or potassium caprate, N- (10- [ 2-hydroxybenzoyl ] amino) capric acid, caprylic acid, sodium or potassium caprylate, N- (8- (2-hydroxybenzoyl) amino) caprylic acid, N- (5-chlorosalicyloyl) -8-aminocaprylic acid, sodium 8- (salicylamido) caprylate, preferably one or more of sodium 8- (salicylamido) caprylate or N- (8- (2-hydroxybenzoyl) amino) caprylate.
13. The pharmaceutical composition of clause 11 or 12, wherein the weight ratio of the absorption enhancer to abiraterone or derivative thereof is not less than 1:100, preferably 1:10 to 20:1, more preferably 1:10 to 10: 1.
14. The pharmaceutical composition according to any one of items 11 to 13, further comprising at least one disintegrant selected from the group consisting of croscarmellose sodium, crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, starch, pregelatinized starch, and alginic acid, preferably in an amount of 0.5 to 20% by weight based on the total weight of the pharmaceutical composition.
15. The pharmaceutical composition according to any one of claims 11 to 14, further comprising at least one stabilizer selected from a cellulose derivative, preferably hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose or sodium carboxymethylcellulose, or a surfactant; the surfactant is preferably polyoxyethylene ether, poloxamer, polyglycolyzed glyceride, polyethoxylated hydrogenated castor oil, sodium lauryl sulfate or sodium cholate.
16. The pharmaceutical composition of item 15, wherein the stabilizer is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium lauryl sulfate, or poloxamer, preferably hydroxypropyl methylcellulose and sodium lauryl sulfate.
17. The pharmaceutical composition according to clause 15 or 16, wherein the abiraterone or derivative thereof is present in an amount of 40 to 95 wt.%, preferably 50 to 75 wt.%, based on the total dry weight of the active ingredient and the surface stabilizer.
18. The pharmaceutical composition of any one of claims 11-17, wherein the derivative is 17- (3-pyridyl) androsta-5, 16-diene-3 β -acetate.
19. The pharmaceutical composition according to any one of claims 11 to 18, wherein the abiraterone or derivative thereof has a particle size D90 value of less than 1000nm, preferably 400-600 nm.
20. The pharmaceutical composition according to any one of claims 11 to 19, further comprising a filler selected from at least one of dextrin, lactose, sucrose, calcium hydrogen phosphate, calcium sulfate, starch, anhydrous calcium hydrogen phosphate, and mannitol, preferably in an amount of 15 to 80%, more preferably 25 to 75%, based on the total weight of the pharmaceutical composition.
21. The pharmaceutical composition according to any one of items 1 to 20, which comprises abiraterone or a derivative thereof, an absorption enhancer, lactose and crospovidone, and does not contain microcrystalline cellulose.
22. The pharmaceutical composition of any one of claims 1-21, wherein the unit dosage form of abiraterone or derivative thereof at a dose of 200-450mg and the unit dosage form of zecade at a dose of 1000mg
Bioequivalence in healthy male subjects in the fasted state.
23. A method of making the pharmaceutical composition of any one of items 1-22, comprising: mixing the nano suspension containing the abiraterone or the derivative thereof with an absorption enhancer and at least one optional excipient, and then granulating by a fluidized bed.
24. The method of clause 23, further comprising the steps of preparing a nanosuspension of abiraterone or a derivative thereof:
(a) preparing a suspension of abiraterone or a derivative thereof in a liquid solvent selected from water, polyethylene glycol, glycerol, propylene glycol or any combination thereof, preferably water;
(b) adding grinding balls to the suspension of step (a) to obtain a slurry for grinding,
(c) grinding to obtain the nano suspension with the particle size D90 value less than 1000 nm.
25. The method of item 24, wherein step (a) further comprises at least one stabilizer selected from a cellulose derivative, preferably hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, or sodium carboxymethyl cellulose, or a surfactant; the surfactant is preferably polyoxyethylene ether, poloxamer, polyglycolyzed glyceride, polyethoxylated hydrogenated castor oil, sodium lauryl sulfate or sodium cholate.
26. A method of making a pharmaceutical composition comprising: mixing the nanometer suspension containing the abiraterone or the derivative thereof with an absorption enhancer and at least one optional excipient, and then granulating by a fluidized bed, wherein the particle size D90 value of the abiraterone or the derivative thereof is less than 1000nm, preferably 400-600 nm.
27. The method of item 26, wherein the weight ratio of the absorption enhancer to abiraterone or derivative thereof is not less than 1:100, preferably 1:10 to 20:1, more preferably 1:10 to 10: 1.
28. The method of item 26 or 27, wherein the absorption enhancer is selected from one or more of capric acid, sodium or potassium caprate, N- (10- [ 2-hydroxybenzoyl ] amino) capric acid, caprylic acid, sodium or potassium caprylate, N- (8- (2-hydroxybenzoyl) amino) caprylic acid, N- (5-chlorosalicyloyl) -8-aminocaprylic acid, sodium 8- (salicylamido) caprylate, preferably one or more of sodium 8- (salicylamido) caprylate or N- (8- (2-hydroxybenzoyl) amino) caprylic acid.
29. The method of any one of items 26 to 28, further comprising the steps of preparing a nanosuspension of abiraterone or a derivative thereof:
(a) preparing a suspension of abiraterone or a derivative thereof in a liquid solvent selected from water, polyethylene glycol, glycerol, propylene glycol or any combination thereof, preferably water;
(b) adding grinding balls to the suspension of step (a) to obtain a slurry for grinding,
(c) grinding to obtain the nano suspension with the particle size D90 value less than 1000 nm.
30. The method of item 29, wherein step (a) further comprises at least one stabilizer selected from a cellulose derivative, preferably hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, or sodium carboxymethyl cellulose, or a surfactant; the surfactant is preferably polyoxyethylene ether, poloxamer, polyglycolyzed glyceride, polyethoxylated hydrogenated castor oil, sodium lauryl sulfate or sodium cholate.
31. The method of item 30, wherein the stabilizer is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium lauryl sulfate, or poloxamer, preferably from hydroxypropyl methylcellulose and sodium lauryl sulfate.
32. The method of clause 30 or 31, wherein the abiraterone or derivative thereof is present in an amount of 40 to 95 wt%, preferably 50 to 75 wt%, based on the total dry weight of active ingredient and surface stabilizer.
33. The method of any one of items 26-32, wherein the derivative is 17- (3-pyridyl) androsta-5, 16-diene-3 β -acetate.
34. The method of any one of claims 26-33, wherein the excipient is selected from one or more of a disintegrant, a filler, a binder, or a lubricant.
35. The method of item 34, wherein the disintegrant is selected from at least one of croscarmellose sodium, crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, starch, pregelatinized starch, alginic acid, preferably in an amount of 0.5 to 20% by weight of the total pharmaceutical composition; the filler is selected from at least one of dextrin, lactose, sucrose, calcium hydrogen phosphate, starch, anhydrous calcium hydrogen phosphate, calcium sulfate and mannitol, and is preferably used in an amount of 15 to 80 percent, more preferably 25 to 75 percent, based on the total weight of the pharmaceutical composition; the adhesive is selected from at least one of polyvinylpyrrolidone, starch, methylcellulose, carboxyl cellulose, hydroxypropyl methylcellulose and alginate, and preferably the amount of the adhesive is 0.5 to 10 percent of the total weight of the pharmaceutical composition; the lubricant is selected from at least one of magnesium stearate, stearic acid, palmitic acid, calcium stearate, talcum powder, colloidal silicon dioxide, carnauba wax and sodium stearyl fumarate, and preferably the lubricant is used in an amount of 0.1 to 5% by weight based on the total weight of the pharmaceutical composition.
36. The method of any one of claims 26-35, wherein the method further comprises the step of granulating, tableting, or encapsulating.
37. A pharmaceutical composition comprising abiraterone or a derivative thereof having a particle size D90 value of less than 1000nm, and an absorption enhancer prepared by the process of item 36.
38. The pharmaceutical composition of item 37, wherein the unit dosage form of abiraterone or derivative thereof at a dose of 200-450mg and the dosage form of zecade at a dose of 1000mg
Bioequivalence in healthy male subjects in the fasted state.
39. Use of a pharmaceutical composition according to any one of claims 1 to 22 or 27 or 38 in the manufacture of a medicament for improving individual variability in the patient taking the medicament.
40. Use of a pharmaceutical composition according to any one of claims 1-22 or 27 or 38 in the manufacture of a medicament for the treatment of prostate cancer.
41. A method of improving individual variability in a patient taking a drug comprising administering to a patient in need thereof a pharmaceutical composition according to any one of claims 1 to 12 or 17 or 38.
Detailed description of the preferred embodiments
The present disclosure is further illustrated in detail by the following examples and experimental examples. These experimental examples are for illustrative purposes only and are not intended to limit the scope of the present disclosure.
Example 1
1) Nanosuspension preparation
19.2g of HPMC E5 LV was added to 739.6g of water and dispersed, dissolved, and 1.92g of SDS was added to dissolve, after which 75g of Compound A was added to the above solution and dispersed with stirring.
A sand mill (grinding chamber volume 160ml, filled with 112ml of 0.3mm grinding beads, feed rate 160rpm, grinding speed 3000rpm) was set up), the dispersed suspension was added to the mill formulation tank, stirring was turned on, and grinding was carried out to give compound A nanosuspension D90 of about 500nm for use.
2) Fluid bed granulation
The nanosuspension 1170.2g g was taken, 105g of the absorption enhancer SNAC was added to the nanosuspension, and the mixture was stirred and dispersed. 168g of lactose, 33.6g of crospovidone XL were added to the fluidized bed and subjected to fluidized bed top spray granulation. And after the granulation is finished, drying the granules, and stopping drying when the water content of the granules is less than 2%.
3) Tabletting
Preparation: mixing the granules obtained by fluidized bed preparation with magnesium stearate, and tabletting to obtain large tablets with specification of 150 mg.
In vitro dissolution test
According to the second method (paddle method) of dissolution determination of the Chinese pharmacopoeia 2015 edition, the dissolution test is carried out according to a reference preparation (250mg) and a reference preparation 1/2 tablet (containing abiraterone acetate 125mg), 900ml of SDS solution with pH of 6.8 and 0.25 percent is adopted as a dissolution medium, and the specific dissolution data are shown in the following table 1
TABLE 1
| Time (min) | Reference preparation whole piece (%) | Reference preparation 1/2 tablets (%) | Prescription 1 (%) |
| 5 | 4.6 | 7 | 11 |
| 10 | 10.1 | 17 | 24 |
| 15 | 17.7 | 30 | 37 |
| 20 | 24.3 | 41 | 48 |
| 25 | 30.1 | 50 | 58 |
| 30 | / | 56 | 68 |
| 45 | 44.8 | 68 | 90 |
| 60 | 51.1 | 74 | 98 |
Note: reference formulation R (commercially available, trade name zeke) 250mg tablets.
Example 2
The formulation described in Table 2 was prepared according to the preparation method of example 1.
TABLE 2
In vitro dissolution test
According to the second method (paddle method) of dissolution determination of the Chinese pharmacopoeia 2015 edition, the dissolution test is carried out according to a reference preparation (250mg) and a reference preparation 1/2 tablet (containing abiraterone acetate 125mg), 900ml of SDS solution with pH of 6.8 and 0.25 percent is adopted as a dissolution medium, and the specific dissolution data are shown in the following table 3
TABLE 3
Note: API is active ingredient abiraterone acetate, and SNAC is 8- (2-hydroxybenzamido) sodium caprylate.
As a result: formula 2 is more easily dissolved than formula 3 in the composition containing lactose, and the dissolution of the composition containing microcrystalline cellulose is correspondingly slower; meanwhile, compared with the prescription 2, the prescription 4 has the advantages that the dosage of the lactose is unchanged, the dosage of the microcrystalline cellulose is increased, the dissolution of the microcrystalline cellulose and the microcrystalline cellulose is not obviously different when the tablet weight is correspondingly increased, and the result shows that the dissolution is not improved by adding the microcrystalline cellulose.
Prescription 1 pharmacokinetic study
8 male cynomolgus monkeys, administered by single oral gavage, contained 4 cycles of 5 days per cycle for 20 days (see table 3 for the protocol).
Table 3: pharmacokinetic protocol
T means test formulation 1, R means reference formulation (commercially available, zecade), and T-24 h.
Animals were fasted prior to dosing in cycle I, II, and high fat chow was administered prior to dosing in cycles III and IV. Animals in cycle I, III were dosed with 300mg of test formulation 1 (abiraterone acetate tablet 2, T, containing abiraterone 300mg), while animals in cycle II and IV were dosed with 1000mg of reference formulation (abiraterone acetate tablet)
Sheet, R). Blood samples were collected from each animal at pre-dose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12 and 24 hours post-dose per week. Concentrations of abiraterone and SNAC in plasma samples were determined using a validated LC-MS/MS analysis method. Abiraterone was only detected for the reference formulation, while abiraterone and SNAC were detected for the test formulation. By means of the concentration data of abiraterone and SNAC in the plasma, Phoenix was used
7.0 software calculates its main pharmacokinetic parameters. The major pharmacokinetic data for abiraterone in plasma from cycle I to IV are shown in table 4, and the major pharmacokinetic data for SNAC in plasma from cycle I and III are shown in table 5.
Table 4 abiraterone major pharmacokinetic parameters in plasma after dosing in cycles I to IV (Mean ± SD, n ═ 8)
Fasting administration (cycles I and II), 300mg C of test formulation 1max638.72 +/-446.43 ng/ml and AUC(0-t)2878.79 + -1887.91 h ng/ml, TmaxIs 2.63h and T1/2At 5.16h, 1.29, 2.29, 0.50 and 0.74 times the reference formulation of 1000mg, respectively. Administration of a high fat diet (cycles III and IV), 300mg C of test formulation 1max1318.03 + -1222.55 ng/ml and AUC(0-t)6693.37 + -4588.85 h ng/ml, which are 0.60 times and 0.37 times the 1000mg reference formulation, respectively. Control formulation fasting versus high fat diet administration (cycles II and IV) comparison of Abiraterone C in plasma of Male cynomolgus monkeys on high fat dietmaxAnd exposure (AUC)(0-t)) Is 7.86 times and 8.00 times of the food under fasting condition respectively, and has remarkable food effect. In contrast to test formulation 1 administered with fasting and high-fat diets (cycles I and III), abiraterone C in cynomolgus plasma under high-fat dietmaxAnd exposure (AUC)(0-t)) 2.07 and 2.33 times respectively under fasting conditions, with some food effect, but lower than the reference formulation.
Table 5 SNAC major pharmacokinetic parameters in plasma after cycle I and III dosing (Mean ± SD, n ═ 8)
Fast peak time of SNAC in plasma of cynomolgus monkey under fasting condition, Tmax0.72 + -0.49 h, maximum plasma drug concentration (C)max) 34165.76 + -18040.59 ng/ml, plasma drug exposure (AUC)(0-24h)) 40349.03 + -10430.88 h ng/ml; while high fat diet condition Tmax2.88 +/-0.74 h, Cmax4656.97 + -2395.17 ng/ml, AUC0-24h18374.08 + -5740.25 h ng/ml. SNAC in cynomolgus monkey T after high fat dietmaxElongation, CmaxAnd AUC0-24hReduction and examinationSNAC is considered an acidic drug (pKa 5.0) and may be associated with an increase in the pH in the gastrointestinal tract under high-fat dietary conditions.
And (4) conclusion: unit dose exposure (AUC) of subject formulation 1 plasma abiraterone in male cynomolgus monkeys dosed with fasting at cycle I, II(0-t)Dose) is 4.29 times of that of the reference preparation, and the bioavailability of abiraterone is obviously improved. Exposure of high fat diet to 300mg of abiraterone test formulation (AUC)(0-t)) And CmaxLess than 1000mg of the reference formulation.
Claims (19)
1. A pharmaceutical composition comprising abiraterone or a derivative thereof, an absorption enhancer and lactose, preferably the lactose is present in an amount of from 15 to 80%, more preferably from 25 to 75%, for example 36%, 36.5%, 37%, 37.5% or 38% by weight of the total pharmaceutical composition.
2. The pharmaceutical composition of claim 1, wherein the absorption enhancer is selected from one or more of capric acid, sodium or potassium caprate, N- (10- [ 2-hydroxybenzoyl ] amino) capric acid, caprylic acid, sodium or potassium caprylate, N- (8- (2-hydroxybenzoyl) amino) caprylic acid, N- (5-chlorosalicyloyl) -8-aminocaprylic acid, sodium 8- (salicyloylamino) caprylate, preferably one or more of sodium 8- (salicyloylamino) caprylate or N- (8- (2-hydroxybenzoyl) amino) caprylate.
3. The pharmaceutical composition according to claim 1 or 2, wherein the weight ratio of the absorption enhancer to abiraterone or derivative thereof is not less than 1:100, preferably 1:10 to 20:1, more preferably 1:10 to 10:1, such as 1:2, 1:1 or 2: 1.
4. The pharmaceutical composition according to any one of claims 1 to 3, further comprising at least one disintegrant selected from the group consisting of croscarmellose sodium, crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, starch, pregelatinized starch, alginic acid, preferably in an amount of 0.5 to 20%, such as 7%, 7.5%, 8% or 8.5% by weight of the total pharmaceutical composition.
5. The pharmaceutical composition according to any one of claims 1 to 4, further comprising at least one stabilizer selected from cellulose derivatives, preferably hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose or sodium carboxymethylcellulose; the surfactant is preferably polyoxyethylene ether, poloxamer, polyglycolyzed glyceride, polyoxyethylated castor oil or polyethoxylated hydrogenated castor oil, sodium dodecyl sulfate or sodium cholate.
6. The pharmaceutical composition according to claim 5, wherein the stabilizer is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium lauryl sulfate or poloxamer, preferably hydroxypropyl methylcellulose and sodium lauryl sulfate.
7. A pharmaceutical composition according to claim 5 or 6, wherein the abiraterone or derivative thereof is present in an amount of 40 to 95 wt%, preferably 60 to 85 wt%, such as 79%, 79.5%, 80%, 80.5% or 81% based on the total dry weight of the active ingredient and surface stabilizer.
8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the derivative is 17- (3-pyridyl) androsta-5, 16-diene-3 β -acetate.
9. A pharmaceutical composition according to any one of claims 1 to 8, wherein the abiraterone or derivative thereof has a particle size D90 value of less than 1000nm, preferably 400 to 600nm, for example 500 nm.
10. The pharmaceutical composition of any one of claims 1-9, wherein microcrystalline cellulose is absent.
11. The pharmaceutical composition according to any one of claims 1 to 10, comprising:
a)10 to 40% of abiraterone or a derivative thereof,
b)10 to 40% of an absorption enhancer, preferably sodium 8- (salicyloylamino) caprylate or N- (8- (2-hydroxybenzoyl) amino) caprylic acid,
c)0.5 to 20% of a stabilizer, preferably at least one of hydroxypropyl methylcellulose or sodium lauryl sulfate,
d) from 25 to 75% of the lactose present,
e)0.5 to 20% of a disintegrant,
further, the pharmaceutical composition preferably further comprises 0.1 to 2.0% of a lubricant.
12. The pharmaceutical composition of any of claims 1-11, wherein the unit dosage form of abiraterone or derivative thereof at a dose of 200-450mg is combined with the unit dosage form of zecade at a dose of 1000mg
Bioequivalence in healthy male subjects in the fasted state.
13. A process for preparing a pharmaceutical composition according to any one of claims 1 to 12, comprising: mixing the nano suspension containing the abiraterone or the derivative thereof with an absorption enhancer and at least one optional excipient, and then granulating by a fluidized bed.
14. The method of claim 13, further comprising the steps of preparing a nanosuspension of abiraterone or a derivative thereof:
(a) preparing a suspension of abiraterone or a derivative thereof in a liquid solvent selected from water, polyethylene glycol, glycerol, propylene glycol or any combination thereof, preferably water,
(b) adding grinding balls to the suspension of step (a) to obtain a slurry for grinding,
(c) grinding to obtain the nano suspension with the particle size D90 value less than 1000 nm.
15. The process of claim 14, wherein step (a) further comprises at least one stabilizer selected from a cellulose derivative, preferably hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose or sodium carboxymethyl cellulose, or a surfactant; the surfactant is preferably polyoxyethylene ether, poloxamer, polyglycolyzed glyceride, polyethoxylated hydrogenated castor oil, sodium lauryl sulfate or sodium cholate.
16. A method of making a pharmaceutical composition comprising: and (2) mixing the nano suspension containing the abiraterone or the derivative thereof with an absorption enhancer and optionally at least one excipient, and then granulating by a fluidized bed, wherein the particle size D90 value of the abiraterone or the derivative thereof is less than 1000nm, preferably 400-600 nm, for example 500 nm.
17. A pharmaceutical composition comprising abiraterone or a derivative thereof having a particle size D90 value of less than 1000nm, and an absorption enhancer prepared by the process of claim 16.
18. Use of a pharmaceutical composition according to any one of claims 1 to 12 or 17 in the manufacture of a medicament for improving individual variability in the patient taking the medicament.
19. Use of a pharmaceutical composition according to any one of claims 1 to 12 or 17 in the manufacture of a medicament for the treatment of prostate cancer.
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| CN112933053A (en) * | 2021-01-29 | 2021-06-11 | 中国药科大学 | Abiraterone acetate nanocrystal and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103446069A (en) * | 2012-05-29 | 2013-12-18 | 重庆医药工业研究院有限责任公司 | Oral solid composition of abiraterone and preparation method thereof |
| WO2014009436A1 (en) * | 2012-07-11 | 2014-01-16 | Sandoz Ag | Nanosuspension of abiraterone acetate |
| CN108883073A (en) * | 2016-12-30 | 2018-11-23 | 江苏恒瑞医药股份有限公司 | A kind of pharmaceutical composition and preparation method thereof of GLP-1 analog |
| CN110636837A (en) * | 2017-08-28 | 2019-12-31 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition of CYP17 inhibitor and preparation method thereof |
-
2020
- 2020-02-27 CN CN202010122422.1A patent/CN111617257A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103446069A (en) * | 2012-05-29 | 2013-12-18 | 重庆医药工业研究院有限责任公司 | Oral solid composition of abiraterone and preparation method thereof |
| WO2014009436A1 (en) * | 2012-07-11 | 2014-01-16 | Sandoz Ag | Nanosuspension of abiraterone acetate |
| CN108883073A (en) * | 2016-12-30 | 2018-11-23 | 江苏恒瑞医药股份有限公司 | A kind of pharmaceutical composition and preparation method thereof of GLP-1 analog |
| CN110636837A (en) * | 2017-08-28 | 2019-12-31 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition of CYP17 inhibitor and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 孙少平: "《高分子材料在纳米给药***中的应用》", 31 August 2017, 黑龙江大学出版社, pages: 91 - 92 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112933053A (en) * | 2021-01-29 | 2021-06-11 | 中国药科大学 | Abiraterone acetate nanocrystal and preparation method thereof |
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