WO2014063596A1 - Formulation orale pour le traitement du diabète - Google Patents

Formulation orale pour le traitement du diabète Download PDF

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Publication number
WO2014063596A1
WO2014063596A1 PCT/CN2013/085588 CN2013085588W WO2014063596A1 WO 2014063596 A1 WO2014063596 A1 WO 2014063596A1 CN 2013085588 W CN2013085588 W CN 2013085588W WO 2014063596 A1 WO2014063596 A1 WO 2014063596A1
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WIPO (PCT)
Prior art keywords
enteric
core
preparation
magnesium
active ingredient
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PCT/CN2013/085588
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English (en)
Chinese (zh)
Inventor
金方
范颖
俞雄
彭程
Original Assignee
中国医药工业研究总院
上海医药工业研究院
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Publication of WO2014063596A1 publication Critical patent/WO2014063596A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • 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
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to an oral preparation of 17 ⁇ -ethynylandrost-5-ene-3 ⁇ ,7 ⁇ ,17 ⁇ -triol ( ⁇ 3286), and a process for the preparation and use of the preparation.
  • Background technique 17 ⁇ -ethynylandrost-5-ene-3 ⁇ ,7 ⁇ ,17 ⁇ -triol
  • a solid form of 17 ⁇ -ethynylandrost-5-ene-3 ⁇ ,7 ⁇ ,17 ⁇ -triol, including amorphous and crystalline forms and specific polymorphs thereof, is provided and described in Chinese Patent Application No. 200980112162.1, Anhydrate, solvate.
  • the invention further relates to the preparation of solid and suspension formulations comprising 17 a-ethynylandrost-5-ene-3 ⁇ , 7 ⁇ , 17 ⁇ -triol in the solid form.
  • the invention indicates that the formulation comprises a composition of a drug and one or more pharmaceutically acceptable carriers, examples of which include micronized mash 3286, sodium lauryl sulfate, microcrystalline cellulose, crosslinked ketone, and stearin.
  • the above patent does not mention the bioavailability of the ⁇ 3286 solid preparation after oral administration, nor does the embodiment provide data support.
  • the amount of surfactant sodium lauryl sulfate in the hard capsule formulation is large (20% of the total prescription), while sodium lauryl sulfate is a moderately toxic substance that stimulates the stomach, mucous membranes, eyes, upper respiratory tract, and skin. Acute toxicity.
  • the results of intravenous injection test showed that sodium lauryl sulfate had obvious toxicity to lung, kidney and liver. Therefore, the above hard capsule prescription may have a toxic reaction to the human body during the production process, and the pharmaceutical preparation may cause irritation to the gastrointestinal tract after oral administration, resulting in various degrees of toxic side effects.
  • a method for the treatment of hyperglycemia or diabetes comprising administration of 17 ⁇ -ethynylandrost-5-ene-3 ⁇ ,7 ⁇ ,17 ⁇ -triol and metformin or glibenclamide is provided in PCT patent application WO/2010/036822.
  • One of the ureas An oral pharmaceutical formulation consisting of a-ethynylandrost-5-ene-3 ⁇ ,7 ⁇ ,17 ⁇ -triol and one or more pharmaceutically acceptable excipients is described in the description of the invention, which may be administered after administration 2
  • the patient's plasma drug concentration is maintained at 0.5 ng/mL to 200 ng/mL for ⁇ 4 hours.
  • the prescription consists of two or more excipients.
  • the lubricant includes sodium lauryl sulfate or magnesium stearate.
  • Other pharmaceutically acceptable excipients include Microcrystalline cellulose or crospovidone, and 17(1-ethynylandrost-5-ene-33,7,17-triol. This formulation rapidly releases the drug after oral administration. II is listed in the examples.
  • an object of the present invention to provide a ⁇ 3286 oral preparation which is stable, effective, safe, and has few side effects.
  • an oral preparation comprising a pharmaceutically acceptable carrier and 17 ⁇ -ethynylandro-5-ene-3 ⁇ , 7 ⁇ , 17 as an active ingredient Beta-triol
  • the oral preparation has the property that the preparation does not release or is substantially not released in an acidic medium.
  • the acidic medium is 0.1 M aqueous hydrochloric acid.
  • the relative bioavailability of the formulation can be increased by more than 50% (the reference formulation is an immediate release capsule), and the preferred relative bioavailability is increased by more than 60%.
  • the release or non-release in the acidic medium means: the preparation is placed (or dissolved) in an acidic medium for 2 hours, and the release amount of the active ingredient ⁇ 3286 is not more than 10% of the labeled amount, preferably Not more than 5% of the indicated amount.
  • the formulation is an enteric formulation.
  • the dosage form of the formulation comprises: a tablet, a capsule, or a pellet.
  • the formulation is selected from the group consisting of:
  • enteric tablet comprising a core, a barrier layer, an enteric coating, wherein the core comprises 17 ⁇ -ethynylandrost-5-ene-3 ⁇ , 7 ⁇ , 17 ⁇ -triol;
  • enteric capsules the capsules comprising enteric capsules and drug particles in enteric capsules Or a powder, wherein the pharmaceutical granule or powder comprises 17 ⁇ -ethynyl androst-5-ene-3 ⁇ , 7 ⁇ , 17 ⁇ -triol;
  • enteric pellets comprising enteric pellets or enteric pellets filled in a capsule, wherein the enteric pellets comprise a pellet core, a pellet isolation layer, and an pellet enteric solution.
  • the formulation has one or more characteristics selected from the group consisting of:
  • the pharmaceutically acceptable carrier described in a) or b) or c) includes a solubilizing agent, an inert substance providing a local alkaline environment, a filler, a disintegrant, a binder, a lubricant;
  • the barrier layer described in a) or c) includes hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, ethylcellulose, poly Vinyl alcohol, polyvinyl acetate, polyethylene glycol, mannitol or a combination thereof, preferably hydroxypropylmethylcellulose and/or polyvinylpyrrolidone;
  • the enteric coating described in a) or c) includes methacrylic acid-methyl methacrylate copolymer, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, adjacent Benzyl hydroxypropyl methylcellulose, cellulose acetate titanate, carboxymethyl vinyl cellulose, cellulose acetate triacetate, phthalic acid poly(vinyl phthalate), hydroxypropyl propyl succinate Base cellulose, cellulose acetate phthalate, shellac or a combination thereof, preferably using methacrylic acid-methyl methacrylate copolymer, phthalyl hydroxypropyl methylcellulose, hydroxypropyl acetate Methylcellulose succinate.
  • the formulation has one or more characteristics selected from the group consisting of:
  • the weight gain of the barrier layer is 1-30% of the weight of the core or core, preferably 2-15%;
  • the weight gain of the enteric layer coating is from 1 to 30%, preferably from 4 to 15% by weight of the core or core.
  • the inert substance providing a local alkaline environment includes calcium oxide, calcium hydroxide, magnesium hydroxide, basic inorganic magnesium salt (such as magnesium carbonate, heavy magnesium carbonate), tryptophan, Histidine, lysine, arginine, sodium tryptophan, sodium histidine, sodium lysinate, sodium arginate, potassium tryptophan, potassium histidine, potassium lysine, arginine Potassium, magnesium tryptophan, magnesium histidine, magnesium lysine, magnesium arginate or a combination thereof, preferably using magnesium hydroxide, magnesium carbonate, histidine; and/or
  • the inert substance is used in an amount of from 0 to 50% by weight, preferably from 0% to 40%, based on the total weight of the active ingredient in the composition.
  • the formulation further has one or more properties selected from the group consisting of:
  • the active ingredient according to (vii) includes pharmaceutically acceptable crystalline form of 17 ⁇ -ethynyl andrhen-5-ene-3 ⁇ , 7 ⁇ , 17 ⁇ -triol, amorphous form, anhydrate, solvate, hydrated And enantiomers;
  • the methacrylic acid-methyl methacrylate copolymer includes Eudragit L series, Eudragit S series, Eudragit series, Eudragit RS series, Eudragit FS series,
  • EudragitNE series enteric type II, enteric type III, Opadry, or a combination thereof;
  • the solubilizing agent of (ix) includes: sodium lauryl sulfate, poloxamer, polysorbate, polyoxyethylene alkyl ether, cyclodextrin, polyethylene glycol, polyoxyethylene hydrogenated castor oil, or a combination thereof ;
  • the filler according to (X) includes microcrystalline cellulose, lactose, sucrose, starch, pregelatinized starch, mannitol, powdered sugar, dextrin, or a combination thereof; and/or the filler is used as an active ingredient. 10 to 5000% by weight, preferably 50 to 3000%, preferably using microcrystalline cellulose, lactose, sucrose, starch, or a combination thereof;
  • the disintegrant comprises crospovidone, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, dry starch, or a combination thereof; and/or The disintegrant is used in an amount of 0.5 to 50%, preferably 1 to 40%, based on the total weight of the core or core;
  • the lubricant includes magnesium stearate, calcium stearate, zinc stearate, stearic acid, glyceryl monostearate, silica gel, talc, hydrated sodium aluminosilicate, polyethylene.
  • the active ingredient is micronized 17 ⁇ -ethynylandrost-5-ene-3 ⁇ ,7 ⁇ ,17 ⁇ -triol with an average particle size (D50) of 0.1 ⁇ ! ⁇ 10 ⁇ m, preferably 0 ⁇ 5 ⁇ m ⁇ 5 ⁇ m.
  • the solubilizer is used in an amount of from 0 to 1000% by weight based on the weight of the active ingredient, preferably from 5 to 30% by weight of the active ingredient;
  • the enteric coating described in a) or c) further comprises a plasticizer, wherein said plasticizing
  • the agent includes triethyl citrate, polyethylene glycol, diethyl phthalate, dibutyl sebacate, triglycerin acetate, castor oil, preferably triethyl citrate, polyethylene glycol More preferably, it is triethyl citrate.
  • the HE3286 granule or powder is filled in an enteric capsule to form an enteric capsule, wherein the granule or powder comprises HE3286 and a pharmaceutically acceptable carrier;
  • enteric pellets are filled into capsules to form enteric pellets, wherein the enteric pellets include a pellet core, a pellet isolation layer, and a pellet enteric coating, wherein the pellet core comprises HE3286 and pharmacy. Acceptable carrier.
  • the core or core may be prepared by wet granulation, dry granulation, or mixed powder compaction.
  • the core or core has a hardness of 4 to 15 kg and a disintegration time of 1 to 15 minutes.
  • the drug core further comprises the step of preparing an oral preparation precursor, wherein the precursor is a mixture of the active ingredient and a pharmaceutically acceptable carrier, and wrapping the barrier layer;
  • the pharmaceutically acceptable carrier includes a solubilizing agent, an inert substance providing a local alkaline environment, a filler, a disintegrant, a binder, a lubricant; and/or
  • the separator comprises hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, ethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, Polyethylene glycol, mannitol or a combination thereof; wherein the weight of the separator is 1-30% of the core or core, preferably 2-15%.
  • the pellet core is formed by mixing 17 ⁇ -ethynylandrost-5-ene-3 ⁇ , 7 ⁇ , 17 ⁇ -triol and a pharmaceutically acceptable carrier, and the average particle size is 100 ⁇ 2000 ⁇ ⁇ .
  • a third aspect of the invention there is provided the use of the oral preparation of the first aspect of the invention for the preparation of a medicament for the prevention and treatment of diabetes, rheumatoid arthritis, ulcerative colitis .
  • the various technical features of the present invention and the technical features specifically described hereinafter may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.
  • Figure 1 shows the release profile of an oral formulation in one embodiment of the invention.
  • Figure 2 shows the release profile of an oral formulation in one embodiment of the invention.
  • Figure 3 shows the release profile of an oral formulation in one embodiment of the invention. detailed description
  • the inventors have extensively and intensively studied and unexpectedly found that ⁇ 3286 is easily decomposed in an acidic environment or in the presence of an acid, resulting in extremely low bioavailability of an oral preparation.
  • the present inventors have for the first time developed an oral preparation which does not substantially release the active ingredient in an acidic medium such as gastric juice and mainly releases the active ingredient in the intestinal tract, thereby remarkably improving the relative bioavailability of the active ingredient (in terms of immediate release capsules as a reference, relative Bioavailability is increased by at least 50%).
  • the inventors have further improved the formulation to provide a safe, bioavailable ingredient by reducing or eliminating the large toxic side effects of existing formulations (such as certain surfactants) and by adding inert materials.
  • High ⁇ 3286 oral preparation On the basis of this, the present invention has been completed.
  • the terms "active ingredient of the invention”, “ ⁇ 3286” or “active ingredient” are used interchangeably and refer to the compound ⁇ 3286 having the chemical name 17 ⁇ -ethynylandrost-5-ene-3 ⁇ , 7 ⁇ , 17 ⁇ -triol.
  • the active ingredient of the present invention may be various crystalline forms, amorphous forms, anhydrates, solvates, hydrates, and enantiomers of pharmaceutically acceptable oxime 3286.
  • ⁇ 3286 refers to the active ingredient of the present invention.
  • ⁇ 3286 is a novel treatment for autoimmune-related compounds, in type II diabetes, It has broad application prospects in the treatment of diseases such as rheumatoid arthritis and ulcerative colitis.
  • the HE3286 which can be used in the present invention may be in various forms such as powder, granules or crystals. Especially the micronized HE3286.
  • the average particle size (D50) is 0. ⁇ ⁇ ⁇ ! ⁇ 10 ⁇ ⁇ , preferably using an average particle diameter (D50) 0. 5 ⁇ ⁇ 5 ⁇ ⁇ .
  • representative micronization treatment methods include, but are not limited to, jet milling, supercritical fluid pulverization, mechanical pulverization, and the like.
  • the general requirements are stable, no compatibility with the main drug, no side effects, no effect, no deformation, cracking, mildew, insects, no human body at normal temperature Harmful, no physiological effects, no physical and chemical effects with the main drug, does not affect the determination of the content of the main drug.
  • the carrier which can be used in the present invention is not particularly limited and may be any pharmaceutically acceptable carrier, including a solubilizing agent, an inert substance providing a local alkaline environment, a filler, a disintegrating agent, a binder, and a lubricant.
  • the solubilizing agent usable in the present invention is not particularly limited and may be any compound which increases the solubility of ⁇ 3286, including sodium lauryl sulfate, poloxamer, polysorbate, polyoxyethylene alkyl ether, cyclodextrin, polyethylene. Alcohol, polyoxyethylene hydrogenated castor oil or a combination thereof.
  • the amount of solubilizer used is from 0 to 1000% by weight based on the weight of ⁇ 3286 in the composition.
  • the oral formulation contains no solubilizer or solubilizer content, such as less than 8%, preferably less than 2%, by total weight of the formulation.
  • the inert substance which can be used in the present invention to provide a local alkaline environment is not particularly limited, and may be any inert substance which provides a local alkaline environment to ensure that ⁇ 3286 does not decompose, and preferably calcium oxide, calcium hydroxide, magnesium oxide, magnesium hydroxide. , basic inorganic magnesium salts (such as magnesium carbonate, heavy magnesium carbonate), tryptophan, histidine, lysine, arginine, sodium tryptophan, sodium histidine, sodium lysine, refined ammonia Sodium, potassium tryptophan, potassium histidine, potassium lysine, potassium arginine, magnesium tryptophan, magnesium histidine, magnesium lysine, magnesium arginate or a combination thereof.
  • the inert substance is used in an amount of from 0 to 40%, preferably from 0% to 30% by weight based on the weight of ⁇ 3286 in the composition.
  • the filler which can be used in the present invention is not particularly limited, and may be any compound which functions to fill, dilute or increase the drug dispersion effect in the HE3286 preparation, including microcrystalline cellulose, lactose, starch, pregelatinized starch, mannitol, sugar. Powder, dextrin or a combination thereof.
  • the filler is used in an amount of 10 to 5000% by weight, preferably 50 to 3000% by weight based on the weight of the HE3286 in the composition.
  • the disintegrant which can be used in the present invention is not limited in any way, and may be any compound which rapidly swells and disintegrates HE3286 into intestinal granules, preferably crospovidone, croscarmellose sodium, carboxy Sodium methyl starch, low substituted hydroxypropyl cellulose, dry starch or a combination thereof.
  • the amount of the disintegrating agent is 0. 5 ⁇ 50%, preferably 1 ⁇ 40%.
  • the adhesive which can be used in the present invention is not particularly limited and may be any compound which causes aggregation or adhesion of HE3286 powder or granules in a preparation, including polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose. , carboxymethylcellulose, copovidone, ethylcellulose, polyvinyl alcohol, polyethylene glycol, xanthan gum, alginic acid, alginate or a combination thereof.
  • the adhesive concentration is 0. 5% ⁇ 50% (w / v), the amount is 0.1-80% of the total weight of the core or core.
  • the lubricant which can be used in the present invention is not particularly limited and may be any compound which reduces the friction between the HE3286 powder or particles and between HE3286 and a pharmaceutical machine to improve the fluidity of the powder or the particles, including magnesium stearate and calcium stearate.
  • the amount of the total weight of the core or the core of the core is 0. 1 ⁇ 20%, preferably 0. 5 ⁇ 5%.
  • Drug core or core is 0. 1 ⁇ 20%, preferably 0. 5 ⁇ 5%.
  • the core of the present invention is formed by mixing HE3286 powder or granules with a pharmaceutically acceptable carrier.
  • the core of the present invention is pressed into a sheet shape by a core, and is applied to the preparation of an enteric tablet.
  • the tableting apparatus includes a single punching machine, a high speed rotary tableting machine, and the like.
  • the core or core which can be used in the present invention can be prepared by wet granulation, dry granulation, mixed powder compaction It has the following characteristics: hardness is 4 ⁇ 15kg, and disintegration time is 1 ⁇ 15 minutes.
  • the pellet core is a small particle size core, and the pellet core can be wrapped layer by layer with the pellet isolation layer, the pellet is enteric coated, and then filled into the capsule, and the enteric pellet is prepared, wherein the particle diameter of the core is average 100 ⁇ 2000 ⁇ ⁇ , or the core weight is 50 ⁇ 2000mg. Separation layer, enteric coating, and enteric capsule
  • HE3286 is a substance that is easily destroyed in an acidic medium. Its degradation half-life in an acidic medium such as artificial gastric juice is about 40 minutes. In order to avoid contact of HE3286 with strongly acidic gastric contents, the active substance, HE3286, is completely intact. It is delivered to the part of the intestine where the pH is near neutral and the active substance can be quickly absorbed. Therefore, coating the outer layer of the core or core with an enteric coating layer or enteric capsule can better prevent the acid in the preparation. Stable active drug contact with acidic gastric contents. However, most of the commonly used enteric coatings or intestinal sac components have acidic groups. If the core is coated directly with an enteric coating, it tends to cause degradation of the acid-labile active drug. Therefore, it is necessary to wrap a barrier layer before wrapping the enteric coating layer. The barrier layer, the enteric coating, and the enteric capsule are all commercially available.
  • a barrier layer useful in the present invention for isolating the core and the acidic enteric coating including hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, ethyl Cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, polyethylene glycol, mannitol or a combination thereof; wherein the weight gain of the separator is 1-30% of the mass of the core or core, preferably 2 -15%.
  • the release layer may also be selected from an anti-adhesive agent, an antistatic agent, a pigment, a lake, etc., wherein the selected anti-adhesive agent and antistatic agent include talc, magnesium stearate, micro-silica gel, methyl silicone oil, silicone oil. , or a combination thereof.
  • the enteric coating which can be used in the present invention is not particularly limited, and may be any external coating structure of a drug which does not dissolve in an acidic medium but dissolves in the intestinal tract, acrylic resin, phthalyl hydroxypropyl methyl group.
  • the preferred enteric coatings are acrylics, including Eudragi t L series, Eudragi t S series, Eudragi t series, Eudragi t RS series, Eudragi t FS series, Eudragi tNE series, enteric type II, enteric type No. III, Opad or a combination thereof.
  • the enteric coating further contains a plasticizer as an auxiliary material thereof, and the plasticizer to be used in the present invention is not particularly limited, and may be a pharmaceutically acceptable compound for increasing the flexibility of the material of HE3286, including citric acid three.
  • a plasticizer as an auxiliary material thereof, and the plasticizer to be used in the present invention is not particularly limited, and may be a pharmaceutically acceptable compound for increasing the flexibility of the material of HE3286, including citric acid three.
  • the enteric coating may also be selected from an anti-adhesive agent, an antistatic agent, a pigment, a lake, etc., wherein the selected anti-adhesive agent and antistatic agent include talc, magnesium stearate, micro-silica gel, methyl silicone oil. , silicone oil, or a combination thereof.
  • the enteric capsule which can be used in the present invention is not particularly limited, and any commercially available enteric capsule shell can be selected, including a capsule shell made of gelatin and an enteric material, a vegetable enteric capsule shell, or a core or a medicine.
  • the core or pellet is filled in a gelatin hollow capsule after enteric coating.
  • the oral preparation of the present invention has high bioavailability and has characteristics such as no release or substantially no release in an acidic medium.
  • the relative bioavailability of the oral preparation of the present invention is increased by more than 50% (the reference preparation is an immediate release capsule) and there is no release or substantially no release of the drug within 2 hours in an acidic medium (release rate 10%, preferably 5%) ); release rate in phosphate buffer for 60 min is greater than 75%.
  • representative oral preparations include: enteric tablets, enteric capsules, and enteric pellets.
  • each oral preparation contains the active ingredient 0.5 mg to 100 mg, preferably 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg.
  • the tablet comprises a core and a layer-by-layer barrier layer and an enteric coating, wherein the core is formed by compressing a core comprising HE3286 and a pharmaceutically acceptable carrier.
  • the capsule comprises an enteric capsule and a core located in the enteric capsule, the core comprising HE3286 and a pharmaceutically acceptable carrier.
  • the enteric pellets include a capsule and an enteric pellet in a capsule, wherein the enteric pellet comprises a pellet core and a layer-by-layer coated pellet isolation layer and a pellet enteric coating,
  • the pellet core is a small particle size core (particle size of 100 to 2000 ⁇ m), and the core comprises HE3286 and a pharmaceutically acceptable carrier.
  • Oral formulations of the invention can be made using conventional methods and equipment in the art. Taking enteric preparations as an example, representative methods include (but are not limited to):
  • a method for preparing an enteric tablet which usually comprises the steps of granulation, tableting, coating, and the like.
  • the active ingredient (such as HE3286 after micronization treatment) can be mixed with a pharmaceutically acceptable carrier to form a core, and is compressed into a tablet, a coated layer, an enteric coating, etc. to prepare an enteric tablet. .
  • a method for preparing an enteric capsule which usually comprises the steps of granulation, capsule filling and the like.
  • a method for preparing an enteric pellet which generally comprises a coating method, a centrifugal layering method, a spherulite granulation method, an emulsification method, an extrusion spheronization method, a fluidized bed granulation coating method, an oscillating dropping method, and the like.
  • the active ingredient e.g., HE3286 after micronization
  • a pharmaceutically acceptable carrier e.g., a pharmaceutically acceptable carrier
  • the pellet-separating layer and the pellets are enteric coated, they are filled into capsules to prepare enteric pellets.
  • the granulation includes granulation by a granulation apparatus and granulation by a granulation apparatus.
  • the granulation equipment comprises the following steps of drying, granulating, adding a lubricant, etc., and the granulating equipment comprises a three-phase cutting and mixing granulator, a centrifugal granulation coating machine, a high-speed stirring granulator, and extrusion-spheronizing granulation.
  • the machine, the swing granulator, the fluidized bed one-step granulator, etc. are preferably a three-phase cutting mixing granulator and a fluidized bed one-stage granulator.
  • Tableting equipment includes (but is not limited to): single punching machine, high speed rotary tablet press.
  • Coating equipment includes, but is not limited to, a conventional coating pan, a high-efficiency coating pan, a fluidized bed, a granulation coating machine, preferably a high-efficiency coating pan, a fluidized bed, and the like.
  • the HE3286 enteric oral preparation of the invention does not contain or only contains a small amount of solubilizing agent (such as sodium lauryl sulfate), thereby reducing the stimulation of the human body during the production process, and avoiding the composition compared with the original preparation. After oral administration, the solubilizing agent stimulates the gastrointestinal tract and reduces the possibility of toxic side effects in the composition.
  • solubilizing agent such as sodium lauryl sulfate
  • the preparation process and equipment used in the present invention are conventional preparations and equipments in the field, and an appropriate amount of the preparation can be adjusted to obtain an enteric preparation which meets the specifications.
  • the invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention.
  • the experimental methods in the following examples that do not specify the specific conditions are usually in accordance with conventional conditions (such as the Chinese Pharmacopoeia (2010 edition)), or in accordance with the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight and parts by weight.
  • Example 1 Degradation half-life of HE3286 in artificial gastric juice solution
  • the preparation process is as follows: The drug and the auxiliary material mixture are granulated by a granulating device, dried, granulated, and tableted to obtain a core having a diameter of about 7 and a weight of about 150 mg.
  • the HE3286 enteric tablet described in this example has a specification of 5 mg (based on the HE3286 content).
  • the preparation steps are as follows: 3. 1 Core preparation:
  • barrier layer Opadry was dissolved in water, stirred overnight, and the obtained product was sprayed on the surface of the core to precipitate. This operation is done in a highly efficient coating pan.
  • the moldability test was carried out according to the Chinese Pharmacopoeia 2010 edition two appendix XG tablet friability test method.
  • Solubilizer sodium lauryl sulfate 250g (accounting for 7.60% of the prescription) Inert matter without
  • the friability is as follows.
  • the quality of the HE3286 core is 330mg, the hardness is 59kg, and the friability meets the requirements.
  • the HE3286 enteric tablet prepared by this method has a mass of 370mg per agent and contains HE3286 5mg. Drug release characteristics test of the product prepared in Example 3
  • the phosphate buffer solution (simulated artificial intestinal juice) was replaced with a 0.1 mol/L hydrochloric acid aqueous solution in a pH of 6.8. 10 ml, 10 ml, 10 min, 30 min, 45 min, 60 min, respectively, and the filtrate was filtered to obtain a test sample;
  • the release curve of this embodiment is shown in Fig. 1.
  • Example 5 Determination of the bioavailability of the original preparation and the product prepared in Example 3 in Beagle dogs The bioavailability of the product prepared in the original preparation and the preparation of Example 3 in Beagle dogs, the procedure as follows
  • the bioavailability of the ⁇ 3286 enteric preparation prepared in Example 3 was significantly improved as compared with the original preparation, suggesting that the dosage form selection (the present invention is ⁇ 3286 enteric tablet) can be carried out without changing the prescription composition.
  • the dosage form selection the present invention is ⁇ 3286 enteric tablet
  • a reasonable dosage form is conducive to the efficacy of the drug.
  • the formulation composition of the ⁇ 3286 enteric preparation is screened according to the formulation characteristics of the composition, that is, core formability and release rate.
  • the purpose of the screening is to reduce the amount of solubilizer (especially surfactant) in the prescription, and to reduce the stimulation of the gastrointestinal mucosa of the human body, thereby reducing side effects.
  • solubilizer especially surfactant
  • the ⁇ 3286 enteric tablet described in this example does not contain a solubilizing agent and has a specification of 2 mg.
  • the preparation and testing procedures are the same as in Example 3, except that the core weight is 150 mg.
  • Disintegrating agent croscarmellose sodium 66g Adhesive 5% PVP ethanol solution appropriate amount of lubricant talcum powder 33
  • the core hardness of the chip core is 5 ⁇ 9kg.
  • the friability is as follows.
  • the quality of the HE3286 core is about 150mg, the hardness is 5 ⁇ 9kg, and the friability is in accordance with the requirements.
  • the quality of the enteric tablet prepared by this method is 165mg. Contains 2 mg of HE3286.
  • Example 7 The drug release characteristics test was carried out on the product prepared in Example 6.
  • the enteric tablet without the solubilizing agent (especially surfactant) shown in the present embodiment has good core formability, suitable core hardness, and friability meets the requirements, and the in vitro release of the HE3286 enteric preparation conforms to the requirements. Requirements, and the side effects of the human body are smaller.
  • Example 8 Preparation and Formability Test of HE3286 Enteric Tablets Containing No Solubilizer and Inert Containing Substance
  • the HE3286 enteric tablet described in this example contains no solubilizing agent and contains an inert substance providing a local alkaline environment. It is 10mg.
  • the preparation and test procedures were the same as in Example 3 except that the core weight was 100 mg.
  • Disintegrant sodium carboxymethyl starch 150g Disintegrant sodium carboxymethyl starch 150g
  • HE3286 core has a mass of about 100 mg, a hardness of 5 to 9 kg, and a friability of the requirements.
  • the enteric tablet thus obtained has a mass of 106 mg per capsule and contains 10 mg of HE3286.
  • Example 9 The drug release characteristic test was carried out on the product prepared in Example 8.
  • the HE3286 enteric preparation did not release the drug in the artificial gastric juice, suggesting that the HE3286 enteric tablet containing no solubilizing agent and inert substance can prevent the drug from premature contact with the acidic stomach contents, and has high stability;
  • the enteric tablet without the solubilizing agent (especially surfactant) shown in the present embodiment has good core formability, suitable core hardness, and friability meets the requirements, and the in vitro release of the HE3286 enteric preparation conforms to the requirements. Requirements, and the side effects of the human body are smaller.
  • Example 10 Preparation and Formability Test of HE3286 Enteric Tablets Without Solubilizer and Inert Substance
  • the HE3286 enteric tablet described in this example does not contain a solubilizing agent and contains an inert substance providing a local alkaline environment. It is 10mg.
  • the preparation and testing procedures were the same as in Example 3 except that the core weight was 120 mg.
  • the HE3286 core thus obtained has a core mass of about 120 mg and a hardness of 5 to 9 kg, and the friability is in accordance with the requirements.
  • the enteric tablet thus obtained has a mass of 133 mg per agent and contains 10 mg of HE3286.
  • Example 11 Preparation and Formability Test of HE3286 Enteric Tablets Containing No Solubilizer and Inert Containing Substance
  • the HE3286 enteric tablet described in this example does not contain a solubilizing agent and contains an inert substance providing a local alkaline environment. It is 10mg.
  • the preparation and testing procedures were the same as in Example 3 except that the core weight was 150 mg.
  • Disintegrant Low-substituted hydroxypropyl cellulose 50g
  • the HE3286 core thus obtained has a core mass of about 150 mg and a hardness of 5 to 9 kg. The friability is in accordance with the requirements. The quality of the enteric tablet thus obtained is 176 mg per dose. HE3286 10mg.
  • Example 12 Preparation of Enteric Capsules
  • the HE3286 enteric capsule according to the present embodiment contains an inert substance which provides a local alkaline environment and has a specification of 10 mg.
  • the preparation steps are:
  • the HE3286 capsule thus obtained has a content of about 150 mg per dose, and contains 10 mg of HE3286, which is filled in an enteric gelatin hollow capsule.
  • Example 13 Drug release characteristics test of the product prepared in Example 12
  • enteric capsules shown in this embodiment have good core formability, and the in vitro release degree of the HE3286 enteric preparation meets the requirements, and the human side has less toxic side effects and higher bioavailability.
  • the HE3286 enteric pellets of the present embodiment are filled with enteric pellets, and the enteric pellets are composed of a blank pellet core, a main drug layer, a separation layer and an enteric layer, and each capsule contains HE3286. 2mg.
  • the specific preparation method is as follows: blank pellet core: commercially available particle size range of 0. 3 ⁇ 0. 5 let blank inert pellets 2000g; main drug layer: HE3286 20g, polyvinylpyrrolidone 30g, talc powder 2g; solvent is 90% 1000ml of ethanol;
  • Isolation layer hydroxypropylmethylcellulose 50g, talcum powder 250g
  • Enteric layer HPMCAS 390g, triethyl citrate 95g, talcum powder 115g
  • enteric pellets The preparation process of enteric pellets is as follows:
  • HE3286 was suspended in a binder (polyvinylpyrrolidone) at a drug concentration of 2%, HE3286 was applied to a blank pellet core using a fluidized bed, and dried to obtain a drug-containing pellet, in a stream Dry in the chemical bed.
  • a binder polyvinylpyrrolidone
  • the isolation layer of hydroxypropylmethylcellulose aqueous solution is applied to the drug-containing pellets, and is dried to contain Separation pellets.
  • enteric layer An enteric coating liquid HPMCAS (hydroxypropylmethylcellulose acetate succinate) was applied to the above pellets, and dried to obtain enteric pellets.
  • HPMCAS hydroxypropylmethylcellulose acetate succinate

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  • Health & Medical Sciences (AREA)
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  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Obesity (AREA)
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Abstract

L'invention concerne une formulation orale, son procédé de préparation et son utilisation. La formulation orale comprend un support pharmaceutiquement acceptable et le 17α-éthynyl-androst-5-ène-3β, 7β, 17β-triol comme principe actif; la formulation n'est pas libérée ou est sensiblement non libérée dans un milieu acide.
PCT/CN2013/085588 2012-10-23 2013-10-21 Formulation orale pour le traitement du diabète WO2014063596A1 (fr)

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CN201210408409.8A CN103768071B (zh) 2012-10-23 2012-10-23 一种治疗糖尿病的口服制剂

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200093750A1 (en) * 2013-01-05 2020-03-26 Alain D. Baron Compositions and methods for treating metabolic disorders
US11974971B2 (en) 2011-01-07 2024-05-07 Anji Pharmaceuticals Inc. Compositions and methods for treating metabolic disorders

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106361761A (zh) * 2016-11-08 2017-02-01 徐州诺克非医药科技有限公司 一种含有哈巴俄苷的药物组合物及其应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2332535A1 (fr) * 2008-09-25 2011-06-15 Takeda Pharmaceutical Company Limited Composition pharmaceutique solide
CN102215845A (zh) * 2008-04-03 2011-10-12 哈博生物科学公司 药学试剂的固体形式
EP2460523A1 (fr) * 2009-07-28 2012-06-06 Takeda Pharmaceutical Company Limited Comprimé

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102215845A (zh) * 2008-04-03 2011-10-12 哈博生物科学公司 药学试剂的固体形式
EP2332535A1 (fr) * 2008-09-25 2011-06-15 Takeda Pharmaceutical Company Limited Composition pharmaceutique solide
EP2460523A1 (fr) * 2009-07-28 2012-06-06 Takeda Pharmaceutical Company Limited Comprimé

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11974971B2 (en) 2011-01-07 2024-05-07 Anji Pharmaceuticals Inc. Compositions and methods for treating metabolic disorders
US20200093750A1 (en) * 2013-01-05 2020-03-26 Alain D. Baron Compositions and methods for treating metabolic disorders

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