WO2017171222A1 - Préparation solide pour administration orale contenant du ténofovir disoproxil et son procédé de préparation - Google Patents

Préparation solide pour administration orale contenant du ténofovir disoproxil et son procédé de préparation Download PDF

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Publication number
WO2017171222A1
WO2017171222A1 PCT/KR2017/001349 KR2017001349W WO2017171222A1 WO 2017171222 A1 WO2017171222 A1 WO 2017171222A1 KR 2017001349 W KR2017001349 W KR 2017001349W WO 2017171222 A1 WO2017171222 A1 WO 2017171222A1
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solid preparation
polyvinylpyrrolidone
granules
binder
pharmaceutically acceptable
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English (en)
Korean (ko)
Inventor
조정현
김형서
김진철
김용일
박재현
우종수
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Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
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Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic

Definitions

  • the present invention relates to a tenofovir disoproxyl-containing oral solid preparation and a preparation method thereof, and more particularly, to a tenofovir disoproxyl-containing oral solid preparation excellent in terms of drug efficacy, productivity, and quality control. It is about a method.
  • Tenofovir (Compound name: ( ⁇ [(2R) -1- (6-amino-9H-purin-9-yl) propan-2-yl] oxy ⁇ methyl) phosphonic acid) is a nucleotide analogue that is a human Nucleoside analog reverse transcriptase inhibitors (NRTIs) that block reverse transcriptase, an enzyme that is critical for the growth of the immunodeficiency virus HIV-1 virus and hepatitis B virus. It is effective in the treatment of HIV-1 infection and chronic hepatitis B by inhibiting the proliferation of viruses such as HBV.
  • NRTIs Nucleoside analog reverse transcriptase inhibitors
  • tenofovir has the disadvantage of low bioavailability.
  • tenofovir disoproxyl compound of Formula 1
  • tenofovir disoproxyl compound of Formula 1
  • Tenofovir disoproxyl is used in the form of 'acceptable salts of tenofovir disoproxyl' with added salts due to its increased bioavailability but poor stability, typically tenofovir disoproxyl fumarate (WO 1999/005150) are available commercially (VIREAD ® , Gilead Sciences, Inc.). In addition, phosphate (WO 2016/003194) has been developed.
  • Tenofovir disoproxyl or salts thereof when administered to the gastrointestinal tract, are rapidly absorbed through the body's cell membranes and change in the form of tenofovir in plasma after absorption to show efficacy.
  • T max the highest blood concentration of tenofovir disoproxyl or salts thereof is fast within 1 hour, so it disintegrates and dissolves rapidly at the beginning after administration in tablet form. It must be absorbed into the body to achieve the desired therapeutic effect.
  • excellent pharmaceutical properties are required in terms of productivity and quality control.
  • An aspect of the present invention is to provide a tenofovir diso- roxyl-containing oral solid preparation that exhibits a high initial dissolution of the active ingredient, yet has high productivity and easy quality control.
  • Another aspect of the present invention is to provide a method for preparing an oral solid preparation containing tenofovir disoproxyl, which exhibits high initial dissolution of the active ingredient and has high productivity and easy quality control.
  • Tenofovir disoproxyl or a pharmaceutically acceptable salt thereof as an active ingredient and a wet granule comprising polyvinylpyrrolidone as a binder.
  • the wet granules included in the oral solid preparations according to an aspect of the present invention may have a high density and a low repose angle by including polyvinylpyrrolidone as a binder, the solids having low mass deviation and excellent productivity when formulated as a solid preparation Not only can the formulation be prepared, but also have a high initial dissolution rate. Therefore, according to an aspect of the present invention, it is possible to manufacture a tenofovir diso- roxyl-containing oral solid preparation having excellent productivity and easy quality control during mass production and excellent efficacy.
  • Tenofovir disoproxyl or salts thereof have a high peak concentration (T max ) of less than 1 hour, which is fast, so that they disintegrate and dissolve rapidly in the early stages of administration as a solid preparation to be absorbed into the body to achieve the desired therapeutic effect.
  • T max peak concentration
  • the productivity of the solid preparations should be excellent, and for this purpose, the flowability of the granules used in the preparation of the solid preparations should be excellent.
  • Tenofovir disoproxyl or a pharmaceutically acceptable salt thereof as an active ingredient and a wet granule comprising polyvinylpyrrolidone as a binder.
  • the pharmaceutically acceptable salts include acid addition salts, and the acid addition salts include inorganic or organic acid salts.
  • the inorganic acid salts include, but are not limited to, hydrochloride, phosphate, sulfate or disulfate.
  • the organic acid salt is an aliphatic organic acid acetate, dichloroacetate, adipate, alginate, ascorbate, camphorate, caprate, caproate, caprylate, cyclate, galactate, gluceptate, glucuronate , Glutamate, oxoglutarate, lactobionate, thiocyanate, malonate, uronate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate, propionol Laterate, malonate, succinate, suverate, sebacate, maleate, orotate, myristate, butyne-1,4-dioate, hexine-1,6-dioate, citrate, lactate, betahydroxy Butyrate, glycorate, malate, tartrate
  • the pharmaceutically acceptable salt of tenofovir disoproxyl may be phosphate, orotate, fumarate or succinate.
  • the pharmaceutically acceptable salt of tenofovir disoproxyl is phosphate.
  • Test results show that the wet granules of tenofovir disoproxil have higher density and smaller angle of repose than the dry granules, which facilitates high productivity and quality control when manufactured as a solid formulation, but is solidified by wet granulation.
  • the formulation showed a lower initial dissolution rate than the solid formulation compressed into dry granules.
  • the wet granules had a smaller angle of repose than the dry granules, but did not fall within the range of 35-40 degrees, which is required for securing productivity (see Test Examples 1 and 2).
  • initial dissolution rate means a dissolution rate within about 1 hour after administration, more specifically, within about 30 minutes after oral administration.
  • the initial dissolution rate may be measured by dissolution test of the solid preparation in about 0.1 N hydrochloric acid solution at a paddle rotation speed of about 50 rpm according to the second method of dissolution of KEPCO.
  • the polyvinylpyrrolidone may be any polyvinylpyrrolidone used as binder in the pharmaceutical field.
  • the polyvinylpyrrolidone may be polyvinylpyrrolidone having a molecular weight of about 30,000 to 100,000.
  • the polyvinylpyrrolidone is polyvinylpyrrolidone having a molecular weight of about 30,000 to 50,000.
  • the content of the polyvinylpyrrolidone in the solid preparation may be appropriately selected by a person skilled in the art and may vary depending on the molecular weight of polyvinylpyrrolidone.
  • the polyvinylpyrrolidone may be contained, for example, in an amount of about 1 to 10% by weight, more specifically about 1 to 5% by weight in the solid preparation.
  • the polyvinylpyrrolidone has a molecular weight of 30,000 or more but less than 50,000, and may be included in an amount of about 1 to 5% by weight based on the total amount of the solid preparation.
  • the oral solid preparation is particularly preferred for mass production.
  • the "mass production” refers to the amount by which the production of dry granules during the formulation of tenofovir disoproxyl may be less productive than that produced by the wet granulation method, which is a condition of the pharmaceutical additive. It may vary depending on the conditions of the specific granule manufacturing method. In one embodiment, mass production means at least 20 kg of granules per batch. In mass production, it is manufactured by wet granules, so the dry granulation method increases polyvinylpyrrolidone as a binder while reducing mass deviation and improving flowability due to increased granular density and decreased angle of repose. By using it, excellent early dissolution can be ensured.
  • solid preparation means a preparation made by molding or encapsulating a drug into a certain shape.
  • the oral solid preparation may be any oral solid preparation prepared by wet granules or containing wet granules, for example, pellets, capsules, tablets (including monolayer tablets, bilayer tablets, inner core tablets), It may be formulated as a dry syrup, granules and the like, but is not limited thereto. More specifically, the oral solid co-formulation may be in the form of capsules, monolayer tablets or bilayer tablets. When the oral solid complex preparation is a capsule, the capsule may be in the form of granules or tablets therein. In one embodiment, the oral solid preparation is a tablet.
  • the oral solid preparation may further include one or more pharmaceutically acceptable additives in addition to polyvinylpyrrolidone as the active ingredient and the binder.
  • the pharmaceutically acceptable additive may further include one or more substances selected from the group consisting of diluents, binders, disintegrants, glidants, and any combination thereof.
  • the diluent is used for the increase, and may be selected from the group consisting of mannitol, lactose, starch, microcrystalline cellulose, rudipress, calcium dihydrogen phosphate, and any combination thereof, but is not limited thereto.
  • the diluent may be included in an amount of about 1 to 99% by weight, preferably about 20 to 80% by weight of the total weight of the solid preparation.
  • the binder may optionally be used in addition to the polyvinylpyrrolidone.
  • it may be selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, carboxymethyl cellulose sodium, and any combination thereof, but is not limited thereto.
  • the binder may be included with the polyvinylpyrrolidone in an amount of about 1 to 10% by weight, preferably about 1 to 5% by weight of the total weight of the solid preparation.
  • the disintegrant may be selected from the group consisting of pregelatinized starch, croscarmellose sodium, crospovidone, sodium starch glycolate, and any combination thereof, but is not limited thereto.
  • the disintegrant may be used in an amount of about 0.5 to 50% by weight, preferably about 1 to 30% by weight, based on the total weight of the solid preparation.
  • the glidants include stearic acid, stearic acid metal salts (e.g. calcium stearate, magnesium stearate, etc.), talc, colloidal silica, sucrose fatty acid esters, hydrogenated vegetable oils, waxes, glyceryl fatty acid esters, glycerol dibehenate, And it may be selected from the group consisting of any combination thereof, but is not limited thereto.
  • the glidant may be included in an amount of 0.3 to 10% by weight, preferably 0.5 to 5% by weight of the total weight of the solid preparation.
  • the wet granules may be prepared by any wet granulation method.
  • the wet granules may be prepared by a fluidized bed granulator.
  • the solid preparation is an active ingredient tenofovir disoproxyl or a pharmaceutically acceptable salt thereof; And wet granules comprising polyvinylpyrrolidone as a binder and prepared by a fluid bed granulator.
  • the oral solid preparation may contain about 0.1 to 500 mg of the active ingredient tenofovir disoproxyl or a pharmaceutically acceptable salt thereof as a free base, and the total weight of the solid preparation It may be contained in a proportion of 0.5 to 60% by weight, specifically 1 to 55% by weight.
  • the solid preparation is at least about 90% at 10 minutes and 30 minutes when the solid preparation is eluted in about 0.1 N hydrochloric acid at a paddle rotation speed of about 50 rpm according to the eluting method of KEPCO. It is a solid formulation which shows the dissolution rate of tenofovir disoproxyl at least about 95%.
  • the oral solid preparation may be administered to a mammal, including a person having any indication of tenofovir disoproxyl or a pharmaceutically acceptable salt thereof. Therefore, the oral solid preparation may be used for the treatment of HIV-1 or chronic hepatitis B, but is not limited thereto.
  • It provides a method for producing an oral solid preparation according to an aspect of the present invention, which is to add polyvinylpyrrolidone as a binder in the granulation step.
  • the granulation step of preparing the wet granules may be prepared according to any wet granule manufacturing method known in the art.
  • the wet granulation method may perform a process of granulating and drying a mixture comprising tenofovir disoproxyl or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive in a binder solution, and drying.
  • a binder polyvinylpyrrolidone may be mixed in addition to the mixture, the binder liquid, or both the mixture and the binder liquid.
  • Pharmaceutically acceptable additives used in the granulation step may be selected from diluents, binders, disintegrants, and any combination thereof.
  • the solvent for preparing the binder solution may be water, ethanol, isopropanol, acetone, or any combination thereof.
  • the binder solution can be prepared by adding to the solvent, in addition to the binder, additional additives commonly used in the pharmaceutical art, such as surfactants, buffers, or combinations thereof.
  • the binder solution is an aqueous solution containing polyvinylpyrrolidone as a binder.
  • the drying process may be carried out through air drying, fluid bed drying, oven drying or microwave drying at a temperature not exceeding about 60, preferably not exceeding about 50, in consideration of the stability of the active ingredient.
  • the additive may be a disintegrant and / or a lubricant.
  • the disintegrant is crospovidone.
  • the glidant is a sucrose fatty acid ester.
  • the formulating step can be carried out according to any method known in the art for formulating into a solid formulation using granules, for example any known formulation for tablets, capsules, pellets, or dry syrups. It can be carried out according to the method. In one embodiment, said formulating is preparing a tablet.
  • the method for preparing a solid preparation includes a method for preparing granules in a mass production of about 20 kg or more based on granules per batch.
  • the granules produced compared to dry granulation method while mass production and wet granulation method without using polyvinylpyrrolidone, the granules produced have a low repose angle and a high density so that the flow of granules It has excellent productivity, low mass deviation, easy quality control, and high dissolution rate of the active ingredient, thus making it possible to prepare an effective tenofovir disoproxyl-containing solid preparation.
  • the granulation step can be made in any wet granulation method known in the art, for example, it can be prepared using a high speed mixer or a fluidized bed granulator. In one embodiment, the granulation step can be granulated using a fluidized bed granulator. If produced by a fluidized bed granulator may be more advantageous in terms of initial dissolution rate.
  • Production Example 1-1 to 1-3 Preparation of granules and tablets according to the granule manufacturing method
  • the granules and tablets were prepared according to Table 1, and the specific preparation method was as follows.
  • tenofovir disoproxyl phosphate was mixed with microcrystalline cellulose, lactose and pregelatinized starch at the ingredients and amounts described in 'Additive Types and Amounts'.
  • the resulting mixture was sieved through a 20 mesh sieve and placed in a polyethylene bag and mixed for 15 minutes. Then, using a roller compactor (TF-1-A60, FREUND VECTOR) was compacted (condition: Roll rate 2rpm, feeding rate 20rpm, hydraulic pressure 5Mpa) and then granulated to 20 mesh to prepare a granule.
  • the obtained granules were mixed with 10 mg of crospovidone and 2 mg of sucrose fatty acid ester. Thereafter, some of them were prepared into tablets using a tablet press.
  • Tenofovir disoproxyl phosphate was mixed with microcrystalline cellulose, lactose and pregelatinized starch with the ingredients and amounts listed in 'Types and amounts of additives' listed in Table 1 above. This was combined with purified water as a binding solution (association conditions: Agitator speed: 150rpm, Agitator pressure: 1.6 A, Chopper speed: 3000rpm), dried and sieved to about 20 mesh to prepare wet granules of tenofovir disoproxyl phosphate. Thereafter, the wet granules are mixed with 10 mg of crospovidone and 2 mg of sucrose fatty acid ester to prepare final granules. Thereafter, some of them were prepared into tablets using a tablet press.
  • Tenofovir disoproxyl phosphate was mixed with microcrystalline cellulose, lactose and pregelatinized starch with the ingredients and amounts listed in 'Types and amounts of additives' listed in Table 1 above.
  • the mixed powder was poured into a fluidized bed granulator, and then the machine was operated at an inlet temperature of 50 degrees and a spray pressure of 0.8 bar, and sprayed at a rate of 10 rpm to inject a binding liquid (purified water).
  • a binding liquid purified water
  • the granules were assembled under the same conditions at the initial stage, and then dried to lower the inlet temperature to 45 degrees, followed by drying. Thereafter, the wet granules were mixed with 10 mg of crospovidone and 2 mg of sucrose fatty acid ester to prepare final granules. Thereafter, some of them were prepared into tablets using a tablet press.
  • Production Example 2 to 4 preparation of wet granules and tablets according to the type of binder
  • Binder type Amount of binder (mg) Granulation plant Process Parameter Set Value Additive Type and Amount (mg) 2-1 HPC-L 2 Fluidized Bed Granulator (NQ-160, Dalton) Capacity: 200-700g Product temperature: 30 °C Spray pressure: 0.8 bar Spraying speed: 10 rpm Drying temperature: 45 °C Tenofovir Disoproxyl Phosphate 100 Microcrystalline Cellulose 40 Lactose 28 Pregelatinized Starch 10 2-2 6 2-3 10 3-1 HPC-M 2 3-2 6 3-3 10 4-1 CMC- Na 2 4-2 6 4-3 10
  • a tablet was prepared according to Table 2, and the specific manufacturing method was as follows.
  • Tenofovir disoproxyl phosphate was mixed with microcrystalline cellulose, lactose and pregelatinized starch at the ingredients and amounts listed in 'Types and amounts of additives' listed in Table 2 above.
  • the mixed powder is put into a fluidized bed granulator and flowed, and the machine is operated at an inlet temperature of 50 degrees and a spray pressure of 0.8 bar, and then sprayed at a speed of 10 rpm so that the binder liquid (the concentration of the binder liquid is about 5% w / w).
  • Purified water was added to each corresponding binder to prepare a binding solution). During the injection of the binding solution, the granules were assembled under the same conditions and then dried to lower the inlet temperature to 45 degrees, and then dried.
  • the dried granules were sieved through about 20 mesh to prepare wet granules. Thereafter, the wet granules were mixed with 10 mg of crospovidone and 2 mg of sucrose fatty acid ester to prepare final granules. Thereafter, some of them were prepared into tablets using a tablet press.
  • Example 1 to 4 Polyvinylpyrrolidone Preparation of Wet Granules and Tablets Including
  • Tablets were prepared according to Table 3, and the specific manufacturing method was as follows.
  • tenofovir disoproxyl phosphate was mixed with microcrystalline cellulose, lactose and pregelatinized starch with the ingredients and amounts described in 'Additive Types and Amounts'.
  • the mixed powder is put into the fluidized bed granulator and flowed, and the machine is operated at an inlet temperature of 50 degrees and a spray pressure of 0.8 bar, and sprayed at a speed of 10 rpm so that the binder liquid (the concentration of the binder liquid is about 5% w / w).
  • Purified water was added to each corresponding binder to prepare a binding solution).
  • Granulation equipment and process parameter set values were the same as those of Preparation Examples 2 to 4 above.
  • the granules were assembled under the same conditions at the initial stage, and then dried to lower the inlet temperature to 45 degrees, followed by drying. Thereafter, wet granules were mixed with 10 mg of crospovidone and 2 mg of sucrose fatty acid ester to prepare final granules. Thereafter, some of them were prepared into tablets using a tablet press.
  • Example 5 After mixing Committed Disintegrant Preparation of wet granules and tablets according to quantity
  • Example 5-1 Tenofovir Disoproxyl Phosphate 100 Microcrystalline Cellulose 40 Lactose 28 Pregelatinized Starch 10 Polyvinylpyrrolidone (MW: 400,000) 2 Example 5-2 10 Example 5-3 15 Example 5-4 20
  • a tablet was prepared according to Table 4, and the specific manufacturing method was as follows.
  • tenofovir disoproxyl phosphate was mixed with microcrystalline cellulose, lactose and pregelatinized starch with the ingredients and amounts listed in 'Additive Types and Amounts'.
  • the mixed powder was introduced into a fluidized bed granulator and flowed, and then the machine was operated at an inlet temperature of 50 degrees and a spray pressure of 0.8 bar. The spray was sprayed at a speed of 10 rpm. purified water was added to make / w%) to prepare a binding solution).
  • Granulation equipment and process parameter set values were the same as those of Preparation Examples 2 to 4 above.
  • the granules were assembled under the same conditions and then dried to lower the inlet temperature to 45 degrees, and then dried.
  • the dried granules were sieved through about 20 mesh to prepare wet granules.
  • the wet granules were mixed with the corresponding amounts of crospovidone and 2 mg of sucrose fatty acid ester to prepare final granules. Thereafter, some of them were prepared into tablets using a tablet press.
  • Test Example One In granulation According to the density and Repose Measure
  • the wet granules have a smaller repose angle than the dry granules, and thus have excellent fluidity and high density. Therefore, it was found that tablets with high productivity and low mass deviation can be produced when filling feeders in a process for tableting wet granules as tablets compared to dry granules. However, it was found that the angle of repose is less than 35 to 40 degrees to ensure excellent productivity during tablet production.
  • Test Example 2 granules according to the granulation method Compressed Dissolution Rate Evaluation of Tablets
  • UV absorbance photometer (wavelength: 260nm)
  • tablets made of dry granules were able to obtain a similar dissolution rate as the control agent, but due to the somewhat lower granule density, as shown in Table 5, may cause mass deviation of the tablet during mass production and repose angle Since it is high, there exists a possibility that productivity may be low because it is low in flowability.
  • wet granules Although they have lower repose angles than dry granules, they did not fall within the range of repose angles to secure excellent productivity in tablet production.
  • the tablets made by wet granules had higher initial dissolution rate than the granules by fluidized bed granulator compared to the granules by high speed mixer, and in both cases significantly increased compared to the tablets made by dry granules. However, it did not reach the 10-minute dissolution rate of the control agent.
  • Test Example 3 Measurement of physical properties of the granules prepared according to the type and amount of binder
  • Test Example 4 Evaluation of Dissolution Rate for Tablets of Granules Prepared According to Binder Type and Amount
  • the granules are high when the wet granules are prepared using the three binders used in Preparation Examples 2 to 4, respectively, and thus, the mass deviation is expected to be low when the tablets are prepared.
  • the angle of repose was 35 ⁇ 40 degrees, which means that it has high flowability and is advantageous in productivity. It is believed that this binder exhibits good flowability as the binding force of the binder is excellent to produce granules of relatively high density.
  • Example 10 min dissolution rate (%) 30 min dissolution rate (%) Average Standard Deviation Average Standard Deviation Control agent 93.5 2.1 98.4 0.6 1-1 92.6 3.2 99.1 1.2 1-2 94.2 3.0 98.5 1.0 1-3 90.2 2.6 98.2 0.8 2-1 92.5 1.8 98.4 0.4 2-2 90.4 2.6 97.5 0.6 2-3 87.8 2.7 95.2 1.2 3-1 81.7 2.1 92.5 1.6 3-2 78.4 1.6 90.4 0.5 3-3 72.6 1.9 88.8 1.5 4-1 50.5 3.1 80.5 2.6 4-2 46.5 3.5 81.4 3.5 4-3 43.4 3.8 79.8 2.4
  • polyvinylpyrrolidone (Example 1-2) having a molecular weight of about 30,000 to 50,000 (Examples 1-2) has been shown to have a 10-minute dissolution rate and a 30-minute dissolution rate that is equivalent to or greater than that of the control agent, whereas polyvinylpyrrolidone having a molecular weight of about 400,000 or more Money was found to be less than the 10-minute and 30-minute dissolution rates of the control formulation.
  • Example 1-2 when polyvinylpyrrolidone having a molecular weight of about 30,000 to 50,000 is used (Example 1-2), the amount of polyvinylpyrrolidin which can exhibit a 10-minute dissolution rate and a 30-minute dissolution rate equivalent to or higher than that of the control agent is molecular weight. It can be changed according to. In the case of Example 1 using the polyvinylpyrrolidone having a molecular weight of about 30,000, the dissolution rate (10 minutes dissolution rate: about 90% or more, 30 minutes or more) equivalent to that of the control agent was used when about 1 to 5% by weight of the total weight of the tablet was used.
  • Dissolution rate about 95% or more
  • Example 2 using polyvinylpyrrolidone having a molecular weight of about 50,000, the dissolution rate was higher than that of the control agent when about 1 to 3% by weight of the total weight of the tablet was used. It was.
  • Test Example 7 Post-mix Committed Disintegrant Measurement of Properties of Wet Granules According to Volume
  • Example 5-1 5-2 5-3 5-4 Density (g / ml) Bulk density 0.51 0.52 0.50 0.45 Tap density 0.66 0.65 0.65 0.64 Repose angle (°) 34.5 36.6 38.0 39.0
  • Test Example 8 Post-mix Committed Disintegrant Wet granules according to the amount Compressed Dissolution Rate Evaluation of Tablets
  • Example 10 min dissolution rate (%) 30 min dissolution rate (%) Average Standard Deviation Average Standard Deviation Control agent 93.5 2.1 98.4 0.6 5-1 82.7 2.5 90.3 1.2 5-2 81.7 2.1 92.5 1.6 5-3 84.3 3.2 87.4 1.9 5-4 83.5 2.7 89.6 2.6
  • Table 11 which is the test result according to the amount of disintegrant (crospovidone) added to the post-mixing after preparing the wet granules with the same composition as in Example 3-1 (MW of 400,000 polyvinylpyrrolidone as a binder). And according to the results of Table 12, Example 5 was found that as the amount of disintegrant added to the post-mixing was reduced compared to Example 3-1 (density increase), the density of the granules, It can increase the side effect which reduces productivity.
  • disintegrant crospovidone
  • Example 5 had only a slight improvement in dissolution rate for 10 minutes compared to Example 3-1, and all of Example 5 was found to be less than the dissolution rate of the control agent. Therefore, in general, increasing the disintegrant used to increase the dissolution of the active ingredient did not significantly improve the dissolution rate of tenofovir disoproxyl. Therefore, the binder selection was more important than the disintegrant to improve the dissolution rate of the tenofovir diso- proxyl wet granule-containing solid preparation.

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Abstract

Un aspect de la présente invention concerne une préparation solide pour administration orale et un procédé de préparation de celle-ci, la préparation solide pour administration orale contenant: en tant que principe actif, du ténofovir disoproxil ou un sel pharmaceutiquement acceptable de celui-ci; et en tant que liant, des granules de type humide comprenant de la polyvinylpyrrolidone.
PCT/KR2017/001349 2016-03-31 2017-02-08 Préparation solide pour administration orale contenant du ténofovir disoproxil et son procédé de préparation Ceased WO2017171222A1 (fr)

Applications Claiming Priority (2)

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KR10-2016-0039649 2016-03-31
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WO2015155673A1 (fr) * 2014-04-08 2015-10-15 Teva Pharmaceutical Industries Ltd Forme pharmaceutique unitaire comprenant de l'emtricitabine, du ténofovir, du darunavir et du ritonavir
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WO2015085976A1 (fr) * 2013-12-09 2015-06-18 Zentiva, K.S. Composition pharmaceutique stable contenant du fumarate de disoproxil de tenofovir
WO2015155673A1 (fr) * 2014-04-08 2015-10-15 Teva Pharmaceutical Industries Ltd Forme pharmaceutique unitaire comprenant de l'emtricitabine, du ténofovir, du darunavir et du ritonavir
KR20160003532A (ko) * 2014-07-01 2016-01-11 한미약품 주식회사 테노포비어 디소프록실 인산염과, 비금속염 붕해제 및 비금속염 활택제를 포함하는 약학 조성물

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