CN113893222B - Pharmaceutical composition and preparation method and application thereof - Google Patents
Pharmaceutical composition and preparation method and application thereof Download PDFInfo
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
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- A61K9/5078—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 having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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Abstract
The invention relates to a pharmaceutical composition, a preparation method and application thereof. The pharmaceutical composition comprises a substrate and a drug-containing layer, wherein: the substrate is selected from povidone, copovidone, microcrystalline cellulose, hydroxypropyl cellulose, lactose, anhydrous calcium hydrogen phosphate, croscarmellose sodium and any combination thereof, or the substrate is a blank pill core; the drug-containing layer comprises bregfran, a carrier and an antioxidant. The medicine composition has high and stable medicine carrying amount, low solvent residue and high safety.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition, and a preparation method and application thereof.
Background
Bugafuran (buagafuran) chemical name (1R,6S,9R) 6,10, 10-trimethyl-2-butyl-oxatricyclo [7.2.1.01,6]The dodeca-2-ene is a derivative of agarofuran which is a chemical component in agilawood and is prepared by a chemical synthesis method. In various animal experiments, the Bugerfuran has an anxiolytic effect and low toxic and side effects.
The Bugenfuran is oily liquid at room temperature, has strong lipophilicity, poor water solubility and unstable quality, is obviously degraded after being placed at room temperature for 3 months, has reduced content, and needs to be stored in a refrigerator (2-8 ℃) for a long time. The key problems to be solved for preparing the medicine into oral preparations comprise: the liquid medicine is solidified, so that the design of a solid oral preparation is convenient; the stability of the medicine is improved, and the preparation is convenient to store for a long time.
The Bugerfuran solid dispersion is prepared by a solvent method by people of the summer army and the like (the summer army, pottery faithfulness, anyplace and the like, in-vitro research on the Bugerfuran solid dispersion, pharmaceutical science, 2008,43(5): 548-doped 552.). The solid dispersion needs to increase the amount of the carrier in order to increase the stability of the solid dispersion, thereby leading to large amount of PVP K30; the solid dispersion adopts absolute ethyl alcohol as a solvent, and the residual quantity of the ethyl alcohol is not easy to meet the limit requirement of 0.5 percent specified by pharmacopoeia and guiding principles; in addition, the solid dispersion is prepared by adopting a rotary evaporation process, and industrial mass production is difficult to realize.
Disclosure of Invention
The invention provides a pharmaceutical composition comprising a substrate and a drug-containing layer, wherein:
the substrate is selected from povidone, copovidone, microcrystalline cellulose, hydroxypropyl cellulose, lactose, anhydrous calcium hydrogen phosphate, croscarmellose sodium and any combination thereof, or the substrate is a blank pill core;
the drug-containing layer comprises bregfran, a carrier and an antioxidant.
The invention also provides a solid oral preparation which comprises the pharmaceutical composition.
The present invention also provides a method of preparing a pharmaceutical composition comprising:
1) dissolving active drug, carrier and antioxidant in organic solvent to obtain drug-containing solution;
2) making the substrate in a suspended fluidized state, and spraying the drug-containing solution to the fluidized substrate to make the substrate form particles and form a drug-containing layer on the surfaces of the particles;
3) spraying an aqueous solution or an aqueous solution onto the product of the previous step in a suspended fluidized state;
4) drying the product of the previous step to obtain the pharmaceutical composition.
The invention also provides the application of the pharmaceutical composition in preparing a medicament for resisting anxiety or treating anxiety disorder or anxiety disorder.
Detailed Description
1. Pharmaceutical composition
The pharmaceutical composition comprises a substrate and a medicine-containing layer, wherein:
the substrate is selected from povidone, copovidone, microcrystalline cellulose, hydroxypropyl cellulose, lactose, anhydrous calcium hydrogen phosphate, croscarmellose sodium and any combination thereof, or the substrate is a blank pill core;
the drug-containing layer comprises bregfran, a carrier and an antioxidant.
In certain embodiments, the drug-containing layer is coated on the surface of the substrate.
In certain embodiments, the carrier is a hydrophilic polymeric material, such as povidone, copovidone, polyethylene glycol, or poloxamer.
In certain embodiments, the carrier is povidone K30, copovidone, polyethylene glycol 6000, or poloxamer 188.
In certain embodiments, the pharmaceutical composition further comprises a coating layer. In certain embodiments, the coating layer is coated on the surface of the drug-containing layer.
In certain embodiments, the coating layer is formed from a coating material selected from the group consisting of opadry film coating premixes, hypromellose, hydroxypropyl cellulose, povidone (e.g., povidone K30), copovidone, and any combination thereof.
In certain embodiments, the antioxidant is selected from Butylated Hydroxyanisole (BHA), dibutylhydroxytoluene (BHT), Propyl Gallate (PG), or any combination thereof.
In certain embodiments, the mass ratio of the budofuran to the carrier in the pharmaceutical composition is 1: 3-16. In certain embodiments, the mass ratio of budefran to carrier in the pharmaceutical composition is 1: 3-15, such as 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1: 14.
In certain embodiments, the mass ratio of the sum of the mass of the budesonide and the carrier to the substrate in the pharmaceutical composition is from 1:0.1 to 5, such as from 1:0.25 to 4, from 1:0.5 to 4, from 1:1 to 4.
In certain embodiments, the antioxidant is present in the pharmaceutical composition in an amount of 0.05 to 0.2 parts per thousand, such as 0.1, 0.15, 0.16, 0.18 parts per thousand of the mass sum of the buflomerin, the carrier and the substrate.
In certain embodiments, the pharmaceutical composition is prepared by a method comprising the steps of:
1) dissolving the Bugenfuran, the carrier and the antioxidant in an organic solvent to prepare a medicine-containing solution;
2) making the substrate in a suspended fluidized state, and spraying the drug-containing solution to the fluidized substrate to make the substrate form particles and form a drug-containing layer on the surfaces of the particles;
3) spraying an aqueous solution or an aqueous solution onto the product of the previous step in a suspended fluidized state;
4) drying the product of the previous step to obtain the pharmaceutical composition.
In certain embodiments, the drug-containing solution has a solid content of 20-40% (w/w).
In certain embodiments, the organic solvent is acetone or ethanol at a concentration of 75-95% (v/v).
In certain embodiments, the aqueous solution is an aqueous solution containing a coating material. In certain embodiments, the coating material is selected from the group consisting of an opadry film coating premix, hypromellose, hydroxypropyl cellulose, povidone (e.g., povidone K30), copovidone, and any combination thereof.
2. Solid oral preparation
The solid oral preparation comprises the pharmaceutical composition. In certain embodiments, the solid oral formulation is a tablet, capsule, or granule.
Methods for preparing such solid oral formulations are well known in the art. For example, the pharmaceutical composition of the present invention may be directly filled into a capsule to obtain a capsule. The pharmaceutical composition of the present invention may also be mixed with pharmaceutically acceptable excipients and granulated, and then put into capsules or compressed into tablets.
The pharmaceutically acceptable excipient refers to an additive in the medicinal preparation except the main medicament, and can also be called as an auxiliary material. The excipient has the general requirements of stable property, no incompatibility with the main drug, no side effect, no influence on curative effect, no deformation, crack, mildew or worm damage at normal temperature, no harm to human body, no physiological effect, no chemical or physical effect with the main drug, no influence on content determination of the main drug and the like. The pharmaceutically acceptable excipients may include binders, fillers, disintegrants, lubricants, and the like, for example, croscarmellose sodium, silicon dioxide, magnesium stearate, and the like.
3. Process for preparing pharmaceutical composition
The method for preparing the pharmaceutical composition comprises the following steps:
1) dissolving active drug, carrier and antioxidant in organic solvent to obtain drug-containing solution;
2) making the substrate in a suspended fluidized state, and spraying the drug-containing solution to the fluidized substrate to make the substrate form particles and form a drug-containing layer on the surfaces of the particles;
3) spraying an aqueous solution or an aqueous solution onto the product of the previous step in a suspended fluidized state;
4) drying the product of the previous step to obtain the pharmaceutical composition.
In certain embodiments, the drug-containing solution has a solid content of 20-40% (w/w).
In certain embodiments, the organic solvent is acetone or ethanol at a concentration of 75-95% (v/v).
In certain embodiments, the aqueous solution is an aqueous solution containing a coating material.
In certain embodiments, the coating material is selected from the group consisting of an opadry film coating premix, hypromellose, hydroxypropyl cellulose, povidone (e.g., povidone K30), copovidone, and any combination thereof.
In certain embodiments, the active agent is budesonide.
In certain embodiments, the substrate is selected from povidone, copovidone, microcrystalline cellulose, hydroxypropyl cellulose, lactose, anhydrous dibasic calcium phosphate, croscarmellose sodium, and any combination thereof, or the substrate is a blank pellet core.
In certain embodiments, the carrier is a hydrophilic polymeric material, such as povidone, copovidone, polyethylene glycol, or poloxamer.
In certain embodiments, the carrier is povidone K30, copovidone, polyethylene glycol 6000, or poloxamer 188.
In certain embodiments, the antioxidant is selected from Butylated Hydroxyanisole (BHA), dibutylhydroxytoluene (BHT), Propyl Gallate (PG), or any combination thereof.
In certain embodiments, the mass ratio of the active agent to the carrier is 1:3 to 16, preferably 1:3 to 15, such as 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1: 14.
In certain embodiments, the mass ratio of the sum of the mass of the active agent and the carrier to the mass of the substrate is 1:0.1 to 5, such as 1:0.25 to 4, 1:0.5 to 4, 1:1 to 4.
In certain embodiments, the antioxidant is present in an amount of 0.05 to 0.2 parts per thousand, such as 0.1, 0.15, 0.16, 0.18 parts per thousand of the sum of the mass of the active drug, carrier and substrate.
In certain embodiments, the pharmaceutical compositions of the present invention are prepared by the methods of the present invention for preparing pharmaceutical compositions.
4. Use of
The pharmaceutical composition of the invention can be used for resisting anxiety or treating anxiety disorder or anxiety disorder.
It is further noted that the dosage and method of use of the pharmaceutical composition of the present invention depends on many factors, including the age, body weight, sex, physical health, nutritional status, activity intensity of the compound, time of administration, metabolic rate, severity of the condition, and subjective judgment of the treating physician. The preferred dosage is between 0.01-1000 mg/kg body weight/day.
In the present invention, unless otherwise specified, scientific and technical terms used in the present invention have meanings commonly understood by those skilled in the art. The raw materials and auxiliary materials used in the invention are conventional raw materials widely used in the field and meet the medicinal standard. The equipment used in the invention is conventional equipment widely used in the corresponding field. Meanwhile, in order to better understand the present invention, the definitions and explanations of related terms are provided below.
In the present invention, the term "solid content" refers to the mass percentage of the budofuran and the auxiliary materials in the drug-containing solution.
In the invention, the blank pellet core can be sucrose pellet core, microcrystalline cellulose pellet core, starch pellet core, lactose pellet core, silicon dioxide pellet core and the like, and the blank pellet cores can be obtained commercially.
In the present invention, the apparatus for carrying out the production method of the present invention is well known in the art, and for example, a top-spouted fluidized bed, a bottom-spouted fluidized bed, a side-spouted fluidized bed, and a swirling fluidized bed can be used to carry out the production method of the present invention.
The invention has the beneficial technical effects
The pharmaceutical composition of the invention has one or more of the following advantages:
1) the drug loading is high;
2) stable, capable of stable existence under high temperature, high humidity and/or light conditions;
3) the residual quantity of the solvent is low;
4) the safety is high;
5) the preparation method is simple;
6) the cost is low;
7) is suitable for industrial production.
The method for preparing the pharmaceutical composition provided by the invention is simple, short in production period, low in cost and suitable for industrial production, and the prepared pharmaceutical composition has less solvent residues.
According to the invention, by adding a small amount of antioxidant, the dosage of the carrier is reduced and the drug-loading rate of the pharmaceutical composition is improved on the premise of ensuring the stability of the pharmaceutical composition.
The invention improves the safety of the medicine by reducing the dosage of the carrier. The maximum daily exposure of povidone K30 in oral capsules as received by the FDA database of inactive ingredients in the united states was 636 mg. Calculated according to the fact that povidone K30/Bugerfuran in the literature is more than or equal to 10, the daily dose of Bugerfuran is 63.6mg at most, and the clinical application is limited to a great extent. Calculated according to povidone K30/Bugelfuran =5 in the invention, the pharmaceutical composition of the invention can enable the maximum daily dose of Bugelfuran to reach 127.2mg, and can meet the requirement of clinical medication.
The method for preparing the pharmaceutical composition provided by the invention can obviously reduce the solvent residue, and the solvent residue of the pharmaceutical composition prepared by the method is within the limit of 0.5% specified by the regulation.
Drawings
FIG. 1: the DSC spectrum of the Bugenfuran pharmaceutical composition prepared by the embodiment of the invention, wherein A is the DSC spectrum of the Bugenfuran bulk drug and the Bugenfuran pharmaceutical composition prepared by the embodiment of the invention; b is a DSC spectrum of a physical mixture of each sample formula in the embodiment of the invention;
FIG. 2: the in-vitro dissolution curve diagram of the Bugenfuran pharmaceutical composition and the Bugenfuran bulk drug prepared by the embodiment of the invention;
FIG. 3: the medicine time curve chart of the Bugelfuran medicine composition prepared by the embodiment of the invention in a beagle dog body is shown.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The raw materials, equipment or instruments used are not indicated by manufacturers, and all the raw materials, equipment or instruments are conventional products which can be obtained commercially.
The raw materials and auxiliary materials used in the embodiment of the invention can be obtained commercially. For example, the bulguran used in the examples of the present invention may be purchased from Beijing collaborator pharmaceutical factory, the povidone K30 may be purchased from Huzhou expecting pharmaceutical Co., Ltd, Basfu (China) Co., Ltd or Asia-Hiragana (China) investment Co., Ltd, the sucrose pellet core may be purchased from Hangzhou high-yield biological nutrition technology Co., Ltd or Anhui mountain river pharmaceutic adjuvant Co., Ltd, the BHA may be purchased from Jiangsu southeast nanomaterial Co., Ltd or Jiangsi alpha high medicine Co., Ltd, the BHT may be purchased from Jiangsi alpha high medicine Co., Ltd, the PG may be purchased from Jiangsu southeast nanomaterial Co., Ltd or Wufeng Chicheng biotech Biotech Co., Ltd, the copovidone may be purchased from Hiragana (China) investment Co., Ltd, the lactose may be purchased from German Meiji, the microcrystalline cellulose may be purchased from German JRS pharmaceutic adjuvant, the anhydrous calcium hydrogen phosphate may be purchased from Huzhou expecting pharmaceutical Co., Ltd, hydroxypropyl cellulose is available from dahlian trade establishment ltd, croscarmellose sodium is available from germany JRS pharmaceutic adjuvant, polyethylene glycol 6000 is available from jiang, alpha high medicine, gmbh, poloxamer 188 is available from basf (china), opadry film coating premix is available from shanghai carrekang coating technology ltd, hydroxypropyl methylcellulose is available from dow chemical, colloidal silicon dioxide is available from winning, magnesium stearate is available from lazhou periscope pharmaceutical ltd, gelatin hollow capsules are available from suzhou capsules ltd.
The equipment used in the embodiment of the invention is as follows:
the method for measuring the solvent residue in the embodiment of the invention is as follows:
1. ethanol residue
The residual amount of ethanol was determined by gas chromatography (the general rule 0521 of the four parts of the 2020 edition of Chinese pharmacopoeia). The chromatographic conditions were as follows:
a chromatographic column: DB-624 (14% cyanopropylphenyl-86% dimethylpolyoxysilane) quartz capillary column;
a detector: FID;
detector temperature: 250 ℃;
sample inlet temperature: 250 ℃;
column temperature: 40 ℃;
carrier gas: nitrogen gas;
flow rate: 2.5 ml/min-1；
The split ratio is as follows: 10: l;
headspace bottle temperature: 85 ℃;
the balance time is as follows: 30 min;
headspace bottle pressurization time: 0.2 min;
sample introduction time: 1.0 min;
sample introduction amount: 1 ml.
Weighing about 500mg of sample, precisely weighing, placing in a 20ml headspace bottle, adding 10ml of water, and sufficiently shaking to obtain a uniform suspension as a test solution. And dissolving 250mg of absolute ethyl alcohol in water, diluting, and preparing a solution containing 0.25mg of ethanol in each 1ml as a reference solution. 10ml of blank solvent and reference substance solution are taken and placed in a headspace bottle. And (3) balancing a blank solvent headspace bottle, a reference substance solution headspace bottle and a test solution headspace bottle at 85 ℃ for 30min, then carrying out headspace sample injection of 1ml, injecting into an Agilent 7890A gas chromatograph, and recording a chromatogram.
2. Acetone residue
The residual amount of acetone was determined by gas chromatography (the general rule 0521 of the four parts of the 2020 edition of Chinese pharmacopoeia). The chromatographic conditions were as follows:
a chromatographic column: 5% phenyl-methyl polysiloxane capillary column;
a detector: FID;
detector temperature: 250 ℃;
sample inlet temperature: 200 ℃;
column temperature: temperature programming is carried out, the initial temperature is 40 ℃, the temperature is maintained for 10 minutes, the temperature is raised to 200 ℃ at the speed of 20 ℃/min, and the temperature is maintained for 5 minutes;
carrier gas: nitrogen gas;
flow rate: 1.0 ml/min-1；
The split ratio is as follows: 10: l;
headspace bottle temperature: 85 ℃;
the balance time is as follows: 20 min;
headspace bottle pressurization time: 0.2 min;
sample introduction time: 1.0 min;
sample introduction amount: 1 ml.
Weighing about 500mg of sample, precisely weighing, placing in a 20ml headspace bottle, adding 10ml of water, and sufficiently shaking to obtain a uniform suspension as a test solution. Separately, 250mg of acetone was dissolved in water and diluted to give a solution containing 0.25mg of acetone per 1ml as a control solution. 10ml of blank solvent and reference substance solution are taken and placed in a headspace bottle. And (3) balancing a blank solvent headspace bottle, a reference substance solution headspace bottle and a test solution headspace bottle at 85 ℃ for 20min, then carrying out headspace sample injection of 1ml, injecting into an Agilent 7890A gas chromatograph, and recording a chromatogram.
The dissolution rate measuring method in the embodiment of the invention is as follows:
a sample was taken and placed in a settling basket, and according to a test conducted by a dissolution rate release measuring method (second method 0931 of the four general guidelines in the 2020 edition of Chinese pharmacopoeia), 500ml of a 0.5% sodium lauryl sulfate solution was used as a dissolution medium at a rotation speed of 100 rpm, and according to the method, 5ml of the sample was taken at 5, 10, 15, 20, 30, 45 and 60 minutes, and 5ml of the solution was replenished. Filtering, and taking the subsequent filtrate as the test solution. Taking about 75mg of Buge furan reference substance, putting the Buge furan reference substance into a 25ml brown measuring flask, adding ethanol to dilute to a scale, and shaking up; 1.0ml of the solution was measured precisely, and the solution was diluted to the desired volume with 0.5% sodium dodecylsulfate solution in a 100ml brown measuring flask, and shaken up to give a control solution (containing 0.03mg of Bugenfuran per 1 ml). Respectively and precisely measuring 20 μ l of reference solution and sample solution, injecting into high performance liquid chromatograph, recording peak area, and calculating dissolution rate by external standard method.
The DSC measurement method in the examples of the present invention is as follows:
DSC is measured by adopting a thermal analysis method (China pharmacopoeia 2020 edition four ministry of general rules 0661), 5-10 mg of a sample is put into a crucible and sealed, the temperature is measured by adopting an METTLER DSC3 STAR differential scanning calorimeter, the temperature rise rate is 10 ℃/min, the temperature is increased from minus 25 ℃ to 200 ℃, the carrier gas is nitrogen, and the sample spectrum is recorded.
The detection method of related substances in the embodiment of the invention is as follows:
the related substances are determined by high performance liquid chromatography (China pharmacopoeia 2020 edition four-part general regulation 0512). The chromatographic conditions were as follows:
a chromatographic column: octyl silane bonded silica gel is used as a filling agent;
mobile phase: acetonitrile-water = 72: 28;
flow rate: 1.0 ml/min-1；
Column temperature: 40 ℃;
detection wavelength: 196nm and 240 nm;
sample introduction amount: 10 μ l.
Taking a proper amount of sample (about 10mg of bulgafuran), placing the sample in a centrifuge tube, adding 2ml of water, whirling, adding 5ml of n-hexane, fully mixing, and taking supernatant to obtain a sample solution. Precisely measuring blank solvent and 10 mul of sample solution, injecting into a liquid chromatograph, recording chromatogram until the retention time of main component chromatogram peak is 2 times, and calculating impurity content according to area normalization method. When the same retention time positions were simultaneously responded at 196nm and 240nm, the calculation was performed with the largest participant, and the calculation was not repeated.
Example 1: preparation example 1 of a pharmaceutical composition containing Bugenfuran
Pharmaceutical compositions containing budofuran were prepared according to the formulations shown in table 1 to obtain samples 1 to 6. The preparation method comprises the following steps:
(1) dissolving the prescribed amount of the budofuran and the auxiliary materials into 85% (v/v) ethanol solution to prepare a drug-containing solution with the solid content of 30% (w/w) for later use;
(2) preheating the fluidized bed to 40-55 ℃, setting the initial fan frequency to be 25-30 Hz, feeding the substrate into the fluidized bed, adjusting the atomization pressure to be 0.14-0.18 Mpa and the flow rate to be 2300-3490 mu l/min, and spraying the completely dissolved medicine-containing solution into the fluidized bed. Properly adjusting the frequency of a fan according to the state of the material to ensure that the material is always in a good fluidization state in a fluidization chamber;
(3) after the medicine-containing solution is sprayed, adjusting the air inlet temperature to be 45-55 ℃ and the flow rate to be 2000-2300 mu l/min, spraying 300g of purified water into the fluidized bed, and adjusting the frequency of a fan to keep the materials in a good fluidized state in the fluidized chamber all the time;
(4) and after the purified water is sprayed, drying the obtained particles in a fluidized bed at 50-55 ℃ for 20-30 min to obtain samples 1-6 of the Bugenfuran pharmaceutical composition.
And filling the prepared Bugelfuran pharmaceutical composition into capsules to obtain Bugelfuran capsules, wherein each Bugelfuran capsule contains 15mg of Bugelfuran.
TABLE 1 formulations of samples 1-6
Example 2: preparation example 2 of a pharmaceutical composition containing Bugenfuran
Pharmaceutical compositions containing budofuran were prepared according to the formulations shown in table 2 to obtain samples 7-9. The preparation method comprises the following steps:
(1) dissolving the prescribed amount of the budofuran and the auxiliary materials into 95 percent (v/v) ethanol solution to prepare a drug-containing solution with the solid content of 25 percent (w/w) for later use;
(2) preheating the fluidized bed to 40-55 ℃, setting the initial fan frequency to be 25-30 Hz, feeding the substrate into the fluidized bed, adjusting the atomization pressure to be 0.14-0.18 Mpa and the flow rate to be 1500-2850 mu l/min, and spraying the completely dissolved medicine-containing solution into the fluidized bed. Properly adjusting the frequency of a fan according to the state of the material to ensure that the material is always in a good fluidization state in a fluidization chamber;
(3) after the medicine-containing solution is sprayed, adjusting the air inlet temperature to be 45-55 ℃ and the flow rate to be 1500-2300 mu l/min, spraying 300g of purified water into the fluidized bed, and adjusting the frequency of a fan to keep the materials in a good fluidized state in the fluidized chamber all the time;
(4) and after the purified water is sprayed, drying the obtained particles in a fluidized bed at 50-55 ℃ for 20-30 min to obtain a sample 7-9 of the Bugenfuran pharmaceutical composition.
And filling the prepared Bugelfuran pharmaceutical composition into capsules to obtain Bugelfuran capsules, wherein each Bugelfuran capsule contains 15mg of Bugelfuran.
TABLE 2 formulations of samples 7-14
Example 3: preparation example 3 of a pharmaceutical composition containing Bugenfuran
A pharmaceutical composition containing budrafuran was prepared according to the formulation shown in table 2 to obtain sample 10. The preparation method comprises the following steps:
(1) dissolving the prescribed amount of the budofuran and the auxiliary materials into 95 percent (v/v) ethanol solution to prepare a drug-containing solution with the solid content of 25 percent (w/w) for later use;
(2) dissolving prescribed dose of povidone K30 and BHA in 95% (v/v) ethanol solution to obtain outer layer solution with solid content of 25% (w/w) for use;
(3) preheating the fluidized bed to 40-55 ℃, setting the initial fan frequency to be 25-30 Hz, feeding the substrate into the fluidized bed, setting the atomization pressure to be 0.14-0.18 Mpa and the flow rate to be 1500-2850 mu l/min, and spraying the completely dissolved medicine-containing solution into the fluidized bed. The frequency of the fan is properly adjusted according to the state of the material, so that the material is always kept in a good fluidization state in the fluidization chamber. After the medicine-containing organic solution is sprayed, spraying the outer layer solution;
(4) after the spraying of the outer layer solution is finished, adjusting the air inlet temperature to be 45-55 ℃ and the flow rate to be 1500-2300 mu l/min, spraying 300g of purified water into the fluidized bed, and adjusting the frequency of a fan to keep the materials in a good fluidized state in the fluidized chamber all the time;
(5) and after the purified water is sprayed, drying the obtained particles in a fluidized bed at 50-55 ℃ for 20-30 min to obtain a sample 10 of the Bugenfuran pharmaceutical composition.
And filling the prepared Bugelfuran pharmaceutical composition into capsules to obtain Bugelfuran capsules, wherein each Bugelfuran capsule contains 15mg of Bugelfuran.
Example 4: preparation example 4 of a pharmaceutical composition containing Bugenfuran
Pharmaceutical compositions containing budofuran were prepared according to the formulations shown in table 2 to give samples 11-14. The preparation method comprises the following steps:
(1) dissolving the prescribed amount of the budofuran and the auxiliary materials into 95 percent (v/v) ethanol solution to prepare a drug-containing solution with the solid content of 40 percent (w/w) for later use;
(2) preheating the fluidized bed to 40-55 ℃, setting the initial fan frequency to be 25-30 Hz, feeding the substrate into the fluidized bed, setting the atomization pressure to be 0.14-0.18 Mpa and the flow rate to be 1500-2850 mu l/min, and spraying the completely dissolved medicine-containing solution into the fluidized bed. Properly adjusting the frequency of a fan according to the state of the material to ensure that the material is always in a good fluidization state in a fluidization chamber;
(3) after the medicine-containing solution is sprayed, adjusting the air inlet temperature to be 45-55 ℃ and the flow rate to be 2000-2300 mu l/min, spraying 300g of purified water into the fluidized bed, and adjusting the frequency of a fan to keep the materials in a good fluidized state in the fluidized chamber all the time;
(4) and after the purified water is sprayed, drying the obtained particles in a fluidized bed at 50-55 ℃ for 20-30 min to obtain samples 11-14 of the Bugenfuran pharmaceutical composition.
And filling the prepared Bugelfuran pharmaceutical composition into capsules to obtain Bugelfuran capsules, wherein each Bugelfuran capsule contains 15mg of Bugelfuran.
Example 5: preparation example 5 of a pharmaceutical composition containing Bugenfuran
Pharmaceutical compositions containing budofuran were prepared according to the formulation shown in table 3 to obtain samples 15-18. The preparation method comprises the following steps:
(1) dissolving the prescribed amount of the budofuran and the auxiliary materials into 75% (v/v) ethanol solution to prepare a drug-containing solution with the solid content of 20% (w/w) for later use;
(2) preheating the fluidized bed to 40-55 ℃, setting the initial fan frequency to be 25-30 Hz, feeding the substrate into the fluidized bed, setting the atomization pressure to be 0.14-0.18 Mpa and the flow rate to be 1500-2850 mu l/min, and spraying the completely dissolved medicine-containing solution into the fluidized bed. Properly adjusting the frequency of a fan according to the state of the material to ensure that the material is always in a good fluidization state in a fluidization chamber;
(3) after the medicine-containing solution is sprayed, adjusting the air inlet temperature to be 45-55 ℃ and the flow rate to be 2000-2300 mu l/min, continuously spraying 300g of purified water into the fluidized bed, and adjusting the frequency of a fan to keep the materials in a good fluidized state in the fluidized chamber all the time;
(4) after spraying purified water, the resulting granules were dried in a fluidized bed at 65 ℃ for about 10min to give samples 15-18 of the Bugenfuran pharmaceutical composition.
And filling the prepared Bugelfuran pharmaceutical composition into capsules to obtain Bugelfuran capsules, wherein each Bugelfuran capsule contains 15mg of Bugelfuran.
TABLE 3 formulations of samples 15-18
Example 6: preparation example 6 of a pharmaceutical composition containing Bugemofuran
Pharmaceutical compositions containing budofuran were prepared according to the formulation shown in table 4 to obtain samples 19-22. The preparation method comprises the following steps:
(1) dissolving the prescribed amount of the budofuran and the auxiliary materials into 85% (v/v) acetone solution to prepare a drug-containing solution with the solid content of 30% (w/w) for later use;
(2) preheating the fluidized bed to 40-55 ℃, setting the initial fan frequency to be 25-30 Hz, feeding the substrate into the fluidized bed, setting the atomization pressure to be 0.14-0.18 Mpa and the flow rate to be 2300-3490 mu l/min, and spraying the completely dissolved medicine-containing solution into the fluidized bed. Properly adjusting the frequency of a fan according to the state of the material to ensure that the material is always in a good fluidization state in a fluidization chamber;
(3) after the medicine-containing solution is sprayed, adjusting the air inlet temperature to be 45-55 ℃ and the flow rate to be 1500-2300 mul/min, continuously spraying 300g of purified water into the fluidized bed, and adjusting the frequency of a fan to keep the materials in a good fluidized state in the fluidized chamber all the time;
(4) after spraying purified water, the resulting granules were dried in a fluidized bed at 40 ℃ for about 40min to give samples 19-22 of the Bugenfuran pharmaceutical composition.
And filling the prepared Bugelfuran pharmaceutical composition into capsules to obtain Bugelfuran capsules, wherein each Bugelfuran capsule contains 15mg of Bugelfuran.
TABLE 4 formulations of samples 19-22
Example 7: preparation example 7 of a pharmaceutical composition containing Bugenfuran
Pharmaceutical compositions containing budofuran were prepared according to the formulation shown in table 5 to obtain samples 23-27. The preparation method comprises the following steps:
(1) dissolving the prescribed amount of the budofuran and the auxiliary materials into 85% (v/v) ethanol solution to prepare a drug-containing solution with the solid content of 30% (w/w) for later use;
(2) dissolving the auxiliary materials in the prescription amount in 300g of purified water to prepare an aqueous solution for later use;
(3) preheating the fluidized bed to 40-55 ℃, setting the initial fan frequency to be 25-30 Hz, feeding the substrate into the fluidized bed, setting the atomization pressure to be 0.14-0.18 Mpa and the flow rate to be 2300-3490 mu l/min, and spraying the completely dissolved medicine-containing solution into the fluidized bed. Properly adjusting the frequency of a fan according to the state of the material to ensure that the material is always in a good fluidization state in a fluidization chamber;
(4) after the medicine-containing solution is sprayed, adjusting the air inlet temperature to be 45-55 ℃ and the flow rate to be 1500-2300 mul/min, continuously spraying the aqueous solution into the fluidized bed, and adjusting the frequency of a fan to keep the material in a good fluidized state in the fluidized chamber all the time;
(5) and after the purified water is sprayed, drying the obtained particles in a fluidized bed at 50-55 ℃ for 20-30 min to obtain samples 23-27 of the Bugenfuran pharmaceutical composition.
TABLE 5 formulations of samples 23-27
Example 8: preparation example 8 of a pharmaceutical composition containing Bugafuran
Referring to the preparation method of example 1, the pharmaceutical composition containing budofuran was prepared according to the formulation of sample 1 in table 1 with adjustment of process parameters to obtain samples 28 to 32, wherein the process parameters are shown in table 6, and the sample 32 was 10-fold the formulation amount.
TABLE 6 Process parameters
Note: spraying for 30min, and stopping for 10 min.
Example 9: preparation example 9 of a pharmaceutical composition containing Bugafuran
Referring to the preparation method of example 1, the pharmaceutical composition containing budofuran was prepared according to the formulation of sample 1 in table 1 by adjusting the spraying process parameters of the aqueous solution to obtain samples 33 to 35, and the process parameters are shown in table 7.
TABLE 7 Process parameters
The residual amount of ethanol in the granules before and after spraying water was measured and the results are shown in Table 7. Therefore, the residual amount of ethanol in the particles can be reduced by spraying the aqueous solution, and the residual amount of ethanol can be lower than 0.5%. In addition, the proportion of fine powder in the obtained granules is less than 50 percent, and the capsule filling can be smoothly carried out.
Referring to Table 7, the preparation process parameters of samples 2-32 were adjusted so that the solvent (ethanol or acetone) residue of the resulting particles was less than 0.5%.
Example 10: preparation of Bugelfuran capsules or tablets
The Bugemofuran pharmaceutical compositions prepared in examples 1-9 were filled in capsules to obtain Bugemofuran capsules, each containing 15mg of Bugemofuran.
The prepared Bugrefuran pharmaceutical composition can also be mixed with pharmaceutically acceptable excipients and then granulated, and then the mixture is filled into capsules or compressed into tablets. For example, the sample 18 can be granulated by a dry granulator, and mixed with a proper amount of croscarmellose sodium (added) and silicon dioxide in an HD series three-dimensional motion mixer for 5 min; stopping the machine, adding magnesium stearate into the premixed material, starting the machine, and continuously mixing for 5 min; and (5) granulating. And filling the granules into capsules to obtain the Bugelfuran capsules, wherein each capsule contains 15mg of Bugelfuran. Tabletting the granules to obtain the Bugelfuran tablets, wherein each tablet contains 15mg of Bugelfuran.
As a result of the tests, solid dispersions of Bugenfuran were formed in the samples 1 to 35 prepared in examples 1 to 9, and the DSC pattern of some of the samples is shown in FIG. 1. The results show that after the formulations of the samples in the examples are physically mixed, the DSC spectrum obtained has obvious Bugenfuran endothermic peak. In the DSC chart of the pharmaceutical composition of bregfran prepared in the example of the present invention, the endothermic peak of bregfran disappears, which indicates that the preparation method of the example of the present invention forms solid dispersion of bregfran.
In vitro dissolution rates of samples 1 to 35 prepared in example 10 were measured, and the in vitro dissolution rate results of some samples are shown in fig. 2. The results show that after the solid dispersion is formed, the in vitro dissolution speed and degree of the budofuran are obviously increased compared with those of the bulk drug, and each sample has the rapid dissolution characteristic similar to that of the comparative example 1.
The samples 1 to 32 prepared in examples 1 to 8 were examined for solvent residue, and the results are shown in Table 8. The results show that samples 1-32 prepared according to the inventive example all had less than 0.5% solvent (ethanol or acetone) residue.
TABLE 8 measurement results of solvent residue
A sample of a part of the Bulgafuran capsules prepared in example 10 was packed in an aluminum bag, and the packed sample was allowed to stand for 10 days under high temperature (60 ℃ C.), high humidity (RH 92.5%) and light (4500 Lx), and the amount of change in the relevant substances was measured, and the results are shown in Table 9. The results show that the samples prepared in the examples of the present invention can be stably stored under high temperature, high humidity or light conditions.
TABLE 9 amount of change in substances
Biggee fasting single oral pharmacokinetic studies were also performed. The test drugs were sample 5 and control sample 1. 10 beagle dogs, male and female halves, were randomly divided into two groups of 5 dogs each, and were administered by crossover with one week of washout between two oral administrations. The dose was 120 mg/dose, and blood samples were collected at different time points after administration for drug determination, and the results are shown in FIG. 3. The results show that the in vivo pharmacokinetics of the budefran pharmaceutical composition prepared by the present invention and the control sample 1 are not significantly different.
Comparative example 1: preparation of Bugenfuran pharmaceutical composition by rotary evaporation method
Placing 20g of budofuran and 300g of povidone K30 in a round bottom flask, adding about 1000ml of absolute ethanol, stirring to completely dissolve, performing rotary evaporation at 45 ℃ under reduced pressure, performing vacuum drying for 12 hours, crushing, and sieving with a 40-mesh sieve to obtain a control sample 1 of the budofuran pharmaceutical composition, wherein the sample is a solid dispersion. And filling the prepared solid dispersion of the brewagofuran into capsules to obtain the brewagofuran capsules. The ethanol residue of the control sample 1 was 2.2%.
The influence of different vacuum drying times on the residual amount of ethanol was examined, and the results were as follows:
the results show that the solid dispersion of Bulgafuran prepared by rotary evaporation method has ethanol residue far higher than the limit value of 0.5%. The ethanol residue is reduced to a certain extent by prolonging the vacuum drying time, but the ethanol residue is kept unchanged after the ethanol residue is reduced to a certain extent, so that the ethanol residue cannot be effectively reduced by prolonging the drying time.
Comparative example 2: preparation of Bugelfuran pharmaceutical composition by spray drying method
Weighing povidone K30150 g, adding 300ml of absolute ethyl alcohol to dissolve the povidone K30150 g, adding 10g of a Bugenfuran raw material drug, clarifying the solution under the action of a high-speed shearing homogenizer, slowly adding 150ml of distilled water, homogenizing to obtain a homogeneous liquid, and performing spray drying, wherein the temperature of an air inlet is controlled to be 160-170 ℃, and the temperature of a discharge port is controlled to be 60-70 ℃, so that a control sample 2 of the Bugenfuran pharmaceutical composition is obtained and is solid dispersion particles. The control sample 2 was tested to have an ethanol residue of 1.4% above the 0.5% limit.
Comparative example 3: preparation of Bugenfuran pharmaceutical composition by conventional fluidized bed granulation method
Aiming at the main parameters of fluidized bed equipment, orthogonal test design of 4-factor 3 level is carried out, and main investigation indexes are ethanol residue, yield, particle bulk density and proportion of fine powder below 80 meshes.
The bregfran and the auxiliary materials are dissolved in the solvent according to the formula of the table 10 to obtain the medicine-containing solution for standby. Feeding 300g of povidone K30 into a fluidized bed, preheating, spraying a medicine-containing solution, keeping the air inlet temperature unchanged after spraying, and drying for 20-30 minutes. The process parameters for spraying the drug-containing solution are shown in Table 11. The ethanol residue and the bulk density of the granules of the prepared bregfran pharmaceutical composition were measured, and the yield and the proportion of fine powder below 80 mesh were calculated, and the results are shown in table 11. The results show that the ethanol residue of the Bugerfuran pharmaceutical composition prepared by the process parameters is higher than 0.5%.
TABLE 10 comparative example 3 formulation composition
TABLE 11 Process parameters for spraying drug-containing solution
The results are visually analyzed, and the statistics of the influence of each factor on each index are summarized in table 12. In the tables, "+" indicates a positive correlation, "-" indicates a negative correlation, and "/" indicates no evidence of regularity.
TABLE 12 influence of the parameters of the spraying process of the drug-containing solution on the index
As a result, in order to further reduce the ethanol residue, the atomization pressure was increased, and the blowing air temperature was decreased appropriately. The results show that by increasing the atomization pressure there is a certain reduction in ethanol retention, but still above the limit of 0.5%. In addition, intermittent liquid spraying tests are also carried out, for example, liquid spraying is suspended for 30min every time, drying is carried out for 10min, the steps are repeated until liquid spraying is finished, drying is carried out for 20min, and material collection is carried out, wherein the ethanol residue is still higher than 0.5% through detection. It can be seen that the conventional fluid bed granulation method cannot further reduce the solvent residue of the budofuran pharmaceutical composition.
Comparative example 4: effect of different drying methods on ethanol residue of Bugerfuran pharmaceutical composition
Bugrefuran and adjuvants were dissolved in a solvent according to the formulation in Table 13 to prepare a drug-containing solution with a solid content of 27.5% (w/w). Preheating a fluidized bed to 52 ℃, setting the frequency of a fan to be 25Hz, feeding 250g of povidone K30, setting the atomizing pressure to be 0.12Mpa, the flow rate to be 2300-2855 mu l/ml and the air inlet temperature to be 52-58 ℃, and spraying the completely dissolved medicine-containing solution into the fluidized bed. The frequency of the fan is properly adjusted according to the state of the material, so that the material is always kept in a good fluidization state in the fluidization chamber. And after the liquid spraying is finished, obtaining the Bugenfuran medicinal composition. The composition was dried by different drying methods such as forced air drying, vacuum drying and fluidized bed drying, and the ethanol content was measured, and the results are shown in table 14.
TABLE 13 comparative example 4 formulation composition
TABLE 14 residual ethanol amounts for different drying modes
The results show that the drying stage can reduce the ethanol residue of the solid dispersion to some extent, but the reduction range is limited, and the ethanol residue cannot be reduced to the limit of 0.5% by prolonging the drying time.
Comparative example 5: preparation of Bugefuran pharmaceutical composition with different drug contents by rotary evaporation method
The pharmaceutical compositions of budofuran and povidone K30 (no antioxidant) were prepared in the same manner as in comparative example 1 using a rotary evaporation method with ratios of 1:5, 1:10, and 1:15, respectively.
0.2 per mill of butyl hydroxy anisol is added into the above formulas to prepare the antioxidant-containing Bugemofuran pharmaceutical composition with the proportion of 1:5, 1:10 and 1:15 of Bugemofuran and povidone K30 respectively.
Each of the control samples was placed in an open brown vial and left at a high temperature of 60 ℃ for 2 months, and the drug content of the sample was measured at 0 day, 5 days, 10 days, 30 days and 60 days, respectively, with the results shown in Table 15.
TABLE 15 stability test results under high temperature conditions
The results show that when the antioxidant is not contained, the content of the samples with the proportions of Bugerfuran/povidone K301: 5 and 1:10 is greatly reduced at the high temperature of 60 ℃ for 2 months, and the 1:15 samples still maintain better content stability, which indicates that the chemical stability of the Bugerfuran is maintained by the povidone with higher proportion when the antioxidant is not contained; after the antioxidant is added, the content of the samples with the proportion of the bulgafuran/povidone K301: 5 and the proportion of the samples with the proportion of the bulgafuran/povidone K1: 10 is kept unchanged at the high temperature of 60 ℃ for 2 months, which shows that the chemical stability of the bulgafuran solid dispersion is remarkably improved by adding the antioxidant. By adding the antioxidant, the dosage of the carrier can be reduced while the stability is ensured.
Comparative example 6: preparation of Bugefuran pharmaceutical composition containing different antioxidants by adopting fluidized bed granulation method
Control samples 3-7 of pharmaceutical compositions containing different antioxidants were prepared according to the formulation of Table 16, as in example 1.
TABLE 16 pharmaceutical composition formulations with different antioxidants
And respectively filling the prepared control samples 1 and 3-7 into capsules to obtain the Bugemofuran capsules, wherein each capsule contains 15mg of Bugemofuran.
The prepared bregfuran capsules were packed in an aluminum bag, and left to stand at high temperature (60 ℃), high humidity (RH 92.5%) and under light (4500 Lx) for 10 days, and the amount of change in the relevant substances was measured, and the results are shown in table 17.
TABLE 17 amount of change of substances involved in the influence factor test
The results show that the control samples in which the antioxidant was sodium thiosulfate, sodium sulfite, calcium sodium edetate, sodium metabisulfite, and sodium bisulfite all exhibited lower growth of the relevant substances than control sample 1, but significantly higher growth than samples 1-10 in which the antioxidant was BHA, BHT, PG.
Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention and not to limit it; although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art will understand that: modifications to the specific embodiments of the invention or equivalent substitutions for parts of the technical features may be made; without departing from the spirit of the present invention, it is intended to cover all aspects of the invention as defined by the appended claims.
Claims (41)
1. A pharmaceutical composition comprising a substrate and a drug-containing layer, wherein:
the substrate is selected from povidone, copovidone, microcrystalline cellulose, hydroxypropyl cellulose, lactose, anhydrous calcium hydrogen phosphate, croscarmellose sodium and any combination thereof, or the substrate is a blank pill core;
the drug-containing layer comprises bulgafuran, a carrier and an antioxidant,
the antioxidant is selected from the group consisting of butylated hydroxyanisole, dibutyl hydroxytoluene, propyl gallate, and any combination thereof.
2. The pharmaceutical composition of claim 1, wherein the drug-containing layer is coated on the surface of the substrate.
3. The pharmaceutical composition of claim 1, wherein the carrier is a hydrophilic polymeric material.
4. The pharmaceutical composition of claim 3, wherein the carrier is povidone, copovidone, polyethylene glycol, or poloxamer.
5. The pharmaceutical composition of claim 4, wherein the carrier is povidone K30, copovidone, polyethylene glycol 6000, or poloxamer 188.
6. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition further comprises a coating layer, wherein the coating layer is coated on the surface of the drug-containing layer.
7. The pharmaceutical composition of claim 6, wherein the coating layer is formed from a coating material selected from the group consisting of an opadry film coating premix, hypromellose, hydroxypropyl cellulose, povidone, copovidone, and any combination thereof.
8. The pharmaceutical composition of claim 7, wherein the povidone is povidone K30.
9. The pharmaceutical composition of any one of claims 1 to 8, wherein the mass ratio of the budofuran to the carrier is 1: 3-16.
10. The pharmaceutical composition of claim 9, wherein the mass ratio of the budofuran to the carrier is 1: 3-15.
11. The pharmaceutical composition according to any one of claims 1 to 8, wherein the mass ratio of the sum of the masses of the budofuran and the carrier to the substrate in the drug-containing layer is 1: 0.1-5.
12. The pharmaceutical composition according to claim 9, wherein the mass ratio of the sum of the masses of the budofuran and the carrier to the substrate in the drug-containing layer is 1: 0.25-4.
13. The pharmaceutical composition according to claim 10, wherein the mass ratio of the sum of the masses of the budofuran and the carrier to the substrate in the drug-containing layer is 1: 0.5-4.
14. The pharmaceutical composition of claim 11, wherein the mass ratio of the sum of the mass of the budofuran and the carrier to the substrate in the drug-containing layer is 1: 1-4.
15. The pharmaceutical composition of any one of claims 1 to 8, wherein the antioxidant is present in an amount of 0.05 to 0.2% o by mass of the sum of the mass of the bregfuran, the carrier and the substrate.
16. The pharmaceutical composition of any one of claims 1 to 7, prepared by a process comprising the steps of:
1) dissolving the Bugenfuran, the carrier and the antioxidant in an organic solvent to prepare a medicine-containing solution;
2) making the substrate in a suspended fluidized state, and spraying the drug-containing solution to the fluidized substrate to make the substrate form particles and form a drug-containing layer on the surfaces of the particles;
3) spraying an aqueous solution or an aqueous solution onto the product of the previous step in a suspended fluidized state;
4) drying the product of the previous step to obtain the pharmaceutical composition.
17. The pharmaceutical composition according to claim 16, wherein the solid content of the drug-containing solution is 20-40 w/w%.
18. The pharmaceutical composition of claim 16, wherein the organic solvent is acetone or ethanol with a concentration of 75-95 v/v%.
19. The pharmaceutical composition of claim 16, wherein the aqueous solution is an aqueous solution containing a coating material.
20. The pharmaceutical composition of claim 19, wherein the coating material is selected from the group consisting of an opadry film coating premix, hypromellose, hydroxypropyl cellulose, povidone, copovidone, and any combination thereof.
21. The pharmaceutical composition of claim 20, wherein the povidone is povidone K30.
22. A solid oral formulation comprising the pharmaceutical composition of any one of claims 1-21.
23. The solid oral formulation of claim 22, wherein the solid oral formulation is a tablet, capsule, or granule.
24. A method of making a pharmaceutical composition comprising:
1) dissolving active drug, carrier and antioxidant in organic solvent to obtain drug-containing solution;
2) making the substrate in a suspended fluidized state, and spraying the drug-containing solution to the fluidized substrate to make the substrate form particles and form a drug-containing layer on the surfaces of the particles;
3) spraying an aqueous solution or an aqueous solution onto the product of the previous step in a suspended fluidized state;
4) drying the product of the previous step to obtain the pharmaceutical composition,
wherein the active drug is a budesonide,
the substrate is selected from povidone, copovidone, microcrystalline cellulose, hydroxypropyl cellulose, lactose, anhydrous calcium hydrogen phosphate, croscarmellose sodium and any combination thereof, or the substrate is a blank pellet core.
25. The method for preparing a pharmaceutical composition according to claim 24, wherein the solid content of the drug-containing solution is 20-40 w/w%.
26. The method for preparing a pharmaceutical composition according to claim 24, wherein the organic solvent is acetone or ethanol at a concentration of 75-95 v/v%.
27. The process for preparing a pharmaceutical composition according to claim 24, wherein the aqueous solution is an aqueous solution containing a coating material.
28. The method of preparing a pharmaceutical composition of claim 27, wherein the coating material is selected from the group consisting of an opadry film coating premix, hypromellose, hydroxypropyl cellulose, povidone, copovidone, and any combination thereof.
29. The process for preparing a pharmaceutical composition according to claim 28, wherein the povidone is povidone K30.
30. The method of preparing a pharmaceutical composition according to claim 24, wherein the carrier is a hydrophilic polymeric material.
31. The method of preparing a pharmaceutical composition of claim 30, wherein the carrier is povidone, copovidone, polyethylene glycol, or poloxamer.
32. The method of preparing a pharmaceutical composition of claim 31, wherein the carrier is povidone K30, copovidone, polyethylene glycol 6000, or poloxamer 188.
33. The process for preparing a pharmaceutical composition according to claim 24, wherein the antioxidant is selected from the group consisting of butylated hydroxyanisole, dibutylhydroxytoluene, propyl gallate, or any combination thereof.
34. The method for preparing a pharmaceutical composition according to claim 24, wherein the mass ratio of the active drug to the carrier is 1: 3-16.
35. The method for preparing a pharmaceutical composition according to claim 34, wherein the mass ratio of the active drug to the carrier is 1: 3-15.
36. The method for preparing a pharmaceutical composition according to claim 24, wherein the mass ratio of the sum of the mass of the active drug and the carrier to the substrate is 1: 0.1-5.
37. The method for preparing a pharmaceutical composition according to claim 36, wherein the mass ratio of the sum of the mass of the active drug and the carrier to the substrate is 1: 0.25-4.
38. The method for preparing a pharmaceutical composition according to claim 37, wherein the mass ratio of the sum of the mass of the active drug and the carrier to the mass of the substrate is 1: 0.5-4.
39. The method for preparing a pharmaceutical composition according to claim 38, wherein the mass ratio of the sum of the mass of the active drug and the carrier to the mass of the substrate is 1: 1-4.
40. The method for preparing a pharmaceutical composition according to claim 24, wherein the antioxidant is present in an amount of 0.05 to 0.2% by mass of the sum of the active drug, the carrier and the substrate.
41. Use of a pharmaceutical composition according to any one of claims 1 to 21 for the manufacture of a medicament for anxiolytic or for the treatment of anxiety disorders or anxiety disorders.
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Address after: 102600 building 7, 37 Yongwang Road, Daxing biomedical industrial base, Zhongguancun Science and Technology Park, Daxing District, Beijing Applicant after: Beijing Xiehe Pharmaceutical Co.,Ltd. Address before: 102600 building 7, 37 Yongwang Road, Daxing biomedical industrial base, Zhongguancun Science and Technology Park, Daxing District, Beijing Applicant before: Beijing Union Pharmaceutical Factory |
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