CN113274351A - Oral megestrol acetate suspension and preparation method thereof - Google Patents
Oral megestrol acetate suspension and preparation method thereof Download PDFInfo
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- CN113274351A CN113274351A CN202010106052.2A CN202010106052A CN113274351A CN 113274351 A CN113274351 A CN 113274351A CN 202010106052 A CN202010106052 A CN 202010106052A CN 113274351 A CN113274351 A CN 113274351A
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- 229960004296 megestrol acetate Drugs 0.000 title claims abstract description 84
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 title claims abstract description 84
- 239000000725 suspension Substances 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 62
- 239000008213 purified water Substances 0.000 claims abstract description 43
- 239000000375 suspending agent Substances 0.000 claims abstract description 24
- 235000003599 food sweetener Nutrition 0.000 claims abstract description 21
- 239000003765 sweetening agent Substances 0.000 claims abstract description 21
- 239000000080 wetting agent Substances 0.000 claims abstract description 20
- 239000000022 bacteriostatic agent Substances 0.000 claims abstract description 17
- 239000000796 flavoring agent Substances 0.000 claims abstract description 17
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 17
- 239000004094 surface-active agent Substances 0.000 claims abstract description 15
- 239000006172 buffering agent Substances 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims description 279
- 239000000243 solution Substances 0.000 claims description 93
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 69
- 239000000230 xanthan gum Substances 0.000 claims description 49
- 229920001285 xanthan gum Polymers 0.000 claims description 49
- 229940082509 xanthan gum Drugs 0.000 claims description 49
- 235000010493 xanthan gum Nutrition 0.000 claims description 49
- 229930006000 Sucrose Natural products 0.000 claims description 44
- 239000005720 sucrose Substances 0.000 claims description 44
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 40
- 238000000034 method Methods 0.000 claims description 36
- 238000010008 shearing Methods 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 30
- 239000002202 Polyethylene glycol Substances 0.000 claims description 25
- 229920001223 polyethylene glycol Polymers 0.000 claims description 25
- 235000005979 Citrus limon Nutrition 0.000 claims description 23
- 244000131522 Citrus pyriformis Species 0.000 claims description 23
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 23
- 235000015165 citric acid Nutrition 0.000 claims description 23
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 23
- 239000004299 sodium benzoate Substances 0.000 claims description 23
- 235000010234 sodium benzoate Nutrition 0.000 claims description 23
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 23
- 229940083575 sodium dodecyl sulfate Drugs 0.000 claims description 21
- 238000000265 homogenisation Methods 0.000 claims description 19
- 238000002156 mixing Methods 0.000 claims description 17
- 239000001509 sodium citrate Substances 0.000 claims description 15
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 15
- 239000003995 emulsifying agent Substances 0.000 claims description 12
- 239000006185 dispersion Substances 0.000 claims description 10
- 239000011259 mixed solution Substances 0.000 claims description 6
- 229940100474 polyethylene glycol 1450 Drugs 0.000 claims description 5
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
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- 239000003002 pH adjusting agent Substances 0.000 claims description 4
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- 239000003795 chemical substances by application Substances 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- 108010011485 Aspartame Proteins 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
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- 229910019142 PO4 Inorganic materials 0.000 claims description 2
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- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 claims description 2
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 239000000605 aspartame Substances 0.000 claims description 2
- 235000010357 aspartame Nutrition 0.000 claims description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 2
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- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
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- 239000004310 lactic acid Substances 0.000 claims description 2
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- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 229940113116 polyethylene glycol 1000 Drugs 0.000 claims description 2
- 229940093430 polyethylene glycol 1500 Drugs 0.000 claims description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 2
- 229940068977 polysorbate 20 Drugs 0.000 claims description 2
- 229920000053 polysorbate 80 Polymers 0.000 claims description 2
- 229940068968 polysorbate 80 Drugs 0.000 claims description 2
- 235000020374 simple syrup Nutrition 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 235000015424 sodium Nutrition 0.000 claims description 2
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 239000001433 sodium tartrate Substances 0.000 claims description 2
- 229960002167 sodium tartrate Drugs 0.000 claims description 2
- 235000011004 sodium tartrates Nutrition 0.000 claims description 2
- 239000004334 sorbic acid Substances 0.000 claims description 2
- 235000010199 sorbic acid Nutrition 0.000 claims description 2
- 229940075582 sorbic acid Drugs 0.000 claims description 2
- 229940100515 sorbitan Drugs 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 229960002920 sorbitol Drugs 0.000 claims description 2
- 229940013618 stevioside Drugs 0.000 claims description 2
- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 claims description 2
- 235000019202 steviosides Nutrition 0.000 claims description 2
- 125000000185 sucrose group Chemical group 0.000 claims description 2
- 239000001069 triethyl citrate Substances 0.000 claims description 2
- 235000013769 triethyl citrate Nutrition 0.000 claims description 2
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
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- 239000000463 material Substances 0.000 description 11
- 229940100692 oral suspension Drugs 0.000 description 11
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 8
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- 150000001298 alcohols Chemical class 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Inorganic Chemistry (AREA)
- Organic Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Biochemistry (AREA)
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- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides an oral megestrol acetate suspension and a preparation method thereof. The suspension comprises the following components: 40.0-120.0 mg/ml of megestrol acetate, 100-300 mg/ml of wetting agent, 0.05-0.5 mg/ml of surfactant, 1.0-3.0 mg/ml of suspending agent, 1.0-4.0 mg/ml of pH regulator, 0.10-0.3 g/ml of buffering agent or deflocculant, 10.0-100.0 mg/ml of sweetening agent, 1.0-3.0 mg/ml of bacteriostatic agent, a proper amount of flavoring agent and purified water. The in-vitro dissolution rate of the oral megestrol acetate suspension prepared by the invention is obviously improved, and the problem of the physical stability of the suspension is solved.
Description
Technical Field
The invention relates to the field of medicines, in particular to an oral megestrol acetate suspension and a preparation method thereof.
Background
Megestrol Acetate (MA) is a progestational drug, is mainly used for treating advanced breast cancer and advanced endometrial cancer, can improve appetite and cachexia of patients with advanced tumors, and has a certain curative effect on renal cancer, prostate cancer and ovarian cancer. Megestrol acetate is used as an insoluble medicine, and dissolution is a main step for limiting the absorption of the medicine in an organism, so that the improvement of the dissolution of the medicine can obviously improve the absorption of the medicine, thereby improving the bioavailability. Various methods are currently available to improve the bioavailability of megestrol acetate, as described in the following references:
chinese patent CN104208072A (publication number) discloses a megestrol acetate hot-melt extrusion preparation, which relates to the invention of a megestrol acetate hot-melt extrusion preparation, and the prepared megestrol acetate hot-melt extrusion preparation can obviously improve the solubility of megestrol acetate in water and improve the bioavailability thereof.
Chinese invention patent CN101671382A (publication number) discloses 'ultra-micro powder megestrol acetate and a pharmaceutical composition containing the same', wherein the invention relates to the invention of ultra-micro powder megestrol acetate with the particle size of less than 10 μm, and the ultra-micro powder megestrol acetate and pharmaceutically acceptable auxiliary materials are prepared into proper pharmaceutical dosage forms, wherein the pharmaceutical dosage forms comprise dispersible tablets, common tablets, capsules and the like.
Chinese invention patent CN1436534A (publication number) discloses a megestrol acetate soft capsule composition, wherein relates to the invention of a megestrol acetate soft capsule, the content is oily suspension, wherein the megestrol acetate uses micronized raw material medicine, the preparation has quick effect, and the defect of low bioavailability of common tablets is overcome.
Chinese invention patent CN1180521A (publication number) discloses a medicinal composition containing megestrol acetate, which relates to the invention of a medicinal composition containing megestrol acetate, and the main preparation process is that after polyethylene glycol is melted, powdery megestrol acetate and other medicinal auxiliary materials are added to prepare capsules or tablets.
Chinese patent CN105769763 provides a megestrol acetate nanosuspension. The cellulose derivative in the suspension is used as a space steric stabilizer, so that the steric hindrance between particles can be increased, the anionic surfactant is used as a charge stabilizer, the charge repulsion force between the particles is increased, the two stabilizers are used in a combined manner, the particle size of the medicine in the prepared nano suspension is small, the average particle size is less than 1000nm, the dissolution rate of megestrol acetate is remarkably improved, and the oral bioavailability of the megestrol acetate is further improved. The megestrol acetate nano suspension and other pharmaceutical excipients are prepared into granules suitable for tabletting by adopting a fluidized bed drying granulation process, and the granules are further pressed into tablets, but the problem of inconvenient administration of high-dose administration (800 mg/day) of patients still exists.
The megestrol acetate oral suspension facilitates individualized dosing scheme of patients, and the dosing dose is easy to adjust and easy to swallow, especially for tumor patients. However, poor physical stability during the shelf life of oral suspensions has been a problem and more convenient and controllable methods are needed to improve in vitro dissolution.
Disclosure of Invention
An object of the present invention is to provide an oral megestrol acetate suspension;
another object of the present invention is to provide a method for preparing an oral megestrol acetate suspension.
In order to achieve the above objects, in one aspect, the present invention provides an oral megestrol acetate suspension, wherein the suspension comprises the following components: 40.0-120.0 mg/ml of megestrol acetate, 100-300 mg/ml of wetting agent, 0.05-0.50 mg/ml of surfactant, 1.0-3.0 mg/ml of suspending agent, 1.0-4.0 mg/ml of pH regulator, 0.10-0.3 g/ml of buffering agent or deflocculant, 10.0-100.0 mg/ml of sweetening agent, 1.0-3.0 mg/ml of bacteriostatic agent, a proper amount of flavoring agent and purified water.
It is understood that the purified water of the present invention is used in a fixed volume.
According to some embodiments of the invention, the suspension comprises the following components: 40.0-100.0 mg/ml of megestrol acetate, 150-250 mg/ml of wetting agent, 0.10-0.30 mg/ml of surfactant, 1.5-2.5 mg/ml of suspending agent, 1.5-3.5 mg/ml of pH regulator, 0.10-0.2 mg/ml of buffering agent or deflocculant, 20.0-80.0 mg/ml of sweetening agent, 1.5-2.5 mg/ml of bacteriostatic agent, a proper amount of flavoring agent and purified water.
Wherein, it can be understood that the amount of the flavoring agent is a proper amount, and those skilled in the art can select the amount of the flavoring agent according to the needs, and according to some specific embodiments of the present invention, the amount of the flavoring agent is 0.1-2.0 mg/ml; according to other embodiments of the invention, the amount of flavoring agent is 0.5-1.5 mg/ml.
According to some embodiments of the invention, wherein,
the wetting agent is a polyethylene glycol wetting agent;
the surfactant is selected from one or more of triethyl citrate, sodium dodecyl sulfate, polysorbate 80, polysorbate 20, sorbitan fatty acid, glyceryl monostearate and sucrose ester;
the suspending agent is selected from one or more of acacia, starch, sodium carboxymethyl starch, xanthan gum, maltodextrin and hydroxypropyl cellulose;
the pH regulator is one or a mixture of more of malic acid, citric acid and lactic acid;
the buffering agent or the deflocculant is selected from one or a mixture of more of sodium tartrate, sodium citrate, phosphate and sodium carbonate;
the sweetener is selected from one or more of simple syrup, sucrose, aspartame, stevioside, sorbitol and mannitol;
the bacteriostatic agent is selected from one or a mixture of more of benzoic acid, sodium benzoate and sorbic acid;
the flavoring agent is one or a mixture of two of orange essence and lemon essence.
According to some embodiments of the present invention, the wetting agent is selected from one or more of polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 1450 and polyethylene glycol 2000.
According to some embodiments of the present invention, the wetting agent is polyethylene glycol 2000, the surfactant is sodium lauryl sulfate, the suspending agent is xanthan gum, the pH adjusting agent is citric acid, the buffering agent or deflocculating agent is sodium citrate, the sweetener is sucrose, the bacteriostatic agent is sodium benzoate, and the flavoring agent is lemon essence.
In another aspect, the invention also provides a preparation method of the oral megestrol acetate suspension, wherein the method comprises the following steps:
(1) preparing a first solution: dispersing a wetting agent, a surfactant and megestrol acetate into purified water to obtain a first solution;
(2) preparing a second solution: dissolving and dispersing the bacteriostatic agent, the suspending agent and the sweetening agent in purified water to obtain a second solution;
(3) mixing: pouring the second solution into the first solution, uniformly mixing at a first stirring speed, continuously adding a pH regulator, a buffering agent or a deflocculant and a flavoring agent, uniformly dispersing, fixing the volume, and stirring for at least 1h to obtain a mixed solution;
(4) homogenizing: and (4) adding purified water to the mixed solution obtained in the step (3) again to fix the volume, uniformly mixing, then carrying out high shear homogenization, and stirring for at least 1h to obtain the oral megestrol acetate suspension.
The invention adopts a preparation process of removing bubbles by low-speed stirring, improves the flocculation state, the appearance and the sedimentation volume ratio of the suspension, thereby increasing the physical stability of the suspension.
The cycling profile of the high shear homogenization process of the present invention may include a single tank cycle and a dual tank cycle.
According to some embodiments of the present invention, step (1) comprises dissolving the wetting agent in a suitable amount of purified water, then adding the surfactant and megestrol acetate in sequence, and mixing uniformly; and (2) dissolving the bacteriostatic agent into a proper amount of purified water, then adding the suspending agent and the sweetening agent, and uniformly mixing.
According to some embodiments of the present invention, the step (1) comprises adding the wetting agent into a proper amount of purified water, stirring and dissolving at 50 ℃, then adding the surfactant, stirring and dissolving, then adding the megestrol acetate, and stirring and dispersing uniformly; and (2) adding the bacteriostatic agent into a proper amount of purified water, stirring for dissolving, then adding the suspending agent and the sweetening agent, stirring for dissolving and dispersing uniformly.
According to some embodiments of the present invention, step (2) comprises dissolving the bacteriostatic agent in a suitable amount of purified water, adding the mixture of the suspending agent and the sweetener, and mixing.
According to some embodiments of the invention, the suspending agent and the sweetener are combined in equal increments.
The suspending agent and the sweetening agent are dispersed in an equivalent increasing mode and then dissolved, so that the problems of agglomeration and uneven dispersion of the suspending agent are solved.
According to some embodiments of the invention, step (3) is adding the second solution to the first solution at a rotation speed of 30-70 rpm.
According to some embodiments of the invention, step (3) is adding the second solution to the first solution at a rotation speed of 55 rpm.
According to some embodiments of the present invention, after the second solution is added to the first solution in step (3) under stirring, the pH adjusting agent, the buffering agent or the deflocculating agent, and the flavoring agent are added and uniformly dispersed at a solution temperature of not higher than 35 ℃.
According to some embodiments of the present invention, in the step (3), after the constant volume is performed, the mixture is obtained by stirring for at least 1 hour at a stirring speed of 10rpm to 20 rpm.
According to some embodiments of the present invention, in the step (3), after the constant volume is completed, the mixture is obtained by stirring for at least 1 hour at a stirring speed of 10 rpm.
According to some specific embodiments of the present invention, the high shear homogenization conditions of step (4) comprise: the rotating speed is 2800-3600 rpm, the time is 90-180 minutes, and the temperature of the shearing solution is 10-40 ℃.
According to some specific embodiments of the present invention, the high shear homogenization conditions of step (4) comprise: the shear rate was 3600rpm, the shear time was 100 minutes, and the shear solution temperature was 30 ℃.
According to some embodiments of the invention, wherein step (4) is high shear homogenization using a high shear dispersion emulsifier with three stator-rotor shearing heads in series.
According to some embodiments of the invention, step (4) is high shear homogenization using a high shear dispersion emulsifier with three stator-rotor shearing heads in series, in a single tank cycle.
The high shear dispersion emulsifier with three stator-rotor shearing heads in series may be, for example, a high shear dispersion emulsifier manufactured by frokk fluko under the equipment model FDC 3-165.
According to the invention, through the shearing process of the high-shear dispersion emulsifier designed by connecting three groups of shearing heads in series, the diameter of the shearing head is 120mm, and the in vitro dissolution speed of the suspension is improved under the condition of not changing the particle size of megestrol acetate.
According to some embodiments of the invention, the stirring speed of step (4) after high shear homogenization is 10rpm to 20 rpm.
According to some embodiments of the invention, the oral megestrol acetate suspension obtained in step (4) is stirred at a stirring speed of 10rpm-20rpm for at least 1h after high shear homogenization.
According to some embodiments of the invention, the oral megestrol acetate suspension obtained in step (4) is stirred at a stirring speed of 10rpm for at least 1h after high shear homogenization.
According to some embodiments of the present invention, the stirring time of step (4) after high shear homogenization is at least 1h, and the stirring time may be 1h, may be 10h, and may be overnight.
According to some embodiments of the invention, the method of the invention comprises:
(1) preparing a first solution: adding a proper amount of purified water into a container (a stirring tank M), adding polyethylene glycol 2000, heating to 50 ℃, stirring for dissolving, stirring at a speed of 20rpm, cooling to a temperature of less than or equal to 35 ℃, adding sodium dodecyl sulfate, stirring for dissolving, adding megestrol acetate, stirring at a speed of 55rpm, and uniformly dispersing;
(2) preparing a second solution: adding a proper amount of purified water into a container (a stirring tank N), heating to 40 ℃, adding sodium benzoate, stirring for dissolving, stirring at the speed of 20rpm, adding xanthan gum and sucrose, stirring at the speed of 55rpm, and dissolving and dispersing uniformly;
(3) mixing: adding the second solution into the first solution, keeping the temperature at 35 ℃ or lower, stirring at the speed of 55rpm, continuously stirring until the solution is uniform, adding citric acid and sodium citrate, stirring for dissolving, adding lemon essence, stirring uniformly, fixing the volume, and stirring at the low speed of 10-20 rpm for at least 1 h;
(4) homogenizing: and (3) fixing the volume of the mixed solution obtained in the step (3) again by using the residual purified water, stirring at the speed of 20rpm, uniformly mixing, and then performing high-shear homogenization at the rotation speed of 2800-3600 rpm for 90-180 minutes, wherein the temperature of the shear solution is 10-40 ℃. Stirring at the speed of 10rpm-20rpm for at least 1h to obtain the oral megestrol acetate suspension.
The preparation process principle of the invention is as follows:
in the formulation of the second solution, when the suspending agent (such as xanthan gum) enters the water, the outermost layer is in contact with the water and immediately absorbs a large amount of water, expanding the volume into a micelle while preventing other water from entering the inner layer, causing dissolution difficulties and ultimately possibly affecting the viscosity of the product. The suspending agent and the sweetener (such as sucrose) are uniformly dispersed in advance by adopting an equivalent increasing mode and then are added into a suspension system, so that the problems of agglomeration and difficult dissolution of the xanthan gum can be solved;
in the homogenizing process, the target material is fully and uniformly dispersed through the shearing process of a high-shear dispersion emulsifying machine designed by serially connecting three groups of stator and rotor shearing heads and the high-speed shearing action of the three groups of serially connected stator and rotor shearing heads. This is different from the high shear recognized by those skilled in the art, which reduces the particle size of the particles, increases the specific surface area of the particles, and increases the dissolution rate in vitro. Under the condition of controlling the high-shear homogenizing rotating speed, the particle size of the particles is not obviously changed, but the in-vitro dissolution speed of the prepared suspension is obviously improved.
The low-speed continuous stirring process slowly recovers the elastic deformation of the high-strength homogenized suspension, and simultaneously removes micro bubbles in a viscous suspension system through low-speed continuous stirring, so that the problem of the physical stability of the suspension is solved.
In conclusion, the invention provides an oral megestrol acetate suspension and a preparation method thereof. The invention has the following advantages:
in the prior art, when the suspending agent xanthan gum is directly put into water, the outermost layer is contacted with the water to immediately absorb a large amount of water, so that the volume is expanded into a micelle, and other water is prevented from entering the inner layer to cause difficulty in dissolution, and the viscosity of the product is possibly influenced finally. According to the invention, the xanthan gum and the sucrose are firstly uniformly dispersed in an equivalent increasing mode and then added into a suspension system, so that the problems of agglomeration and difficult dissolution of the xanthan gum can be solved, the preparation time is shortened, and the efficiency of the preparation process is improved;
in the prior art, the in-vitro dissolution speed is improved by adopting a common homogenization process and increasing the specific surface area of particles by reducing the particle size through shearing. According to the invention, the target material is sufficiently and uniformly dispersed by the shearing process of the high-shear dispersion emulsifier designed by the shearing heads of the three groups of stators and rotors connected in series and the high-speed shearing action of the three groups of stators and rotors connected in series. Under the condition of controlling the high-shear homogenizing rotating speed, the particle size of the particles is not obviously changed, but the in-vitro dissolution speed of the prepared suspension is obviously improved.
In the prior art, alcohols or silicone oil substances are mostly added to prepare the suspension for removing bubbles, new auxiliary materials or reagents are additionally introduced, micron-level bubbles cannot be removed, and the physical stability of the suspension is always a problem in research. The invention adopts a low-speed continuous stirring process, slowly restores the elastic deformation of the high-strength homogenized suspension, and simultaneously removes micro bubbles in a viscous suspension system through low-speed continuous stirring, thereby solving the problem of the physical stability of the suspension.
Drawings
FIG. 1 is a stability profile of example 2;
FIG. 2 is a stability profile of example 5.
Detailed Description
The following detailed description is provided for the purpose of illustrating the embodiments and the advantageous effects thereof, and is not intended to limit the scope of the present disclosure.
Example 1
| Name of material | Unit dose (mg/ml) | Percentages (weight/volume) |
| Megestrol acetate | 40.00 | 4％ |
| Polyethylene glycol 2000 | 180.00 | 18％ |
| Sodium dodecyl sulfate | 0.50 | 0.05％ |
| Sucrose | 50.00 | 5％ |
| Xanthan gum | 1.8 | 0.18％ |
| Sodium benzoate | 2.00 | 0.2％ |
| Citric acid | 2.44 | 0.244％ |
| Citric acid sodium salt | 0.17 | 0.017％ |
| Lemon essence | 0.8 | 0.08％ |
| Purified water | Proper amount of | Proper amount of |
The process is described as follows:
step 1 (preparation of first solution)
Adding part of purified water into the stirring tank (M), adding polyethylene glycol 2000 in a formula amount, heating to 50 ℃, stirring to dissolve, stirring at the speed of 20rpm, and cooling to be less than or equal to 35 ℃.
Adding the sodium dodecyl sulfate with the prescription amount, and stirring to dissolve.
The megestrol acetate with the prescription amount is added, stirred and dispersed evenly, and the stirring speed is 55 rpm.
Step 2 (preparation of second solution)
Adding a proper amount of water into the stirring tank (N), heating to 40 ℃, adding the sodium benzoate with the prescription amount, stirring to dissolve, and stirring at the speed of 20 rpm.
Directly adding xanthan gum and sucrose in the prescribed amount, adjusting the stirring speed to 55rpm, and stirring for 2 hours.
Step 3 (Mixed)
After the solution in the stirring tank (N) is transferred to the stirring tank (M), the temperature is kept to be less than or equal to 35 ℃, the stirring speed is 55rpm, and the solution is continuously stirred until the solution is uniform.
Adding citric acid and sodium citrate according to the prescription amount, and stirring for dissolving.
Adding the lemon essence according to the prescription amount, and uniformly stirring
The volume is fixed, the low-speed stirring time is 10h, and the stirring speed is 10 rpm.
Step 4 (homogeneous)
And (5) fixing the volume again, and uniformly stirring.
The product is homogenized by high shear emulsification with a high shear emulsifying device (Frouk fluko FDC3-165 high shear dispersing emulsifier) at 3600rpm for 100 min and at 30 deg.C.
Step 5 (Low speed continuous stirring)
Stirring at low speed for 10h and at 10 rpm. Megestrol acetate oral suspension is prepared.
Example 2
Mixing xanthan gum and sucrose in advance by equal amount increasing method, adding into suspension system (homogenizing 3600rpm, time 120 min)
| Name of material | Unit dose (mg/ml) | Percentages (weight/volume) |
| Megestrol acetate | 40.00 | 4％ |
| Polyethylene glycol 2000 | 180.00 | 18％ |
| Sodium dodecyl sulfate | 0.50 | 0.05％ |
| Sucrose | 50.00 | 5％ |
| Xanthan gum | 1.8 | 0.18％ |
| Sodium benzoate | 2.00 | 0.2％ |
| Citric acid | 2.44 | 0.244％ |
| Citric acid sodium salt | 0.17 | 0.017％ |
| Lemon essence | 0.8 | 0.08％ |
| Purified water | Proper amount of | Proper amount of |
The process is described as follows:
step 1 (preparation of first solution)
Adding part of purified water into the stirring tank (M), adding polyethylene glycol 2000 in a prescription amount, heating to 50 ℃, stirring at the speed of 20rpm, and cooling to be less than or equal to 35 ℃.
Adding the sodium dodecyl sulfate with the prescription amount, and stirring to dissolve.
Adding megestrol acetate according to the prescription amount, and stirring and dispersing uniformly. The stirring speed was 55 rpm.
Step 2 (preparation of second solution)
Adding a proper amount of water into the stirring tank (N), heating to 40 ℃, adding the sodium benzoate with the prescription amount, stirring to dissolve, and stirring at the speed of 20 rpm.
The xanthan gum and the sucrose in the prescription amount are pre-dispersed on the principle of equivalent incremental increase before adding, namely, the sucrose in the prescription amount and the xanthan gum in the same amount are mixed and dispersed, then the xanthan gum in the same amount as the mixture is mixed and dispersed, and the mixture is mixed by analogy. The dispersed mixture was then added to a stirring tank, and the stirring speed was adjusted to 55rpm for 1 hour.
Step 3 (Mixed)
After the solution in the stirring tank (N) is transferred to the stirring tank (M), the temperature is kept to be less than or equal to 35 ℃, the stirring speed is 55rpm, and the solution is continuously stirred until the solution is uniform.
Adding citric acid and sodium citrate according to the prescription amount, and stirring for dissolving.
Adding the lemon essence according to the prescription amount, and uniformly stirring
The volume is fixed, the low-speed stirring time is 10 hours, and the stirring speed is 10 rpm.
Step 4 (homogeneous)
And (5) fixing the volume again, and uniformly stirring.
The product is homogenized by high shear using a high shear emulsifying and dispersing device (a Frouk fluko FDC3-165 high shear dispersing and emulsifying machine), the shearing speed is 3600rpm, the shearing time is 120 minutes, and the temperature of the shearing solution is 30 ℃.
Step 5 (Low speed continuous stirring)
Stirring at low speed, wherein the low-speed stirring time is 10h, and the stirring speed is 10 rpm. Megestrol acetate oral suspension is prepared.
Example 3
Mixing xanthan gum and sucrose in advance by an equivalent increasing mode, and adding into a suspension system (homogeneous rotation speed 3600rpm, time 90 minutes)
The process is described as follows:
step 1 (preparation of first solution)
Adding part of purified water into the stirring tank (M), adding polyethylene glycol 2000 in a prescription amount, heating to 50 ℃, stirring at the speed of 20rpm, and cooling to be less than or equal to 35 ℃.
Adding the sodium dodecyl sulfate with the prescription amount, and stirring to dissolve.
Adding megestrol acetate according to the prescription amount, and stirring and dispersing uniformly. The stirring speed was 55 rpm.
Step 2 (preparation of second solution)
Adding a proper amount of water into the stirring tank (N), heating to 40 ℃, adding the sodium benzoate with the prescription amount, stirring to dissolve, and stirring at the speed of 20 rpm.
The xanthan gum and the sucrose with the prescription amount are pre-dispersed by the principle of equivalent incremental increase before the xanthan gum and the sucrose are added, and the dispersed mixture is added into a stirring tank, the stirring speed is adjusted to 55rpm, and the stirring time is 1 hour.
Step 3 (Mixed)
After the solution in the stirring tank (N) is transferred to the stirring tank (M), the temperature is kept to be less than or equal to 35 ℃, the stirring speed is 55rpm, and the solution is continuously stirred until the solution is uniform.
Adding citric acid and sodium citrate according to the prescription amount, and stirring for dissolving.
Adding the lemon essence according to the prescription amount, and uniformly stirring
The volume is fixed, the low-speed stirring time is 10 hours, and the stirring speed is 10 rpm.
Step 4 (homogeneous)
And (5) fixing the volume again, and uniformly stirring.
The product is homogenized by high shear emulsification with a high shear emulsifying device (Frouk fluko FDC3-165 high shear dispersing emulsifier) at 3600rpm for 90min and at 30 deg.C.
Step 5 (Low speed continuous stirring)
Stirring at low speed, wherein the low-speed stirring time is 10h, and the stirring speed is 10 rpm. Megestrol acetate oral suspension is prepared.
Example 4
Mixing xanthan gum and sucrose in advance by an equivalent increasing mode, and adding into a suspension system (homogenizing process rotating speed of 3600rpm, time of 70 minutes)
| Name of material | Unit dose (mg/ml) | Percentages (weight/volume) |
| Megestrol acetate | 40.00 | 4％ |
| Polyethylene glycol 2000 | 180.00 | 18％ |
| Sodium dodecyl sulfate | 0.50 | 0.05％ |
| Sucrose | 50.00 | 5％ |
| Xanthan gum | 1.8 | 0.18％ |
| Sodium benzoate | 2.00 | 0.2％ |
| Citric acid | 2.44 | 0.244％ |
| Citric acid sodium salt | 0.17 | 0.017％ |
| Lemon essence | 0.8 | 0.08％ |
| Purified water | Proper amount of | Proper amount of |
The process is described as follows:
step 1 (preparation of first solution)
Adding part of purified water into the stirring tank (M), adding polyethylene glycol 2000 in a prescription amount, heating to 50 ℃, stirring at the speed of 20rpm, and cooling to be less than or equal to 35 ℃.
Adding the sodium dodecyl sulfate with the prescription amount, and stirring to dissolve.
Adding megestrol acetate according to the prescription amount, and stirring and dispersing uniformly. The stirring speed was 55 rpm.
Step 2 (preparation of second solution)
Adding a proper amount of water into the stirring tank (N), heating to 40 ℃, adding the sodium benzoate with the prescription amount, stirring to dissolve, and stirring at the speed of 20 rpm.
The xanthan gum and the sucrose with the prescription amount are pre-dispersed by the principle of equivalent incremental increase before the xanthan gum and the sucrose are added, and the dispersed mixture is added into a stirring tank, the stirring speed is adjusted to 55rpm, and the stirring time is 1 hour.
Step 3 (Mixed)
After the solution in the stirring tank (N) is transferred to the stirring tank (M), the temperature is kept to be less than or equal to 35 ℃, the stirring speed is 55rpm, and the solution is continuously stirred until the solution is uniform.
Adding citric acid and sodium citrate according to the prescription amount, and stirring for dissolving.
Adding the lemon essence according to the prescription amount, and uniformly stirring
The volume is fixed, the low-speed stirring time is 10 hours, and the stirring speed is 10 rpm.
Step 4 (homogeneous)
And (5) fixing the volume again, and uniformly stirring.
The product was homogenized by high shear homogenizing with a high shear emulsifying and dispersing apparatus (Frouk fluko FDC3-165 high shear dispersing emulsifier) at 3600rpm for 70 minutes at a shear solution temperature of 30 ℃.
Step 5 (Low speed continuous stirring)
Stirring at low speed, wherein the low-speed stirring time is 10h, and the stirring speed is 10 rpm. Megestrol acetate oral suspension is prepared.
Example 5
Premixing xanthan gum and sucrose in equal amount increasing manner, adding into suspension system (homogenizing process rotating speed of 3200rpm for 120 min), and continuously stirring for 10 hr without low speed
| Name of material | Unit dose (mg/ml) | Percentages (weight/volume) |
| Megestrol acetate | 40.00 | 4％ |
| Polyethylene glycol 2000 | 180.00 | 18％ |
| Sodium dodecyl sulfate | 0.50 | 0.05％ |
| Sucrose | 50.00 | 5％ |
| Xanthan gum | 1.8 | 0.18％ |
| Sodium benzoate | 2.00 | 0.2％ |
| Citric acid | 2.44 | 0.244％ |
| Citric acid sodium salt | 0.17 | 0.017％ |
| Lemon essence | 0.8 | 0.08％ |
| Purified water | Proper amount of | Proper amount of |
The process is described as follows:
step 1 (preparation of first solution)
Adding part of purified water into the stirring tank (M), adding polyethylene glycol 2000 in a prescription amount, heating to 50 ℃, stirring at the speed of 20rpm, and cooling to be less than or equal to 35 ℃.
Adding the sodium dodecyl sulfate with the prescription amount, and stirring to dissolve.
Adding megestrol acetate according to the prescription amount, and stirring and dispersing uniformly. The stirring speed was 55 rpm.
Step 2 (preparation of second solution)
Adding a proper amount of water into the stirring tank (N), heating to 40 ℃, adding the sodium benzoate with the prescription amount, stirring to dissolve, and stirring at the speed of 20 rpm.
The xanthan gum and the sucrose with the prescription amount are pre-dispersed by the principle of equivalent incremental increase before the xanthan gum and the sucrose are added, and the dispersed mixture is added into a stirring tank, the stirring speed is adjusted to 55rpm, and the stirring time is 1 hour.
Step 3 (Mixed)
After the solution in the stirring tank (N) is transferred to the stirring tank (M), the temperature is kept to be less than or equal to 35 ℃, the stirring speed is 55rpm, and the solution is continuously stirred until the solution is uniform.
Adding citric acid and sodium citrate according to the prescription amount, and stirring for dissolving.
Adding the lemon essence according to the prescription amount, and uniformly stirring
The volume is fixed, the low-speed stirring time is 10 hours, and the stirring speed is 10 rpm.
Step 4 (homogeneous)
And (5) fixing the volume again, and uniformly stirring.
The product is homogenized by high shear using a high shear emulsifying and dispersing device (a Frouk fluko FDC3-165 high shear dispersing and emulsifying machine), the shearing speed is 3200rpm, the shearing time is 120 minutes, and the temperature of the shearing solution is 30 ℃. Megestrol acetate oral suspension is prepared.
Example 6
Megestrol acetate dosage is 120mg/ml
| Name of material | Unit dose (mg/ml) | Percentages (weight/volume) |
| Megestrol acetate | 120.00 | 12％ |
| Polyethylene glycol 2000 | 300.00 | 30％ |
| Sodium dodecyl sulfate | 0.50 | 0.05％ |
| Sucrose | 100.00 | 10％ |
| Xanthan gum | 3.0 | 0.3％ |
| Sodium benzoate | 3.00 | 0.3％ |
| Citric acid | 4.0 | 0.4％ |
| Citric acid sodium salt | 0.3 | 0.03％ |
| Lemon essence | 2.0 | 0.2％ |
| Purified water | Proper amount of | Proper amount of |
The process is described as follows:
step 1 (preparation of first solution)
Adding part of purified water into the stirring tank (M), adding polyethylene glycol 2000 in a prescription amount, heating to 50 ℃, stirring at the speed of 20rpm, and cooling to be less than or equal to 35 ℃.
Adding the sodium dodecyl sulfate with the prescription amount, and stirring to dissolve.
Adding megestrol acetate according to the prescription amount, and stirring and dispersing uniformly. The stirring speed was 55 rpm.
Step 2 (preparation of second solution)
Adding a proper amount of water into the stirring tank (N), heating to 40 ℃, adding the sodium benzoate with the prescription amount, stirring to dissolve, and stirring at the speed of 20 rpm.
The xanthan gum and the sucrose with the prescription amount are pre-dispersed by the principle of equivalent incremental increase before the xanthan gum and the sucrose are added, and the dispersed mixture is added into a stirring tank, the stirring speed is adjusted to 55rpm, and the stirring time is 1 hour.
Step 3 (Mixed)
After the solution in the stirring tank (N) is transferred to the stirring tank (M), the temperature is kept to be less than or equal to 35 ℃, the stirring speed is 55rpm, and the solution is continuously stirred until the solution is uniform.
Adding citric acid and sodium citrate according to the prescription amount, and stirring for dissolving.
Adding the lemon essence according to the prescription amount, and uniformly stirring
The volume is fixed, the low-speed stirring time is 10 hours, and the stirring speed is 10 rpm.
Step 4 (homogeneous)
And (5) fixing the volume again, and uniformly stirring.
The product is homogenized by high shear using a high shear emulsifying and dispersing device (a Frouk fluko FDC3-165 high shear dispersing and emulsifying machine), the shearing speed is 3600rpm, the shearing time is 120 minutes, and the temperature of the shearing solution is 30 ℃.
Step 5 (Low speed continuous stirring)
Stirring at low speed, wherein the low-speed stirring time is 10h, and the stirring speed is 10 rpm. Megestrol acetate oral suspension is prepared.
Example 7
Megestrol acetate dosage is 80mg/ml
The process is described as follows:
step 1 (preparation of first solution)
Adding part of purified water into the stirring tank (M), adding polyethylene glycol 2000 in a prescription amount, heating to 50 ℃, stirring at the speed of 20rpm, and cooling to be less than or equal to 35 ℃.
Adding the sodium dodecyl sulfate with the prescription amount, and stirring to dissolve.
Adding megestrol acetate according to the prescription amount, and stirring and dispersing uniformly. The stirring speed was 55 rpm.
Step 2 (preparation of second solution)
Adding a proper amount of water into the stirring tank (N), heating to 40 ℃, adding the sodium benzoate with the prescription amount, and stirring to dissolve. The stirring speed was 20 rpm.
The xanthan gum and the sucrose with the prescription amount are pre-dispersed by the principle of equivalent incremental increase before the xanthan gum and the sucrose are added, and the dispersed mixture is added into a stirring tank, the stirring speed is adjusted to 55rpm, and the stirring time is 1 hour.
Step 3 (Mixed)
After the solution in the stirring tank (N) is transferred to the stirring tank (M), the temperature is kept to be less than or equal to 35 ℃, the stirring speed is 55rpm, and the solution is continuously stirred until the solution is uniform.
Adding citric acid and sodium citrate according to the prescription amount, and stirring for dissolving.
Adding the lemon essence according to the prescription amount, and uniformly stirring
The volume is fixed, the low-speed stirring time is 10 hours, and the stirring speed is 10 rpm.
Step 4 (homogeneous)
And (5) fixing the volume again, and uniformly stirring.
The product is homogenized by high shear using a high shear emulsifying and dispersing device (a Frouk fluko FDC3-165 high shear dispersing and emulsifying machine), the shearing speed is 3600rpm, the shearing time is 120 minutes, and the temperature of the shearing solution is 30 ℃.
Step 5 (Low speed continuous stirring)
Stirring at low speed, wherein the low-speed stirring time is 10h, and the stirring speed is 10 rpm. Megestrol acetate oral suspension is prepared.
Example 8
The dosage of megestrol acetate is 40mg/ml, and the dosage of polyethylene glycol 2000 is 100.0mg/ml
| Name of material | Unit dose (mg/ml) | Percentages (weight/volume) |
| Megestrol acetate | 40.00 | 4％ |
| Polyethylene glycol 2000 | 100.0 | 10％ |
| Sodium dodecyl sulfate | 0.05 | 0.005％ |
| Sucrose | 10.0 | 1％ |
| Xanthan gum | 1.0 | 0.1％ |
| Sodium benzoate | 1.0 | 0.1％ |
| Citric acid | 1.0 | 0.1％ |
| Citric acid sodium salt | 0.1 | 0.01％ |
| Lemon essence | 0.1 | 0.01％ |
| Purified water | Proper amount of | Proper amount of |
The process is described as follows:
step 1 (preparation of first solution)
Adding part of purified water into the stirring tank (M), adding polyethylene glycol 2000 in a prescription amount, heating to 50 ℃, stirring at the speed of 20rpm, and cooling to be less than or equal to 35 ℃.
Adding the sodium dodecyl sulfate with the prescription amount, and stirring to dissolve.
Adding megestrol acetate according to the prescription amount, and stirring and dispersing uniformly. The stirring speed was 55 rpm.
Step 2 (preparation of second solution)
Adding a proper amount of water into the stirring tank (N), heating to 40 ℃, adding the sodium benzoate with the prescription amount, and stirring to dissolve. The stirring speed was 20 rpm.
The xanthan gum and the sucrose with the prescription amount are pre-dispersed by the principle of equivalent incremental increase before the xanthan gum and the sucrose are added, and the dispersed mixture is added into a stirring tank, the stirring speed is adjusted to 55rpm, and the stirring time is 1 hour.
Step 3 (Mixed)
After the solution in the stirring tank (N) is transferred to the stirring tank (M), the temperature is kept to be less than or equal to 35 ℃, the stirring speed is 55rpm, and the solution is continuously stirred until the solution is uniform.
Adding citric acid and sodium citrate according to the prescription amount, and stirring for dissolving.
Adding the lemon essence according to the prescription amount, and uniformly stirring
The volume is fixed, the low-speed stirring time is 10 hours, and the stirring speed is 10 rpm.
Step 4 (homogeneous)
And (5) fixing the volume again, and uniformly stirring.
The product is homogenized by high shear using a high shear emulsifying and dispersing device (a Frouk fluko FDC3-165 high shear dispersing and emulsifying machine), the shearing speed is 3600rpm, the shearing time is 120 minutes, and the temperature of the shearing solution is 30 ℃.
Step 5 (Low speed continuous stirring)
Stirring at low speed, wherein the low-speed stirring time is 10h, and the stirring speed is 10 rpm. Megestrol acetate oral suspension is prepared.
Example 9
The rotation speed of the homogenizing process is 2800rpm and the time is 180 minutes
| Name of material | Unit dose (mg/ml) | Percentages (weight/volume) |
| Megestrol acetate | 40.00 | 4％ |
| Polyethylene glycol 2000 | 180.00 | 18％ |
| Sodium dodecyl sulfate | 0.50 | 0.05％ |
| Sucrose | 50.00 | 5％ |
| Xanthan gum | 1.8 | 0.18％ |
| Sodium benzoate | 2.00 | 0.2％ |
| Citric acid | 2.44 | 0.244％ |
| Citric acid sodium salt | 0.17 | 0.017％ |
| Lemon essence | 0.8 | 0.08％ |
| Purified water | Proper amount of | Proper amount of |
The process is described as follows:
step 1 (preparation of first solution)
Adding part of purified water into the stirring tank (M), adding polyethylene glycol 2000 in a prescription amount, heating to 50 ℃, stirring at the speed of 20rpm, and cooling to be less than or equal to 35 ℃.
Adding the sodium dodecyl sulfate with the prescription amount, and stirring to dissolve.
Adding megestrol acetate according to the prescription amount, and stirring and dispersing uniformly. The stirring speed was 55 rpm.
Step 2 (preparation of second solution)
Adding a proper amount of water into the stirring tank (N), heating to 40 ℃, adding the sodium benzoate with the prescription amount, stirring to dissolve, and stirring at the speed of 20 rpm.
The xanthan gum and the sucrose with the prescription amount are pre-dispersed by the principle of equivalent incremental increase before the xanthan gum and the sucrose are added, and the dispersed mixture is added into a stirring tank, the stirring speed is adjusted to 55rpm, and the stirring time is 1 hour.
Step 3 (Mixed)
After the solution in the stirring tank (N) is transferred to the stirring tank (M), the temperature is kept to be less than or equal to 35 ℃, the stirring speed is 55rpm, and the solution is continuously stirred until the solution is uniform.
Adding citric acid and sodium citrate according to the prescription amount, and stirring for dissolving.
Adding the lemon essence according to the prescription amount, and uniformly stirring
The volume is fixed, the low-speed stirring time is 10 hours, and the stirring speed is 10 rpm.
Step 4 (homogeneous)
And (5) fixing the volume again, and uniformly stirring.
The product was homogenized by high shear homogenizing with a high shear emulsifying and dispersing apparatus (Frouk fluko FDC3-165 high shear dispersing emulsifier) at 2800rpm for 180 minutes at a shear solution temperature of 30 ℃.
Step 5 (Low speed continuous stirring)
Stirring at low speed, wherein the low-speed stirring time is 10h, and the stirring speed is 10 rpm. Megestrol acetate oral suspension is prepared.
Example 10
The wetting agent adopts polyethylene glycol 1450, the rotation speed of the homogenizing process is 3600rpm, and the time is 100 minutes
| Name of material | Unit dose (mg/ml) | Percentages (weight/volume) |
| Megestrol acetate | 40.00 | 4％ |
| Polyethylene glycol 1450 | 180.00 | 18％ |
| Sodium dodecyl sulfate | 0.50 | 0.05％ |
| Sucrose | 50.00 | 5％ |
| Xanthan gum | 1.8 | 0.18％ |
| Sodium benzoate | 2.00 | 0.2％ |
| Citric acid | 2.44 | 0.244％ |
| Citric acid sodium salt | 0.17 | 0.017％ |
| Lemon essence | 0.8 | 0.08％ |
| Purified water | Proper amount of | Proper amount of |
The process is described as follows:
step 1 (preparation of first solution)
Adding part of purified water into the stirring tank (M), adding polyethylene glycol 1450 according to the prescription amount, heating to 50 ℃, stirring at the speed of 20rpm, and cooling to be less than or equal to 35 ℃.
Adding the sodium dodecyl sulfate with the prescription amount, and stirring to dissolve.
Adding megestrol acetate according to the prescription amount, and stirring and dispersing uniformly. The stirring speed was 55 rpm.
Step 2 (preparation of second solution)
Adding a proper amount of water into the stirring tank (N), heating to 40 ℃, adding the sodium benzoate with the prescription amount, stirring to dissolve, and stirring at the speed of 20 rpm.
The xanthan gum and the sucrose with the prescription amount are pre-dispersed by the principle of equivalent incremental increase before the xanthan gum and the sucrose are added, and the dispersed mixture is added into a stirring tank, the stirring speed is adjusted to 55rpm, and the stirring time is 1 hour.
Step 3 (Mixed)
After the solution in the stirring tank (N) is transferred to the stirring tank (M), the temperature is kept to be less than or equal to 35 ℃, the stirring speed is 55rpm, and the solution is continuously stirred until the solution is uniform.
Adding citric acid and sodium citrate according to the prescription amount, and stirring for dissolving.
Adding the lemon essence according to the prescription amount, and uniformly stirring
The volume is fixed, the low-speed stirring time is 10 hours, and the stirring speed is 10 rpm.
Step 4 (homogeneous)
And (5) fixing the volume again, and uniformly stirring.
The product is homogenized by high shear emulsification with a high shear emulsifying device (Frouk fluko FDC3-165 high shear dispersing emulsifier) at 3600rpm for 100 min and at 30 deg.C.
Step 5 (Low speed continuous stirring)
Stirring at low speed, wherein the low-speed stirring time is 10h, and the stirring speed is 10 rpm. Megestrol acetate oral suspension is prepared.
Results evaluation 1:
the addition mode of the xanthan gum and the sucrose in the comparative preparation process of the example 1 and the example 2 is carried out, and the evaluation result of the intermediate of the example 1 is as follows: in the preparation of the above example 1, the addition mode of the xanthan gum and the sucrose is direct addition, and the experimental phenomenon is that the xanthan gum floats on the liquid surface and is agglomerated after being added, and has more sticky walls and sticky blades, and when the stirring time is 2 hours, a sample is taken and passes through a 50-mesh screen to find that the agglomerated xanthan gum still exists.
The intermediate results of example 2 were evaluated as: in the preparation of the above example 2, the addition mode of the xanthan gum and the sucrose is to pre-disperse the prescription amount of the xanthan gum and the sucrose in an equal incremental manner before adding, and then add the dispersed mixture into the stirring tank, and the experimental phenomenon is that the mixture floating on the liquid surface is gradually dispersed into the liquid after adding, and less adheres to the wall and the paddle blade, and the sampling is carried out by a 50-mesh screen when the stirring time is 1 hour, and the agglomerated xanthan gum is not found, so that the dispersion is uniform and the process time is short.
Results evaluation 2:
the results of detecting the particle size distribution, viscosity and dissolution curve of the homogenized product according to the difference of the homogenizing rotation speed in the comparative preparation process of the embodiment 2, the embodiment 3 and the embodiment 4 are as follows:
from the above results, it can be seen that the particle size distribution has no significant change when the homogenizing speed is 3600rpm and the homogenizing time is 90-120 min, and the f2 similarity factors of the dissolution curve are all greater than 50 and are all fitted with the commercially available product. In example 4 with a homogenization time of 70min, the dissolution was slower than that of the sample with a homogenization time of more than 90min, and the particle size distribution did not change significantly.
Results evaluation 3:
the results of comparing example 2 and example 5 with the results of whether or not the low-speed continuous stirring was performed for 10 hours after homogenization in the preparation process were as follows
| Sample (I) | Volume ratio of sedimentation after 10 days | Physical stability after 10 days | Scoring (1-5 points, best 5 points) |
| Example 2 | 0.92 | Stable flocculated state | 4.5 |
| Example 5 | < 0.9, indistinct from the limits | Obvious flocculence and multi-section hollow | 1 |
Physical stability appearance picture as follows
| Example 2 | Example 5 | |
| Physical appearance of flocculating suspension for 10 days | FIG. 1 shows a schematic view of a | FIG. 2 |
Results evaluation 4:
the evaluation of the key quality attributes of the finished products was performed for example 2 and example 6, example 7, example 8, example 9, and example 10, and the results are as follows
From the above results, the above key quality attributes of the finished product all meet the requirements.
Claims (17)
1. An oral megestrol acetate suspension, wherein the suspension comprises the following components: 40.0-120.0 mg/ml of megestrol acetate, 100-300 mg/ml of wetting agent, 0.05-0.50 mg/ml of surfactant, 1.0-3.0 mg/ml of suspending agent, 1.0-4.0 mg/ml of pH regulator, 0.10-0.3 g/ml of buffering agent or deflocculant, 10.0-100.0 mg/ml of sweetening agent, 1.0-3.0 mg/ml of bacteriostatic agent, a proper amount of flavoring agent and purified water.
2. The suspension according to claim 1, wherein the suspension comprises the following ingredients: 40.0-100.0 mg/ml of megestrol acetate, 150-250 mg/ml of wetting agent, 0.1-0.3 mg/ml of surfactant, 1.5-2.5 mg/ml of suspending agent, 1.5-3.5 mg/ml of pH regulator, 0.10-0.2 mg/ml of buffering agent or deflocculant, 20.0-80.0 mg/ml of sweetening agent, 1.5-2.5 mg/ml of bacteriostatic agent, a proper amount of flavoring agent and purified water.
3. The suspension according to claim 1 or 2,
the wetting agent is a polyethylene glycol wetting agent;
the surfactant is selected from one or more of triethyl citrate, sodium dodecyl sulfate, polysorbate 80, polysorbate 20, sorbitan fatty acid, glyceryl monostearate and sucrose ester;
the suspending agent is selected from one or more of acacia, starch, sodium carboxymethyl starch, xanthan gum, maltodextrin and hydroxypropyl cellulose;
the pH regulator is one or a mixture of more of malic acid, citric acid and lactic acid;
the buffering agent or the deflocculant is selected from one or a mixture of more of sodium tartrate, sodium citrate, phosphate and sodium carbonate;
the sweetener is selected from one or more of simple syrup, sucrose, aspartame, stevioside, sorbitol and mannitol;
the bacteriostatic agent is selected from one or a mixture of more of benzoic acid, sodium benzoate and sorbic acid;
the flavoring agent is one or a mixture of two of orange essence and lemon essence.
4. The suspension according to claim 1 or 2, wherein the wetting agent is selected from one or a mixture of polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 1450 and polyethylene glycol 2000.
5. The suspension according to claim 1 or 2, wherein the wetting agent is polyethylene glycol 2000, the surfactant is sodium lauryl sulfate, the suspending agent is xanthan gum, the pH adjusting agent is citric acid, the buffering agent or deflocculating agent is sodium citrate, the sweetening agent is sucrose, the bacteriostatic agent is sodium benzoate, and the flavoring agent is lemon essence.
6. A method of preparing an oral megestrol acetate suspension according to any one of claims 1 to 5, wherein the method comprises the steps of:
(1) preparing a first solution: dispersing a wetting agent, a surfactant and megestrol acetate into purified water to obtain a first solution;
(2) preparing a second solution: dissolving and dispersing the bacteriostatic agent, the suspending agent and the sweetening agent in purified water to obtain a second solution;
(3) mixing: pouring the second solution into the first solution, uniformly mixing at a first stirring speed, continuously adding a pH regulator, a buffering agent or a deflocculant and a flavoring agent, uniformly dispersing, fixing the volume, and stirring for at least 1h to obtain a mixed solution;
(4) homogenizing: and (4) adding purified water to the mixed solution obtained in the step (3) again to fix the volume, uniformly mixing, then carrying out high shear homogenization, and stirring for at least 1h to obtain the oral megestrol acetate suspension.
7. The preparation method according to claim 6, wherein the step (1) comprises dissolving the wetting agent in a proper amount of purified water, then sequentially adding the surfactant and megestrol acetate, and mixing uniformly; and (2) dissolving the bacteriostatic agent into a proper amount of purified water, then adding the suspending agent and the sweetening agent, and uniformly mixing.
8. The preparation method according to claim 6, wherein the step (1) comprises adding the wetting agent into a proper amount of purified water, stirring and dissolving at 50 ℃, then adding the surfactant, stirring and dissolving, then adding the megestrol acetate, and stirring and dispersing uniformly; and (2) adding the bacteriostatic agent into a proper amount of purified water, stirring for dissolving, then adding the suspending agent and the sweetening agent, stirring for dissolving and dispersing uniformly.
9. The method according to any one of claims 6 to 8, wherein step (2) comprises dissolving the bacteriostatic agent in a suitable amount of purified water, adding the uniformly mixed mixture of suspending agent and sweetener, and mixing uniformly.
10. The method of any one of claims 6 to 9, wherein the suspending agent and the sweetener are combined in equal increments.
11. The production method according to any one of claims 6 to 10, wherein the second solution is added to the first solution in step (3) at a rotation speed of 30 to 70 rpm.
12. The production method according to any one of claims 6 to 10, wherein the second solution is added to the first solution in step (3) at a rotation speed of 55 rpm.
13. The preparation method according to any one of claims 6 to 12, wherein the second solution is added to the first solution in step (3) under stirring, and then the pH adjuster, the buffer or the deflocculant, and the flavoring agent are added and uniformly dispersed at a solution temperature of not higher than 35 ℃.
14. The preparation method according to any one of claims 6 to 12, wherein the mixed solution is obtained by stirring in the step (3) at a stirring speed of 10rpm to 20rpm for at least 1 hour after the volume is fixed.
15. The preparation method according to any one of claims 6 to 12, wherein the oral megestrol acetate suspension is obtained in step (4) by stirring at a stirring speed of 10rpm to 20rpm for at least 1h after high-shear homogenization.
16. The method of any one of claims 6 to 15, wherein the conditions for high shear homogenization in step (4) comprise: the rotating speed is 2800-3600 rpm, the time is 90-180 minutes, and the temperature of the shearing solution is 10-40 ℃.
17. The method of any one of claims 6 to 16, wherein step (4) is high shear homogenisation using a high shear dispersion emulsifier having three sets of stator-rotor shearing heads in series.
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| TW202131928A (en) | 2021-09-01 |
| TWI807234B (en) | 2023-07-01 |
| CN113274351B (en) | 2024-04-12 |
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