CN116370427A - Olopatadine hydrochloride tablet and preparation method thereof - Google Patents
Olopatadine hydrochloride tablet and preparation method thereof Download PDFInfo
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- CN116370427A CN116370427A CN202310599428.1A CN202310599428A CN116370427A CN 116370427 A CN116370427 A CN 116370427A CN 202310599428 A CN202310599428 A CN 202310599428A CN 116370427 A CN116370427 A CN 116370427A
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- olopatadine hydrochloride
- polyvinyl alcohol
- aqueous solution
- solid composition
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- HVRLZEKDTUEKQH-NOILCQHBSA-N Olopatadine hydrochloride Chemical compound Cl.C1OC2=CC=C(CC(O)=O)C=C2C(=C/CCN(C)C)\C2=CC=CC=C21 HVRLZEKDTUEKQH-NOILCQHBSA-N 0.000 title claims abstract description 64
- 229960003139 olopatadine hydrochloride Drugs 0.000 title claims abstract description 64
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 40
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 40
- 239000007864 aqueous solution Substances 0.000 claims abstract description 37
- 238000005550 wet granulation Methods 0.000 claims abstract description 21
- 239000000314 lubricant Substances 0.000 claims abstract description 15
- 239000008247 solid mixture Substances 0.000 claims abstract description 14
- 239000000945 filler Substances 0.000 claims abstract description 13
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 48
- 239000008187 granular material Substances 0.000 claims description 28
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 24
- 235000019359 magnesium stearate Nutrition 0.000 claims description 24
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 24
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 24
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 24
- 229920002472 Starch Polymers 0.000 claims description 22
- 239000008107 starch Substances 0.000 claims description 22
- 235000019698 starch Nutrition 0.000 claims description 22
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 20
- 239000008101 lactose Substances 0.000 claims description 20
- 238000002156 mixing Methods 0.000 claims description 18
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 14
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 14
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 14
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 14
- 238000003825 pressing Methods 0.000 claims description 14
- 229940083542 sodium Drugs 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 235000015424 sodium Nutrition 0.000 claims description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 229960000913 crospovidone Drugs 0.000 claims description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 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
- 229930195725 Mannitol Natural products 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 239000008119 colloidal silica Substances 0.000 claims description 2
- 239000007884 disintegrant Substances 0.000 claims description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 238000007873 sieving Methods 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 238000010981 drying operation Methods 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 16
- 239000003814 drug Substances 0.000 abstract description 14
- 229940079593 drug Drugs 0.000 abstract description 8
- 230000011218 segmentation Effects 0.000 abstract description 7
- 239000000853 adhesive Substances 0.000 abstract description 6
- 230000001070 adhesive effect Effects 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000003826 tablet Substances 0.000 description 74
- 230000000052 comparative effect Effects 0.000 description 41
- 229940032147 starch Drugs 0.000 description 20
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 19
- 229960001375 lactose Drugs 0.000 description 19
- 239000004615 ingredient Substances 0.000 description 12
- 239000000463 material Substances 0.000 description 10
- 230000004580 weight loss Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 5
- 238000000227 grinding Methods 0.000 description 5
- 238000005520 cutting process Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000007919 dispersible tablet Substances 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 201000004624 Dermatitis Diseases 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000007935 oral tablet Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 238000004080 punching Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- OHVLMTFVQDZYHP-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CN1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O OHVLMTFVQDZYHP-UHFFFAOYSA-N 0.000 description 1
- KZEVSDGEBAJOTK-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[5-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CC=1OC(=NN=1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O KZEVSDGEBAJOTK-UHFFFAOYSA-N 0.000 description 1
- WTFUTSCZYYCBAY-SXBRIOAWSA-N 6-[(E)-C-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-N-hydroxycarbonimidoyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C/C(=N/O)/C1=CC2=C(NC(O2)=O)C=C1 WTFUTSCZYYCBAY-SXBRIOAWSA-N 0.000 description 1
- UXCAQJAQSWSNPQ-XLPZGREQSA-N Alovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](F)C1 UXCAQJAQSWSNPQ-XLPZGREQSA-N 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 206010048768 Dermatosis Diseases 0.000 description 1
- 206010015218 Erythema multiforme Diseases 0.000 description 1
- 102000003834 Histamine H1 Receptors Human genes 0.000 description 1
- 108090000110 Histamine H1 Receptors Proteins 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- HVAUUPRFYPCOCA-AREMUKBSSA-O PAF Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP(O)(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-O 0.000 description 1
- 206010037083 Prurigo Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 102000003141 Tachykinin Human genes 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 201000010435 allergic urticaria Diseases 0.000 description 1
- 229950004424 alovudine Drugs 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 229940124623 antihistamine drug Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000007373 indentation Methods 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229960004114 olopatadine Drugs 0.000 description 1
- JBIMVDZLSHOPLA-LSCVHKIXSA-N olopatadine Chemical compound C1OC2=CC=C(CC(O)=O)C=C2C(=C/CCN(C)C)\C2=CC=CC=C21 JBIMVDZLSHOPLA-LSCVHKIXSA-N 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000001823 pruritic effect Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 108060008037 tachykinin Proteins 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- 229920003170 water-soluble synthetic polymer Polymers 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention provides an olopatadine hydrochloride solid composition, and relates to the technical field of medicines. The invention discloses an olopatadine hydrochloride solid composition which comprises an active component olopatadine hydrochloride, a filler, a disintegrating agent, a lubricant and a polyvinyl alcohol 5-88 aqueous solution. The preparation method has the advantages that the polyvinyl alcohol 5-88 aqueous solution with the concentration of 0.1% -10% is used as the adhesive for wet granulation tabletting, the hardness of the tablet is controlled to be 60-100N, the obtained tablet has good segmentation performance, good dissolution performance and stability, the production process is simple, and the preparation method is suitable for industrial production and clinical use.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to olopatadine hydrochloride and a preparation method thereof.
Background
Olopatadine hydrochloride is a second generation antihistamine drug, has high-efficiency antagonism of histamine H1 receptor activity, inhibits the generation and the dissociation of chemical transmitters (leukotriene, thromboxane, PAF and the like), has inhibition effect on the dissociation of neurotransmitter tachykinin, is not easy to penetrate through the blood brain barrier, has no obvious central inhibition effect, is clinically used for treating allergic rhinitis, urticaria and pruritic dermatosis (eczema, dermatitis, prurigo, skin pruritus, psoriasis vulgaris, exudative erythema multiforme), and is required to be rapidly dissolved clinically to ensure curative effect.
The oral solid tablet is the most commonly used dosage form in clinic, and is used for conveniently adjusting the dosage of medicine in clinic, reducing the treatment cost, solving the medicine taking problem of special people such as the old, children and the like, and often being used after being manually divided (called tablet splitting in pharmacy). Tablets with functional scores (meaning tablets with one or more scores to facilitate dose splitting).
Olopatadine hydrochloride is marketed in China under the name Kyowa Hakko Kirin Co., only 5mg of a standard with scores is available in an original preparation (trade name of alovudine) of Ltd, so that whether the olopatadine hydrochloride is convenient to split or not is of great significance in clinical special crowd administration and personalized treatment.
The patent CN101695480A disclosed in China relates to olopatadine hydrochloride dispersible tablets, a preparation method and a quality control method thereof, the CN101632646A discloses olopatadine hydrochloride dispersible tablets, a preparation method and a detection method thereof, and the CN110882223A discloses that the formula of the olopatadine hydrochloride dispersible tablets subjected to direct compression only focuses on the dissolution of the preparation and the condition of related substances, but does not focus on the accuracy of the split dosage of the olopatadine dispersible tablets.
Scored tablets are continuous indentations through the surface of the tablet for dividing the tablet into smaller subunits. The problems of the existing forms of scored tablets are well known. These problems include loss of active drug, inaccurate breaking of tablets, large friability of broken pieces or poor stability, etc., so that breaking of tablets is often less than ideal. Moreover, for different medicines, the properties of materials are different, so that the difficulty of breaking off is different. Breaking the wafer can enhance the compliance of clinical administration for dysphagia patients or to meet the treatment of patients who need non-full tablet quantities. However, achieving accurate dosing of the split tablets and dose flexibility in clinical use is a technical challenge faced by all split oral solid tablets: the FDA guidelines require manual and instrumental post-breaking testing, respectively, with less than 3.0% mass loss after breaking, no greater than 1.0% friability of the cut pieces, a cut-piece CU meeting USP <905> requirements, a cut-piece dissolution similar to a full piece (testing tablets with upper and lower hardness limits, respectively), a cut-piece required to remain stable in a medical drug storage case/bottle for at least 3 months, etc.
The inventor finds that in the research process, 0.1-10% (mass concentration) polyvinyl alcohol 5-88 aqueous solution is adopted as an adhesive for wet granulation tabletting, and when the hardness of the tablet is controlled to be 60-100N, the prepared segmented tablet has higher accuracy of dose division, better dissolution performance and stability, and more convenient and safer use for patients.
The polyvinyl alcohol is a water-soluble synthetic polymer, has hydrophilic groups and hydrophobic groups in molecules, has better adhesion and adhesiveness by controlling viscosity through polymerization degree and hydrolysis, and can be used as tablet film coating components, wet granulation adhesives, liquid preparation dispersing agents and the like in the pharmaceutical field. Polyvinyl alcohol is classified according to viscosity and degree of hydrolysis, and the two-digit nomenclature of the different grades consists of the viscosity at 20 ℃ (first digit) and 4% solution and the degree of hydrolysis of the polymer (second digit). Polyvinyl alcohol 5-88 shows a viscosity of 5 mPas and a degree of hydrolysis of 88%, which viscosity is suitable as a wet granulation binder and the aqueous solution stability is high, and the use of the binder as a tablet influences the hardness and wear properties of the tablet.
Hardness is the compressive strength of a tablet, i.e. its radial crushing force. The hardness has important influence on the production and quality of the medicine, and the inventor discovers that the hardness of the olopatadine hydrochloride is controlled to be 60-100N in the research, so that the segmentation performance of the tablet can be effectively improved, the manual segmentation process is smooth, and the tablet breaking of a patient is facilitated to use the medicine.
According to the invention, 0.1% -10% (mass concentration) of polyvinyl alcohol 5-88 aqueous solution is used as an adhesive for wet granulation and tabletting, and the hardness of the tablet is controlled to be 60-100N, so that the obtained tablet has good segmentation performance, good dissolution performance and stability, and simple production process, and is suitable for industrial production and clinical use.
Disclosure of Invention
Aiming at the problems, the invention provides the olopatadine hydrochloride solid composition and the preparation method thereof, and the obtained tablet has better segmentation performance, better dissolution performance and stability, simple production process and suitability for industrial production and clinical use.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
in one aspect, the invention provides an olopatadine hydrochloride solid composition comprising the active components of olopatadine hydrochloride, a filler, a disintegrant, a lubricant and an aqueous solution of polyvinyl alcohol 5-88.
Preferably, the parts by weight of the combination may be: 2-8 parts of olopatadine hydrochloride, 95-115 parts of filler, 5-12 parts of disintegrating agent, 1-4 parts of lubricant and 20-60 parts of polyvinyl alcohol 5-88 aqueous solution.
Further preferably, the parts by weight of the combination may be: 4-6 parts of olopatadine hydrochloride, 100-110 parts of filler, 6-10 parts of disintegrating agent, 1-3 parts of lubricant and 30-50 parts of polyvinyl alcohol 5-88 aqueous solution.
More preferably, the parts by weight of the combination may be: 5 parts of olopatadine hydrochloride, 105 parts of filler, 8 parts of disintegrating agent, 2 parts of lubricant and 40 parts of polyvinyl alcohol 5-88 aqueous solution.
Preferably, the filler comprises at least one of microcrystalline cellulose, lactose, starch, mannitol; further preferably, in some embodiments, the filler may be a mixture of microcrystalline cellulose and lactose or starch.
Preferably, the disintegrating agent comprises at least one of low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch and crospovidone; further preferably, the disintegrating agent may be at least one of sodium carboxymethyl starch and crospovidone.
Preferably, the lubricant comprises at least one of stearic acid, magnesium stearate, silica, colloidal silica; further preferably, the lubricant may be magnesium stearate.
Preferably, the mass concentration of the polyvinyl alcohol 5-88 aqueous solution can be 0.1% -10%; further preferably, the mass concentration of the polyvinyl alcohol 5-88 aqueous solution comprises, but is not limited to, 1%, 5% and 10%.
Preferably, the olopatadine hydrochloride content is 5mg.
On the other hand, the invention also provides a preparation method of the olopatadine hydrochloride solid composition, which comprises the following steps:
1) Mixing olopatadine hydrochloride, a filler, a disintegrating agent and a lubricant uniformly according to the formula amount;
2) Adding 5-88 aqueous solution of polyvinyl alcohol for wet granulation, drying and sieving to obtain wet granules;
3) Adding lubricant, mixing, and pressing into tablet with notched punch die, wherein the hardness of tablet is 60-100N.
Preferably, the specific operation of the drying is as follows: the wet granules are dried in an oven at 50-70 ℃ for 120-180 minutes.
Compared with the prior art, the invention has the following beneficial effects:
the olopatadine hydrochloride segmented tablet prepared by the invention has higher dosage accuracy, better dissolution performance and stability, and more convenient and safer use for patients by adding 0.1-10 percent (mass concentration) of polyvinyl alcohol 5-88 aqueous solution as an adhesive for wet granulation and tabletting and controlling the hardness of the tablet to be 60-100N.
Detailed Description
In order to make the technical means, the creation features, the achievement of the purpose and the effect of the present invention easy to understand, the present invention will be further elucidated with reference to the specific embodiments, but the following embodiments are only preferred embodiments of the present invention, not all of them. Based on the examples in the embodiments, those skilled in the art can obtain other examples without making any inventive effort, which fall within the scope of the invention. It is to be noted that the raw materials used in the present invention are all common commercial products, and the sources thereof are not particularly limited. Technical and scientific terms used in the examples have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
Example 1
Olopatadine hydrochloride was prepared using the ingredients listed in table 1.
TABLE 1
The preparation process comprises the following steps:
olopatadine hydrochloride, microcrystalline cellulose, lactose and croscarmellose sodium are uniformly mixed, 5 percent polyvinyl alcohol 5-88 aqueous solution is added for wet granulation, wet granules are dried in a 60 ℃ oven for 150 minutes, a 24-mesh sieve is used for finishing, magnesium stearate is added for uniform mixing, and a scored die is used for pressing the granules into tablets, wherein the hardness of the tablets is 60-80N.
Example 2
Olopatadine hydrochloride was prepared using the ingredients listed in table 2.
TABLE 2
| Raw and auxiliary materials | Content of each tablet (mg) |
| Olopatadine hydrochloride | 5 |
| Microcrystalline cellulose | 30 |
| Starch | 75 |
| Sodium carboxymethyl starch | 8 |
| Magnesium stearate | 2 |
| 5% aqueous solution of polyvinyl alcohol 5-88 | 40 |
The preparation process comprises the following steps:
olopatadine hydrochloride, microcrystalline cellulose, starch and sodium carboxymethyl starch are uniformly mixed, 5 percent polyvinyl alcohol 5-88 aqueous solution is added for wet granulation, wet granules are dried in a 60 ℃ oven for 150 minutes, a 24-mesh sieve is used for finishing, magnesium stearate is added for uniformly mixing, and a scored die is used for pressing the granules into tablets, wherein the hardness of the tablets is 80-100N.
Example 3
Olopatadine hydrochloride was prepared using the ingredients listed in table 3.
TABLE 3 Table 3
| Raw and auxiliary materials | Content of each tablet (mg) |
| Olopatadine hydrochloride | 5 |
| Microcrystalline cellulose | 30 |
| Starch | 75 |
| Sodium carboxymethyl starch | 8 |
| Magnesium stearate | 2 |
| 1% aqueous solution of polyvinyl alcohol 5-88 | 40 |
The preparation process comprises the following steps:
olopatadine hydrochloride, microcrystalline cellulose, starch and sodium carboxymethyl starch are uniformly mixed, 1% polyvinyl alcohol 5-88 aqueous solution is added for wet granulation, wet granules are dried in a 60 ℃ oven for 150 minutes, a 24-mesh sieve is used for finishing, magnesium stearate is added for uniformly mixing, and a scored die is used for pressing the granules into tablets, wherein the hardness of the tablets is 60-80N.
Example 4
Olopatadine hydrochloride was prepared using the ingredients listed in table 4.
TABLE 4 Table 4
| Raw and auxiliary materials | Content of each tablet (mg) |
| Olopatadine hydrochloride | 5 |
| Microcrystalline cellulose | 30 |
| Starch | 75 |
| Crosslinked povidone | 8 |
| Magnesium stearate | 2 |
| 10% aqueous solution of polyvinyl alcohol 5-88 | 40 |
The preparation process comprises the following steps:
mixing olopatadine hydrochloride, microcrystalline cellulose, starch and crosslinked povidone uniformly, adding 10% polyvinyl alcohol 5-88 aqueous solution for wet granulation, drying wet granules in a 60 ℃ oven for 150 minutes, finishing by a 24-mesh sieve, adding magnesium stearate, mixing uniformly, and pressing the granules into tablets by using a punching die with nicks, wherein the hardness of the tablets is 80-100N.
Comparative example 1
Olopatadine hydrochloride was prepared using the ingredients listed in table 5.
TABLE 5
| Raw and auxiliary materials | Content of each tablet (mg) |
| Olopatadine hydrochloride | 5 |
| Microcrystalline cellulose | 30 |
| Lactose and lactose | 75 |
| Croscarmellose sodium | 8 |
| Magnesium stearate | 2 |
| 5% polyvinyl alcohol 4-88 | 40 |
The preparation process comprises the following steps:
olopatadine hydrochloride, microcrystalline cellulose, lactose and croscarmellose sodium are uniformly mixed, 5% polyvinyl alcohol 4-88 aqueous solution is added for wet granulation, wet granules are dried in a 60 ℃ oven for 150 minutes, a 24-mesh sieve is used for finishing, magnesium stearate is added for uniform mixing, and a scored die is used for pressing the granules into tablets, wherein the hardness of the tablets is 60-80N.
Comparative example 2
Olopatadine hydrochloride was prepared using the ingredients listed in table 6.
TABLE 6
| Raw and auxiliary materials | Content of each tablet (mg) |
| Olopatadine hydrochloride | 5 |
| Microcrystalline cellulose | 30 |
| Lactose and lactose | 75 |
| Croscarmellose sodium | 8 |
| Magnesium stearate | 2 |
| Purified water | 40 |
The preparation process comprises the following steps:
mixing olopatadine hydrochloride, microcrystalline cellulose, lactose and croscarmellose sodium uniformly, adding purified water for wet granulation, drying the wet granules in a 60 ℃ oven for 150 minutes, finishing with a 24-mesh sieve, adding magnesium stearate, mixing uniformly, and pressing the granules into tablets with 60-80N hardness by using a punching die with nicks.
Comparative example 3
Olopatadine hydrochloride was prepared using the ingredients listed in table 7.
TABLE 7
| Raw and auxiliary materials | Content of each tablet (mg) |
| Olopatadine hydrochloride | 5 |
| Microcrystalline cellulose | 30 |
| Starch | 75 |
| Sodium carboxymethyl starch | 8 |
| Magnesium stearate | 2 |
| 5% aqueous solution of polyvinyl alcohol 5-88 | 40 |
The preparation process comprises the following steps:
olopatadine hydrochloride, microcrystalline cellulose, starch and sodium carboxymethyl starch are uniformly mixed, 5 percent polyvinyl alcohol 5-88 aqueous solution is added for wet granulation, wet granules are dried in a 60 ℃ oven for 150 minutes, a 24-mesh sieve is used for finishing, magnesium stearate is added for uniformly mixing, and a scored die is used for pressing the granules into tablets, wherein the hardness of the tablets is 30-50N.
Comparative example 4
Olopatadine hydrochloride was prepared using the ingredients listed in table 8.
TABLE 8
The preparation process comprises the following steps:
olopatadine hydrochloride, microcrystalline cellulose, starch and sodium carboxymethyl starch are uniformly mixed, 5 percent polyvinyl alcohol 5-88 aqueous solution is added for wet granulation, wet granules are dried in a 60 ℃ oven for 150 minutes, a 24-mesh sieve is used for finishing, magnesium stearate is added for uniformly mixing, and a scored die is used for pressing the granules into tablets, wherein the hardness of the tablets is 110-130N.
Comparative example 5
Olopatadine hydrochloride was prepared using the ingredients listed in table 9.
TABLE 9
| Raw and auxiliary materials | Content of each tablet (mg) |
| Olopatadine hydrochloride | 5 |
| Microcrystalline cellulose | 30 |
| Lactose and lactose | 75 |
| Croscarmellose sodium | 8 |
| Magnesium stearate | 2 |
| 0.01% polyvinyl alcohol 5-88 aqueous solution | 40 |
The preparation process comprises the following steps:
olopatadine hydrochloride, microcrystalline cellulose, lactose and croscarmellose sodium are uniformly mixed, 0.01% polyvinyl alcohol 5-88 aqueous solution is added for wet granulation, the wet granules are dried in a 60 ℃ oven for 150 minutes, a 24-mesh sieve is used for finishing, magnesium stearate is added for uniform mixing, and a scored die is used for pressing the granules into tablets with the hardness of 60-80N.
Comparative example 6
Olopatadine hydrochloride was prepared using the ingredients listed in table 10.
Table 10
The preparation process comprises the following steps:
olopatadine hydrochloride, microcrystalline cellulose, lactose and croscarmellose sodium are uniformly mixed, 15% polyvinyl alcohol 5-88 aqueous solution is added for wet granulation, wet granules are dried in a 60 ℃ oven for 150 minutes, a 24-mesh sieve is used for finishing, magnesium stearate is added for uniform mixing, and a scored die is used for pressing the granules into tablets, wherein the hardness of the tablets is 60-80N.
Comparative example 7
Olopatadine hydrochloride was prepared using the ingredients listed in table 11.
TABLE 11
| Raw and auxiliary materials | Content of each tablet (mg) |
| Olopatadine hydrochloride | 5 |
| Microcrystalline cellulose | 30 |
| Lactose and lactose | 75 |
| Croscarmellose sodium | 8 |
| Magnesium stearate | 2 |
| 5% aqueous solution of polyvinyl alcohol 8-88 | 40 |
The preparation process comprises the following steps:
olopatadine hydrochloride, microcrystalline cellulose, lactose and croscarmellose sodium are uniformly mixed, 5% polyvinyl alcohol 8-88 aqueous solution is added for wet granulation, wet granules are dried in a 60 ℃ oven for 150 minutes, a 24-mesh sieve is used for finishing, magnesium stearate is added for uniform mixing, and a scored die is used for pressing the granules into tablets, wherein the hardness of the tablets is 60-80N.
Comparative example 8
Olopatadine hydrochloride was prepared using the ingredients listed in table 12.
Table 12
| Raw and auxiliary materials | Content of each tablet (mg) |
| Olopatadine hydrochloride | 5 |
| Microcrystalline cellulose | 30 |
| Lactose and lactose | 75 |
| Croscarmellose sodium | 8 |
| Magnesium stearate | 2 |
| 5% aqueous solution of polyvinyl alcohol 17-88 | 40 |
The preparation process comprises the following steps:
olopatadine hydrochloride, microcrystalline cellulose, lactose and croscarmellose sodium are uniformly mixed, 5% polyvinyl alcohol 17-88 aqueous solution is added for wet granulation, wet granules are dried in a 60 ℃ oven for 150 minutes, a 24-mesh sieve is used for finishing, magnesium stearate is added for uniform mixing, and a scored die is used for pressing the granules into tablets, wherein the hardness of the tablets is 60-80N.
Test example 1
In vitro study of scored tablets
The examples, comparative examples and the original formulation alovum were studied by referring to the guidelines (trial) for design and study of functional scores of pharmaceutical-simulated oral tablets by the national drug administration drug review center 2020, 10 and 22, and using two modes of manual segmentation and blade segmentation.
(1) Weight difference
Taking 30 pieces, weighing one divided part of each piece, calculating the average weight of the rest parts, wherein the weight of the divided parts is not more than 1 which exceeds 85-115% of the average weight, and judging that the divided parts are unqualified if more than one divided part weight exceeds 85-115% of the average weight or one divided part weight exceeds 75-125% of the average weight.
Table 13 number (number) of tablets exceeding 85% -115%
| Division mode | Manual work | Blade |
| Example 1 | 0 | 0 |
| Example 2 | 0 | 0 |
| Example 3 | 0 | 0 |
| Example 4 | 0 | 0 |
| Comparative example 1 | 2 | 3 |
| Comparative example 2 | 3 | 4 |
| Comparative example 3 | 4 | 3 |
| Comparative example 4 | 2 | 3 |
| Comparative example 5 | 4 | 4 |
| Comparative example 6 | 2 | 3 |
| Comparative example 7 | 3 | 2 |
| Comparative example 8 | 5 | 4 |
| Original grinding | 0 | 0 |
(2) Content uniformity
Because the content of the main medicine in the divided part of the product is less than 25%, the content uniformity inspection should be performed according to the requirement of <0941 content uniformity inspection method in four parts of Chinese pharmacopoeia 2020 edition. Taking 10 whole sheets, taking one divided part in each sheet for content uniformity detection, and leaving other parts unused. The two methods of manual breaking and blade cutting are adopted for measurement respectively. A+2.2s should be less than 15.
TABLE 14 uniformity of content (A+2.2S value)
| Division mode | Manual work | Blade |
| Example 1 | 7.51 | 6.37 |
| Example 2 | 5.26 | 5.68 |
| Example 3 | 8.12 | 7.65 |
| Example 4 | 7.97 | 6.51 |
| Comparative example 1 | 15.18 | 16.56 |
| Comparative example 2 | 19.22 | 20.23 |
| Comparative example 3 | 17.27 | 17.61 |
| Comparative example 4 | 18.62 | 19.22 |
| Comparative example 5 | 18.31 | 19.37 |
| Comparative example 6 | 17.56 | 19.62 |
| Comparative example 7 | 16.83 | 15.98 |
| Comparative example 8 | 23.65 | 20.36 |
| Original grinding | 13.86 | 14.92 |
(3) Weight loss
15 whole tablets are taken, precisely weighed before being divided, and precisely weighed after being divided, scattered medicine scraps are removed. The weight loss was calculated by comparing the divided parts (30 half pieces) with 15 complete pieces. The two methods of manual breaking and blade cutting are adopted for measurement respectively. The weight loss should be less than 3%.
TABLE 15 weight loss (%)
(4) Friability degree of friability
About 6.5g of the tablet is taken, and the friability detection is carried out on the segmented tablet according to the four parts <0923 tablet friability detection method of the Chinese pharmacopoeia 2020 edition. The two methods of manual breaking and blade cutting are adopted for measurement respectively. The weight loss should not exceed 1%.
TABLE 16 friability (%)
| Division mode | Manual work | Blade |
| Example 1 | 0.19 | 0.25 |
| Example 2 | 0.15 | 0.20 |
| Example 3 | 0.32 | 0.26 |
| Example 4 | 0.09 | 0.17 |
| Comparative example 1 | 1.25 | 1.36 |
| Comparative example 2 | 1.53 | 1.62 |
| Comparative example 3 | 1.42 | 1.45 |
| Comparative example 4 | 1.08 | 0.98 |
| Comparative example 5 | 1.56 | 1.35 |
| Comparative example 6 | 1.21 | 1.08 |
| Comparative example 7 | 1.31 | 1.45 |
| Comparative example 8 | 0.78 | 1.02 |
| Original grinding | 0.52 | 0.42 |
(5) Dissolution rate
The dissolution conditions specified for olopatadine hydrochloride in the japanese pharmacopoeia (JP 18) are selected: the dissolution device adopts a paddle method and uses a sedimentation basket, the dissolution medium is water, the volume of the dissolution medium is 900ml, the dissolution temperature is 37+/-0.5 ℃, the dissolution degree of an undivided tablet is inspected, the dissolution degree of a divided tablet produced by cutting the two dividing modes of manual tablet breaking and blade is inspected, and the dissolution degree of the divided tablet is not less than 85% in 15 minutes.
Table 17 dissolution results (n=12)
(6) Stability study
According to the recommended investigation conditions of 25 ℃ +/-2 ℃/60%RH+/-5%RH in the functional score design and research technical guidelines (trial) of chemical imitation drug oral tablets issued by a drug examination center, placing the segmented parts into a high-density polyethylene bottle, unsealing, closing a bottle cap, and investigating the stability of the bottle cap for 90 days, and investigating the related substances.
Table 18 stability investigation results (%)
| Time point | 0d | 90d |
| Example 1 | 0.15 | 0.21 |
| Example 2 | 0.13 | 0.25 |
| Example 3 | 0.08 | 0.16 |
| Example 4 | 0.11 | 0.18 |
| Comparative example 1 | 0.09 | 0.26 |
| Comparative example 2 | 0.16 | 0.53 |
| Comparative example 3 | 0.11 | 0.31 |
| Comparative example 4 | 0.10 | 0.35 |
| Comparative example 5 | 0.13 | 0.44 |
| Comparative example 6 | 0.08 | 0.27 |
| Comparative example 7 | 0.11 | 0.21 |
| Comparative example 8 | 0.12 | 0.19 |
| Original grinding | 0.15 | 0.27 |
The results show that the wet granulation tabletting method uses 0.1-10% (mass concentration) polyvinyl alcohol 5-88 aqueous solution as the adhesive, and the weight difference, content uniformity, weight loss, friability and dissolution degree of the segmented tablet obtained by controlling the tablet hardness to be 60-100N meet the requirements, and the segmented tablet is stable after being placed for 90 days. And is superior to the original grinding preparation in content uniformity, weight loss and friability after being divided.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.
Claims (10)
1. The olopatadine hydrochloride solid composition is characterized by comprising an active component olopatadine hydrochloride, a filler, a disintegrating agent, a lubricant and a polyvinyl alcohol 5-88 aqueous solution.
2. The solid composition according to claim 1, wherein the combination comprises, in parts by weight: 2-8 parts of olopatadine hydrochloride, 95-115 parts of filler, 5-12 parts of disintegrating agent, 1-4 parts of lubricant and 20-60 parts of polyvinyl alcohol 5-88 aqueous solution.
3. The solid composition according to claim 2, wherein the combination comprises, in parts by weight: 4-6 parts of olopatadine hydrochloride, 100-110 parts of filler, 6-10 parts of disintegrating agent, 1-3 parts of lubricant and 30-50 parts of polyvinyl alcohol 5-88 aqueous solution.
4. The solid composition of claim 1, wherein the filler comprises at least one of microcrystalline cellulose, lactose, starch, and mannitol.
5. The solid composition of claim 1, wherein the disintegrant comprises at least one of low substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, crospovidone.
6. The solid composition of claim 1, wherein the lubricant comprises at least one of stearic acid, magnesium stearate, silica, colloidal silica.
7. The solid composition according to claim 1, wherein the aqueous solution of polyvinyl alcohol 5-88 has a mass concentration of 0.1% -10%.
8. The solid composition of claim 1, wherein the olopatadine hydrochloride is present in an amount of 5mg.
9. A process for the preparation of an olopatadine hydrochloride solid composition comprising the steps of:
1) Mixing olopatadine hydrochloride, a filler, a disintegrating agent and a lubricant uniformly according to the formula amount;
2) Adding 5-88 aqueous solution of polyvinyl alcohol for wet granulation, drying and sieving to obtain wet granules;
3) Adding lubricant, mixing, and pressing into tablet with notched punch die, wherein the hardness of tablet is 60-100N.
10. The preparation method according to claim 9, wherein the specific drying operation is as follows: the wet granules are dried in an oven at 50-70 ℃ for 120-180 minutes.
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| CN202310599428.1A CN116370427A (en) | 2023-05-25 | 2023-05-25 | Olopatadine hydrochloride tablet and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310599428.1A CN116370427A (en) | 2023-05-25 | 2023-05-25 | Olopatadine hydrochloride tablet and preparation method thereof |
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