CN117159446A - Ambroxol hydrochloride oral gel preparation, preparation method and application thereof - Google Patents
Ambroxol hydrochloride oral gel preparation, preparation method and application thereof Download PDFInfo
- Publication number
- CN117159446A CN117159446A CN202310650942.3A CN202310650942A CN117159446A CN 117159446 A CN117159446 A CN 117159446A CN 202310650942 A CN202310650942 A CN 202310650942A CN 117159446 A CN117159446 A CN 117159446A
- Authority
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- China
- Prior art keywords
- sodium
- acid
- gel
- oral gel
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229940041672 oral gel Drugs 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 52
- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 229960000985 ambroxol hydrochloride Drugs 0.000 title claims abstract description 50
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 75
- 239000000499 gel Substances 0.000 claims description 75
- 239000011159 matrix material Substances 0.000 claims description 65
- 239000000243 solution Substances 0.000 claims description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 54
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 51
- 239000008213 purified water Substances 0.000 claims description 41
- 239000000203 mixture Substances 0.000 claims description 38
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 36
- 239000003381 stabilizer Substances 0.000 claims description 26
- 238000009472 formulation Methods 0.000 claims description 25
- 229960004063 propylene glycol Drugs 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 23
- 239000006184 cosolvent Substances 0.000 claims description 22
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 18
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 18
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 18
- 230000001954 sterilising effect Effects 0.000 claims description 18
- 229960005150 glycerol Drugs 0.000 claims description 17
- 235000011187 glycerol Nutrition 0.000 claims description 17
- 235000010418 carrageenan Nutrition 0.000 claims description 15
- 239000000679 carrageenan Substances 0.000 claims description 15
- 229920001525 carrageenan Polymers 0.000 claims description 15
- 229940113118 carrageenan Drugs 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 15
- 238000004659 sterilization and disinfection Methods 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 claims description 15
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical group [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 229920002125 Sokalan® Polymers 0.000 claims description 10
- 235000020357 syrup Nutrition 0.000 claims description 10
- 239000006188 syrup Substances 0.000 claims description 10
- 229920001285 xanthan gum Polymers 0.000 claims description 10
- 239000000230 xanthan gum Substances 0.000 claims description 10
- 235000010493 xanthan gum Nutrition 0.000 claims description 10
- 229940082509 xanthan gum Drugs 0.000 claims description 10
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 9
- 229960001631 carbomer Drugs 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 8
- 235000003599 food sweetener Nutrition 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 7
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 7
- 239000004299 sodium benzoate Substances 0.000 claims description 7
- 235000010234 sodium benzoate Nutrition 0.000 claims description 7
- 239000003765 sweetening agent Substances 0.000 claims description 7
- OEGPRYNGFWGMMV-UHFFFAOYSA-N (3,4-dimethoxyphenyl)methanol Chemical compound COC1=CC=C(CO)C=C1OC OEGPRYNGFWGMMV-UHFFFAOYSA-N 0.000 claims description 6
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims description 6
- SVTBMSDMJJWYQN-UHFFFAOYSA-N 2-methylpentane-2,4-diol Chemical compound CC(O)CC(C)(C)O SVTBMSDMJJWYQN-UHFFFAOYSA-N 0.000 claims description 6
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 claims description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 6
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 claims description 6
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 claims description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 6
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 229920001615 Tragacanth Polymers 0.000 claims description 6
- 239000003963 antioxidant agent Substances 0.000 claims description 6
- 230000003078 antioxidant effect Effects 0.000 claims description 6
- 235000006708 antioxidants Nutrition 0.000 claims description 6
- 239000002738 chelating agent Substances 0.000 claims description 6
- 239000003086 colorant Substances 0.000 claims description 6
- 239000000796 flavoring agent Substances 0.000 claims description 6
- 229910021645 metal ion Inorganic materials 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 claims description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 6
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 claims description 5
- 150000004676 glycans Chemical class 0.000 claims description 5
- 229920001282 polysaccharide Polymers 0.000 claims description 5
- 239000005017 polysaccharide Substances 0.000 claims description 5
- 239000004302 potassium sorbate Substances 0.000 claims description 5
- 235000010241 potassium sorbate Nutrition 0.000 claims description 5
- 229940069338 potassium sorbate Drugs 0.000 claims description 5
- 229960003415 propylparaben Drugs 0.000 claims description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 4
- 108010010803 Gelatin Proteins 0.000 claims description 4
- 229960005174 ambroxol Drugs 0.000 claims description 4
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 claims description 4
- 239000000305 astragalus gummifer gum Substances 0.000 claims description 4
- 239000000022 bacteriostatic agent Substances 0.000 claims description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 4
- -1 dibutyl-creosol Chemical compound 0.000 claims description 4
- 229960004756 ethanol Drugs 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 4
- 239000008273 gelatin Substances 0.000 claims description 4
- 229920000159 gelatin Polymers 0.000 claims description 4
- 229940014259 gelatin Drugs 0.000 claims description 4
- 235000019322 gelatine Nutrition 0.000 claims description 4
- 235000011852 gelatine desserts Nutrition 0.000 claims description 4
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 4
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 4
- 229960002216 methylparaben Drugs 0.000 claims description 4
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 4
- 229920000573 polyethylene Polymers 0.000 claims description 4
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 4
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 4
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims description 3
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 3
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 claims description 3
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
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- 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 claims description 3
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- 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 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 3
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Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The application relates to an ambroxol hydrochloride (Ambroxol Hydrochloride) oral gel preparation, a preparation method and application thereof. Besides good bioadhesion and sustained-release effects, the gel preparation is a novel dosage form which is developed rapidly in recent years due to low production cost, high bioavailability and good taste of single-dose package, and provides convenience for administration for the aged, children and dysphagia patients.
Description
Technical Field
The application relates to the technical field of pharmacy, in particular to ambroxol hydrochloride oral gel and a preparation method thereof.
Background
Ambroxol hydrochloride (Ambroxol Hydrochloride) is an in vivo active metabolite of bromhexine, is mainly used for treating acute and chronic respiratory diseases, especially for eliminating phlegm of chronic bronchitis in clinic at present, and can obviously improve phlegm and respiratory conditions. Ambroxol injection, granule, capsule, tablet, oral solution and syrup are marketed in the market, wherein the oral solution dosage form still needs to be further excavated and developed in terms of convenient and proper performances of taking, transporting and storing.
Meanwhile, because ambroxol hydrochloride can generate ambroxol hydrochloride free alkali precipitation in the solution under the condition of oxidation or alkaline solution, the increase of precipitation substances is more obvious in the long-term storage process, so that the risk that ambroxol hydrochloride is possibly damaged by oxidation substances in the preparation process needs to be effectively reduced, and the stability of the medicine is improved.
The oral gel is a novel dosage form which has rapid development in recent years due to single dose package, low production cost, high bioavailability and good taste, provides convenient administration for the aged, children and dysphagia patients, and is an ideal administration dosage form for children or elderly patients.
Disclosure of Invention
Aiming at the problems existing in the prior art, the application provides a novel ambroxol hydrochloride oral gel preparation, and a preparation method and application thereof. In particular, the application relates to the following aspects:
1. an oral gel preparation is characterized by comprising ambroxol hydrochloride, a gel matrix, a cosolvent, a stabilizer, a pH value regulator and pharmaceutical excipients.
2. The oral gel preparation according to claim 1, wherein the ambroxol hydrochloride is 0.1 to 0.6 part by weight, the gel matrix is 0.1 to 8 parts by weight, the cosolvent is 2 to 70 parts by weight, and the stabilizer is 0.01 to 0.2 part by weight based on 100 parts by weight of the oral gel preparation.
3. The oral gel formulation according to item 1, wherein the gel matrix is selected from one or more of xanthan gum, jelly powder, konjak powder, carrageenan, agar, carbomer, hypromellose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, alginate, tragacanth gum, glycerol, gelatin, pectin, gums, ethylene polymers, non-cellulosic polysaccharides such as chitosan, poloxamer, β -cyclodextrin, preferably xanthan gum, carrageenan or carbomer.
4. The oral gel formulation according to claim 1, wherein the cosolvent is selected from one or more of propylene glycol, glycerol, ethanol, polyethylene glycol 400, polyvinyl alcohol, polysorbate 80, polysorbate 20, polysorbate 40, polysorbate 60, triethylene glycol, hexylene glycol, veratryl alcohol, span, preferably a mixture of propylene glycol and glycerol.
5. The oral gel formulation of claim 1, wherein the pH adjuster is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, boric acid, tartaric acid, maleic acid, citric acid, sodium dihydrogen phosphate, and buffered saline solutions comprising acetate, citrate, phosphate, or formate solutions.
6. The oral gel formulation according to claim 1, wherein the stabilizer comprises an antioxidant and a metal ion chelating agent, wherein the antioxidant is selected from one or more of sodium metabisulfite, ambroxol (potassium) hydrochloride, sodium formaldehyde metabisulfite, sodium thiosulfate, sodium hydroxymethane sulfonate, thioglycerol, thiourea, thioglycolic acid, tocopherol, hydroquinone, propyl gallate, t-butyl-p-hydroxyanisole, dibutyl-creosol, ascorbic acid and salts thereof, gentisic acid and salts thereof or thiosulfate, and the metal ion chelating agent is selected from disodium edetate, calcium sodium edetate or diethylenetriamine pentaacetic acid, preferably the stabilizer is sodium metabisulfite and disodium edetate.
7. The oral gel preparation according to claim 1, wherein the pharmaceutical excipients are one or more selected from the group consisting of bacteriostats, sweeteners, fragrances, colorants; wherein,
the antibacterial agent is one or more selected from sodium benzoate, potassium sorbate, methylparaben, ethylparaben, propylparaben, butylparaben, benzyl alcohol, phenethyl alcohol, phenoxyethanol, chlorobutanol, benzalkonium chloride, benzalkonium bromide, preferably hydroxyphenyl esters; or alternatively
The sweetener is selected from sucrose, mannitol, sucralose, aspartame, xylitol, xylose, lactose, maltose, glucose, fructose, sorbitol, glycerol, phyllanthin, glycyrrhizin, stevioside, saccharin sodium, glycine, alanine, cherry syrup, cinnamon syrup, citric syrup, orange peel syrup, and licorice syrup; or alternatively
The flavoring agent is selected from peppermint water, menthol, mel, fructus Citri sinensis essence, apple essence, banana essence, fructus Persicae essence, cinnamomum cassia water, oleum Caryophylli, and cardamom oil; or alternatively
The colorant is selected from lemon yellow, carmine, amaranth, and beet red.
8. The oral gel formulation according to any one of claims 1 to 7, wherein the pH of the gel formulation is 4.0 to 6.0.
9. A method of preparing an oral gel formulation according to any one of claims 1 to 8, characterized in that the method comprises the steps of:
adding a stabilizing agent and a gel matrix into purified water, and uniformly dispersing to obtain a gel matrix solution;
adding cosolvent and ambroxol hydrochloride into the purified water, dissolving, adding into the gel matrix solution, adding medicinal auxiliary materials, adjusting the pH value to 4.0-6.0, adding the rest of purified water to a set weight, stirring until the mixture is uniformly clarified, and filtering to obtain the oral gel preparation.
10. The method of claim 9, wherein the pharmaceutical adjuvant comprises a bacteriostatic agent
11. The method according to claim 9, further comprising a step of damp heat sterilization, preferably after filtration.
The application has the following beneficial effects: the proper cosolvent, stabilizer and the like are added in the formulation process of the oral gel preparation, so that the problem of precipitation during storage is effectively solved, and the risk of damage of ambroxol hydrochloride by oxidized substances during storage is effectively reduced. Furthermore, the pH value is controlled, so that the precipitation of ambroxol hydrochloride free alkali is reduced, the stability of the medicine is improved, and the life cycle of the product is prolonged. In addition, the gel provided by the application has no risk of microbial contamination by adopting single-dose packaging in commercial production, and the product has stable property and safe and reliable quality. The gel also has the unique advantage of dosage form, is semi-solid or thick liquid in shape, soft and mild in taste, and is an ideal administration dosage form for children or elderly patients.
Detailed Description
The application will be further illustrated with reference to the following examples, which are to be understood as merely further illustrating and explaining the application and are not to be construed as limiting the application.
Unless defined otherwise, technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, the materials and methods are described herein below. In case of conflict, the present specification, including definitions therein, will control and materials, methods, and examples, will control and be in no way limiting. The application is further illustrated below in connection with specific examples, which are not intended to limit the scope of the application.
The application provides an oral gel preparation, which comprises ambroxol hydrochloride, a gel matrix, a cosolvent, a stabilizer, a pH value regulator and pharmaceutical excipients.
Ambroxol hydrochloride is white to yellowish crystalline powder, almost odorless, soluble in methanol, slightly soluble in water, and slightly soluble in ethanol.
In a specific embodiment, the oral gel preparation contains 0.1 to 0.6 parts by weight of ambroxol hydrochloride, for example, 0.1, 0.15, 0.2, 0.22, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.38, 0.4, 0.45, 0.5, 0.55, 0.6 parts by weight based on 100 parts by weight of the oral gel preparation; the gel matrix is 0.1 to 8 parts by weight, and for example, may be 0.1, 0.5, 0.8, 1.0, 1.5, 2.0, 2.5, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0 parts by weight, etc.; the cosolvent is 2 to 70 parts by weight, for example, 2, 5, 10, 20, 30, 35, 40, 45, 50, 60, 70 parts by weight and the like; the stabilizer may be 0.01 to 0.2 parts by weight, for example, 0.01, 0.02, 0.05, 0.08, 0.1, 0.12, 0.15, 0.18, 0.2 parts by weight, and the like.
The gel preparation consists of medicine and matrix, and the matrix is the carrier of medicine. The gel matrix belongs to a single-phase dispersion system, has oily and aqueous components, and consists of liquid paraffin, polyethylene, colloidal silicon or aluminum soap, zinc soap and the like. The oral gel is usually selected from aqueous matrix. The choice of matrix has an important impact on the rheological properties and drug release properties of the oral gel. The water-soluble matrix is usually composed of water, glycerol or propylene glycol and cellulose derivatives, carbomers, xanthan gum, tragacanth gum, gelatin and other non-cellulose polysaccharides, and the aqueous gel matrix is mostly swelled in water to aqueous gel without dissolution, and the swelling rate in low pH environment is significantly lower than in high pH environment. The aqueous gel has smaller consistency and has the advantage of being beneficial to drug release. In a specific embodiment of the application, the oral gel matrix is an aqueous matrix.
In some preferred embodiments of the application, the gel matrix is selected from one or more of xanthan gum, jelly powder, konjak powder, carrageenan, agar, carbomer, hypromellose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, alginate, tragacanth, glycerol, gelatin, pectin, gums, ethylene polymers, non-cellulosic polysaccharides such as chitosan, poloxamer, beta-cyclodextrin.
In some specific embodiments, the gel matrix is selected from xanthan gum, carrageenan, or carbomer.
Because ambroxol hydrochloride is slightly soluble in water, the problem of solubility needs to be solved in preparing the gel preparation, and therefore, a proper cosolvent needs to be selected to ensure good solubility.
In one specific embodiment of the present application, the cosolvent may be selected from one of propylene glycol, glycerol, ethanol, polyethylene glycol 400, polyvinyl alcohol, polysorbate 80, polysorbate 20, polysorbate 40, polysorbate 60, triethylene glycol, hexylene glycol, veratryl alcohol, or span, and in other embodiments, two or more of the cosolvent may be selected.
In a preferred embodiment, the co-solvent is propylene glycol. In another preferred embodiment, the co-solvent is a mixture of propylene glycol and glycerol.
In a specific embodiment of the present application, the pH adjustor is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, boric acid, tartaric acid, maleic acid, citric acid, sodium dihydrogen phosphate, and a buffer solution thereof, wherein the buffer solution may be selected from the group consisting of acetate, citrate, phosphate, and formate solutions.
The control of pH is important for oral gels. Under the condition of oxidizing or alkaline solution, ambroxol hydrochloride can generate ambroxol hydrochloride free alkali precipitation in the solution, and related substances are obviously increased in the storage process. It was found that the pH was controlled to be 4.0 to 6.0, and for example, it was 4.0, 4.2, 4.4, 4.5, 4.6, 4.8, 5.0, 5.2, 5.4, 5.5, 5.6, 5.8, 6.0 and the like, and the gel preparation thus prepared was relatively more stable.
In a preferred embodiment, citrate, hydrochloric acid, acetic acid are selected as pH adjusting agents. More preferably, the pH regulator is a citric acid-sodium citrate buffer system.
In a specific embodiment of the present application, the stabilizer comprises an antioxidant and a metal ion chelating agent. The addition of the stabilizer can effectively reduce the risk of being damaged by oxidized substances in the gel preparation process and enhance the stability of the preparation.
In a specific embodiment, the antioxidant is selected from one or more of sodium metabisulfite, ambroxol (potassium) hydrochloride, sodium formaldehyde metabisulfite, sodium thiosulfate, sodium hydroxymethane sulfonate, thioglycerol, thiourea, thioglycolic acid and other sulfur-containing compounds, tocopherol, hydroquinone, propyl gallate, tert-butyl p-hydroxyanisole, dibutyl methylphenol, ascorbic acid and salts thereof, gentisic acid and salts thereof or thiosulfate.
In a specific embodiment, the metal ion chelating agent is selected from disodium edetate, calcium sodium edetate, or diethylenetriamine pentaacetic acid.
In a preferred embodiment, the stabilizers are sodium metabisulfite and disodium edetate.
In a specific embodiment of the present application, the pharmaceutical excipients in the gel preparation are selected from one or more than two of bacteriostat, sweetener, aromatic and colorant.
Wherein, the bacteriostat can prevent the medicine from being polluted by microorganisms during storage and ensure the quality of the medicine. In a specific embodiment, the bacteriostat is selected from one or more of sodium benzoate, potassium sorbate, methylparaben, ethylparaben, propylparaben, butylparaben, benzyl alcohol, phenethyl alcohol, phenoxyethanol, t-butyl alcohol, benzalkonium chloride, benzalkonium bromide, and in some preferred embodiments, the bacteriostat is potassium sorbate, sodium benzoate, benzyl alcohol, and a paraben. More preferably, it is methyl or propyl hydroxybenzoate.
In a specific embodiment of the present application, the sweetener may be selected from sucrose, mannitol, sucralose, aspartame, xylitol, xylose, lactose, maltose, glucose, fructose, sorbitol, glycerol, phyllanthin, glycyrrhizin, stevioside, saccharin, sodium saccharin, glycine, alanine, cherry syrup, cinnamon syrup, citric syrup, orange peel syrup, or licorice syrup.
In a specific embodiment of the present application, the flavoring agent may be selected from peppermint, menthol, honey, orange flavor, apple flavor, banana flavor, honey peach flavor, cinnamon, clove oil, or cardamon oil.
In a specific embodiment of the application, the colorant may be selected from lemon yellow, carmine, amaranth or beet red.
The application also provides a method for preparing the ambroxol hydrochloride oral gel preparation, which specifically comprises the following steps:
adding a stabilizing agent and a gel matrix into purified water, and uniformly dispersing to obtain a gel matrix solution;
adding cosolvent and ambroxol hydrochloride into the purified water, dissolving, adding into the gel matrix solution, adding medicinal auxiliary materials, adjusting the pH value to 4.0-6.0, adding the rest of purified water to a set weight, stirring until the mixture is uniformly clarified, and filtering to obtain the oral gel preparation.
Furthermore, the method for preparing the ambroxol hydrochloride oral gel preparation further comprises the step of sterilizing the gel preparation.
In some embodiments, sterilization is performed by the addition of a bacteriostatic agent. Preferably, the pharmaceutical excipients comprise a bacteriostatic agent, for example, one or more selected from potassium sorbate, sodium benzoate, benzyl alcohol or hydroxyphenyl esters, more preferably, selected from methylparaben or propylparaben.
In other embodiments, the gel formulation is sterilized by wet heat sterilization. Preferably, the total mixed solution is subjected to wet heat sterilization after being filtered.
The wet heat sterilization method is a method of sterilizing in a closed autoclave with saturated steam having a pressure higher than normal pressure. The method can kill bacterial propagules and spores, and has the advantages of reliable sterilization effect, short time and easy control.
In a specific embodiment, the total mixed solution is sterilized under heat and pressure from 115 ℃ (68 kPa) to 121 ℃ (98 kPa) for 10 to 15 minutes. For example, 115℃for 30 minutes, 121℃for 10 minutes, 121℃for 15 minutes, etc. are used.
In a preferred embodiment of the present application, the method for preparing an ambroxol hydrochloride oral gel formulation comprises the steps of:
weighing purified water with the prescription amount of 50-70%, adding a stabilizer, and slowly adding carrageenan to uniformly disperse the carrageenan to obtain gel matrix solution; and (3) adding 25% -45% of purified water into propylene glycol and ambroxol hydrochloride, stirring to dissolve, transferring into gel matrix solution, adding bacteriostat, sweetener, aromatic, pH value regulator and the like, regulating the pH value of the solution to be within the range of 4.0-6.0, adding the rest of purified water to the set weight, stirring to be clear, and filtering to obtain the oral gel preparation.
Further, in a preferred embodiment, the stabilizer is sodium metabisulfite and disodium edetate, the bacteriostat is sodium benzoate, and the pH regulator is a citric acid-sodium citrate buffer system.
Examples
Ambroxol hydrochloride used in the application is purchased from Shandong Roxin pharmaceutical group Hengxin pharmaceutical industry Co., ltd, propylene glycol and glycerol are purchased from Hunan Erkang pharmaceutical Co., ltd, and other materials, reagents and the like can be obtained from commercial approaches unless specified.
Example 1 cosolvent selection for oral gels
Ambroxol hydrochloride solutions were prepared with different solvents and their solubility was examined.
The specific experimental method comprises the following steps: 3g of ambroxol hydrochloride is weighed and slowly added into a cosolvent with a certain concentration, purified water is added to prepare 1000mL of ambroxol hydrochloride solution, the mixture is stirred uniformly, and the properties of each sample and the content of the ambroxol hydrochloride are detected. The composition and results of each solution are shown in Table 1.
Table 1: ambroxol hydrochloride solution formula and results
Numbering device | Ambroxol hydrochloride | Cosolvent | Results of traits |
Prescription 1 | 0.3% | Propylene glycol 2-70% | Clarifying the solution |
Prescription 2 | 0.3% | Propylene glycol and glycerol 2-50% + 1-30% | Clarifying the solution |
Prescription 3 | 0.3% | Propylene glycol plus polyethylene glycol 400-50% + 1-30% | Clarifying the solution |
Prescription 4 | 0.3% | Polyethylene glycol 400-80% | Clarifying the solution |
Prescription 5 | 0.3% | Propylene glycol plus polysorbate 80-50% + 1-30% | Clarifying the solution |
Prescription 6 | 0.3% | Polysorbate 80-80% | Clarifying the solution |
The experimental results show that: ambroxol hydrochloride has better solubility in the cosolvent, wherein the cosolvent with the optimal dissolution effect is a mixture of propylene glycol and glycerol.
Example 2 gel matrix selection for oral gels
The oral gel matrix is generally an aqueous matrix, and the choice of the aqueous matrix has important influence on the rheological property and drug release property of the oral gel, so that different matrix prescriptions are screened.
The specific experimental method comprises the following steps: weighing matrix components with corresponding concentration ratio according to the total 1000mL, slowly adding the matrix components into purified water, stirring and swelling to completely dissolve or uniformly disperse the matrix, and taking the matrix as a solution (1); weighing and adding active ingredient solution, and making into gel. And detecting the properties, compatibility and the like of the prepared gel matrix. The composition of each matrix and the results are shown in Table 2.
Table 2: matrix solution formulation and results
The choice of matrix is important for the gelling agent. The water-soluble matrix is usually composed of water, glycerol or propylene glycol, cellulose derivatives, carbomer, xanthan gum, tragacanth gum and the like and non-cellulose polysaccharide, and the water-based gel matrix is mostly swelled into water-based gel in water but not dissolved, the swelling rate of the hydrogel in a low pH environment is obviously lower than that in a high pH environment, the consistency of the water-based gel is smaller, and the medicine release is facilitated. The gel matrix has better physical properties. The above practical results show that the physical properties are better with the preferred xanthan gum, carrageenan or carbomer as the gel matrix.
Example 3pH Range selection
Adding 10g of carrageenan into the purified water, and uniformly dispersing to obtain gel matrix solution; adding 80g of propylene glycol and 3g of ambroxol hydrochloride into purified water, dissolving, adding into the gel matrix solution, adding 0.05g of disodium edentate, 0.1g of sodium metabisulfite, adding 2g of sodium citrate, adding 0.5mol/L of citric acid, respectively adjusting each sample to different pH values (pH 3.0, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5 and 7.0), adding the balance of purified water to a set weight, stirring until the mixture is uniformly clarified, and filtering to obtain the oral gel preparation. Respectively at 0 day, 10 days under illumination and high temperature (60deg.C) 1 Under the condition of 0 days, ambroxol hydrochloride and related substances in each sample are measured according to high performance liquid chromatography (the rule 0512 of the fourth edition of Chinese pharmacopoeia 2020), so as to examine the stability of gel products with different pH values. The specific detection results are shown in Table 3.
Table 3: results of detection of stability of liquid medicine at different pH values
The experimental results show that: the gel with different pH values has no obvious change in properties and pH values after being irradiated for 10 days and heated for 10 days, and compared with the gel with different pH values at 0 day, the impurity I of the solution is obviously increased and the content is obviously reduced after the solution is heated for 10 days under the high temperature condition of pH 4.0; the N, N' -diacetyl cystine hydrolysis impurity of the solution is increased and the content of the acetylcysteine is reduced under the condition of pH6.5, and the solution is more stable when comprehensively considering the pH value within the range of 4.0-6.0
Example 4 stabilizer selection
Adding 10g of carrageenan into the purified water, and uniformly dispersing to obtain gel matrix solution; and adding 80g of propylene glycol and 3g of ambroxol hydrochloride into the purified water, dissolving, adding the solution into the gel matrix solution, then adding different stabilizers respectively (wherein, prescription 10 is that no stabilizer is added, prescription 11 is that sodium ascorbate is 0.1%, prescription 12 is that disodium edetate is 0.005%, prescription 13 is that disodium edetate is 0.005% + sodium metabisulfite is 0.01%), adding 2g of sodium citrate and 0.5mol/L of citric acid to adjust the pH value to 4.0-6.0, adding the rest of purified water to the set weight, stirring until the mixture is uniformly clarified, and filtering to obtain the oral gel preparation. The ambroxol hydrochloride and related substances in each sample are measured according to high performance liquid chromatography (four general rules 0512 of Chinese pharmacopoeia 2020 edition) under the conditions of 0 day, illumination and high temperature (60 ℃) for 10 days respectively, so as to investigate the stability of gel products with different pH values. The specific detection results are shown in Table 4.
Table 4: screening and detecting result of stabilizer
Conclusion: the property and the pH value of the solution without the stabilizer are not obviously changed after the solution is irradiated for 10 days and at high temperature for 10 days, the impurity I, other single impurities and total impurities are obviously increased after the solution is irradiated for 10 days and at high temperature, and the content is obviously reduced; the prescription with sodium ascorbate and disodium edentate as stabilizers has no obvious change in properties, pH value and content after 10 days of illumination, and related substances are slightly increased, and the solution with disodium edentate and sodium metabisulfite added in the prescription is considered comprehensively to be relatively stable.
Example 5 Sterilization mode selection
Adding 10g of carrageenan into the purified water, and uniformly dispersing to obtain gel matrix solution; adding 80g of propylene glycol and 3g of ambroxol hydrochloride into purified water, dissolving, adding into the gel matrix solution, adding 0.05g of edetate disodium and 0.1g of sodium metabisulfite, adding 2g of sodium citrate and 0.5mol/L of citric acid to adjust the pH value to 4.0-6.0, adding the balance of purified water to a set weight, stirring until the mixture is uniformly clarified, and filtering to obtain the oral gel preparation. The three sterilization methods were respectively used for wet heat sterilization (115℃30min,121℃10min,121℃15 min). And detecting indexes such as properties, pH value, content, related substances, microorganism limit and the like of each prescription sample. The results of the sterilization process are shown in Table 5.
Table 5: detection result of sterilization method
Conclusion: the results of the sample, such as properties, pH value, content, related substances and the like, are inspected by three sterilization conditions, and are not obviously changed compared with the non-sterilized sample, and the three sterilization modes can be used as the final sterilization conditions of the product, so that the quality and safety of the product are ensured, and the product is sterilized at 115 ℃ for 30 min.
EXAMPLE 6 preparation of oral gel formulations
(1) Preparation of gel formulation sample 1:
adding 10g of carrageenan into the purified water, and uniformly dispersing to obtain gel matrix solution; adding 80g of propylene glycol and 3g of ambroxol hydrochloride into purified water, dissolving, adding into the gel matrix solution, adding 0.05g of edetate disodium and 0.1g of sodium metabisulfite, adding 2g of sodium citrate and 0.5mol/L of citric acid to adjust the pH value to 4-6, adding the balance of purified water to a set weight, stirring to be uniform and clear, and filtering to obtain the oral gel preparation.
(2) Preparation of gel formulation sample 2:
adding 10g of xanthan gum into purified water, and uniformly dispersing to obtain gel matrix solution; adding 80g of propylene glycol and 3g of ambroxol hydrochloride into purified water, dissolving, adding into the gel matrix solution, adding 0.05g of edetate disodium and 0.1g of sodium metabisulfite, adding 2g of sodium citrate and 0.5mol/L of citric acid to adjust the pH value to 4-6, adding the balance of purified water to a set weight, stirring to be uniform and clear, and filtering to obtain the oral gel preparation.
(3) Preparation of gel formulation sample 3:
adding 10g of tragacanth into purified water, and uniformly dispersing to obtain gel matrix solution; adding 80g of propylene glycol and 3g of ambroxol hydrochloride into purified water, dissolving, adding into the gel matrix solution, adding 0.05g of edetate disodium and 0.1g of sodium metabisulfite, adding 2g of sodium citrate and 0.5mol/L of citric acid to adjust the pH value to 4-6, adding the balance of purified water to a set weight, stirring to be uniform and clear, and filtering to obtain the oral gel preparation.
(4) Preparation of gel formulation sample 4:
adding 10g of carbomer into the purified water, and uniformly dispersing to obtain a gel matrix solution; adding 80g of propylene glycol and 3g of ambroxol hydrochloride into purified water, dissolving, adding into the gel matrix solution, adding 0.05g of edetate disodium and 0.1g of sodium metabisulfite, adding 2g of sodium citrate and 0.5mol/L of citric acid to adjust the pH value to 4-6, adding the balance of purified water to a set weight, stirring to be uniform and clear, and filtering to obtain the oral gel preparation.
(5) Preparation of gel formulation sample 5:
adding 10g of carrageenan into the purified water, and uniformly dispersing to obtain gel matrix solution; adding 80g of propylene glycol and 3g of ambroxol hydrochloride into purified water, dissolving, adding into the gel matrix solution, adding 0.05g of disodium edentate and 0.1g of sodium metabisulfite, adding 2g of sodium citrate and 0.5mol/L of citric acid to adjust the pH value to 4-6, adding the rest of purified water to a set weight, stirring to be uniform and clear, filtering, filling, and sterilizing at 115 ℃ for 30 minutes to obtain the oral gel preparation.
(6) Preparation of gel formulation sample 6:
adding 10g of carrageenan into the purified water, and uniformly dispersing to obtain gel matrix solution; adding 80g of propylene glycol and 3g of ambroxol hydrochloride into purified water, dissolving, adding into the gel matrix solution, adding 0.05g of disodium edentate, 0.1g of sodium metabisulfite, adding 10g of sodium benzoate, adding 2g of sodium citrate and 0.5mol/L of citric acid to adjust the pH value to 4-6, adding the balance of purified water to a set weight, stirring to be uniform and clear, and filtering to obtain the oral gel preparation.
The experimental method comprises the following steps: measuring ambroxol hydrochloride and related substances and content in each sample according to high performance liquid chromatography (China Pharmacopeia 2020 edition four general rules 0512).
Table 6: example test results
Impurity I: trans-4 (6, 8-dibromo-1, 4-dihydroquinazolin-3 (2H) -yl) cyclohexanol.
Conclusion: the results of 6 months acceleration in stability show that the properties, pH value, content and related substances have no obvious change compared with 0 day, which shows that the addition of disodium edentate and sodium metabisulfite as stabilizers can effectively reduce the increase of impurity I and related substances.
The foregoing description of the embodiments has been provided for the purpose of illustrating the general principles of the application, and is not meant to limit the application thereto, but to limit the application thereto, and any modifications, equivalents, improvements and equivalents thereof may be made without departing from the spirit and principles of the application.
Claims (11)
1. An oral gel preparation is characterized by comprising ambroxol hydrochloride, a gel matrix, a cosolvent, a stabilizer, a pH value regulator and pharmaceutical excipients.
2. The oral gel preparation according to claim 1, wherein the ambroxol hydrochloride is 0.1 to 0.6 part by weight, the gel matrix is 0.1 to 8 parts by weight, the cosolvent is 2 to 70 parts by weight, and the stabilizer is 0.01 to 0.2 part by weight based on 100 parts by weight of the oral gel preparation.
3. The oral gel formulation according to claim 1, wherein the gel matrix is selected from one or more of xanthan gum, jelly powder, konjak powder, carrageenan, agar, carbomer, hypromellose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, alginate, tragacanth gum, glycerol, gelatin, pectin, gums, ethylene polymers, non-cellulosic polysaccharides such as chitosan, poloxamer, β -cyclodextrin, preferably xanthan gum, carrageenan or carbomer.
4. The oral gel formulation according to claim 1, wherein the co-solvent is selected from one or more of propylene glycol, glycerol, ethanol, polyethylene glycol 400, polyvinyl alcohol, polysorbate 80, polysorbate 20, polysorbate 40, polysorbate 60, triethylene glycol, hexylene glycol, veratryl alcohol, span, preferably a mixture of propylene glycol and glycerol.
5. The oral gel formulation of claim 1, wherein the pH adjuster is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, boric acid, tartaric acid, maleic acid, citric acid, sodium dihydrogen phosphate, and buffered saline solutions comprising acetate, citrate, phosphate, or formate solutions.
6. The oral gel formulation according to claim 1, wherein the stabilizer comprises an antioxidant and a metal ion chelating agent, wherein the antioxidant is selected from one or more of sodium metabisulfite, ambroxol (potassium) hydrochloride, sodium formaldehyde metabisulfite, sodium thiosulfate, sodium hydroxymethane sulfonate, thioglycerol, thiourea, thioglycolic acid, tocopherol, hydroquinone, propyl gallate, t-butyl-p-hydroxyanisole, dibutyl-creosol, ascorbic acid and salts thereof, gentisic acid and salts thereof or thiosulfate, and the metal ion chelating agent is selected from disodium edetate, calcium sodium edetate or diethylenetriamine pentaacetic acid, preferably the stabilizer is sodium metabisulfite and disodium edetate.
7. The oral gel preparation according to claim 1, wherein the pharmaceutical excipients are selected from one or more of bacteriostats, sweeteners, fragrances, colorants; wherein,
the antibacterial agent is one or more selected from sodium benzoate, potassium sorbate, methylparaben, ethylparaben, propylparaben, butylparaben, benzyl alcohol, phenethyl alcohol, phenoxyethanol, chlorobutanol, benzalkonium chloride, benzalkonium bromide, preferably hydroxyphenyl esters; or alternatively
The sweetener is selected from sucrose, mannitol, sucralose, aspartame, xylitol, xylose, lactose, maltose, glucose, fructose, sorbitol, glycerol, phyllanthin, glycyrrhizin, stevioside, saccharin sodium, glycine, alanine, cherry syrup, cinnamon syrup, citric syrup, orange peel syrup, and licorice syrup; or alternatively
The flavoring agent is selected from peppermint water, menthol, mel, fructus Citri sinensis essence, apple essence, banana essence, fructus Persicae essence, cinnamomum cassia water, oleum Caryophylli, and cardamom oil; or alternatively
The colorant is selected from lemon yellow, carmine, amaranth, and beet red.
8. The oral gel formulation according to any one of claims 1 to 7, wherein the pH of the gel formulation is 4.0-6.0.
9. A method of preparing an oral gel formulation according to any one of claims 1 to 8, characterized in that the method comprises the steps of:
adding a stabilizing agent and a gel matrix into purified water, and uniformly dispersing to obtain a gel matrix solution;
adding cosolvent and ambroxol hydrochloride into the purified water, dissolving, adding into the gel matrix solution, adding medicinal auxiliary materials, adjusting the pH value to 4.0-6.0, adding the rest of purified water to a set weight, stirring until the mixture is uniformly clarified, and filtering to obtain the oral gel preparation.
10. The method of claim 9, wherein the pharmaceutical adjuvant comprises a bacteriostatic agent.
11. The method according to claim 9, further comprising a step of damp heat sterilization, preferably after filtration.
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