CN111759806A - Compound ketoconazole suspension spray and preparation method thereof - Google Patents
Compound ketoconazole suspension spray and preparation method thereof Download PDFInfo
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- CN111759806A CN111759806A CN202010824060.0A CN202010824060A CN111759806A CN 111759806 A CN111759806 A CN 111759806A CN 202010824060 A CN202010824060 A CN 202010824060A CN 111759806 A CN111759806 A CN 111759806A
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- suspension spray
- ketoconazole
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- compound ketoconazole
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- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 title claims abstract description 123
- 229960004125 ketoconazole Drugs 0.000 title claims abstract description 123
- 239000007921 spray Substances 0.000 title claims abstract description 91
- 239000000725 suspension Substances 0.000 title claims abstract description 90
- 150000001875 compounds Chemical class 0.000 title claims abstract description 83
- 238000002360 preparation method Methods 0.000 title claims description 22
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 claims abstract description 37
- CAOOISJXWZMLBN-PPHPATTJSA-N htn0d03vrz Chemical compound Cl.C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 CAOOISJXWZMLBN-PPHPATTJSA-N 0.000 claims abstract description 36
- 239000003381 stabilizer Substances 0.000 claims abstract description 20
- 239000000375 suspending agent Substances 0.000 claims abstract description 18
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical group [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 18
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- 230000000694 effects Effects 0.000 abstract description 21
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- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 8
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- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 3
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- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
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- 241000588652 Neisseria gonorrhoeae Species 0.000 description 1
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- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 206010039101 Rhinorrhoea Diseases 0.000 description 1
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- 241001085826 Sporotrichum Species 0.000 description 1
- 241000223238 Trichophyton Species 0.000 description 1
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- 229940047650 haemophilus influenzae Drugs 0.000 description 1
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- 238000000265 homogenisation Methods 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000007373 indentation Methods 0.000 description 1
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- 230000004048 modification Effects 0.000 description 1
- 239000006070 nanosuspension Substances 0.000 description 1
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- 230000019612 pigmentation Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61K9/10—Dispersions; Emulsions
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P17/04—Antipruritics
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- A61P31/10—Antimycotics
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- B82—NANOTECHNOLOGY
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- B82Y40/00—Manufacture or treatment of nanostructures
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
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- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
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Abstract
The compound ketoconazole suspension spray adopts the synergistic administration of ketoconazole, levofloxacin hydrochloride and chlorphenamine maleate, and can obviously improve the treatment effect on contact dermatitis; the suspension spray prepared can obviously improve the bioavailability of the medicine and is very convenient for the application of skin mucosa; in addition, the stability of the spray can be obviously improved by adding a suspending agent, a stabilizing agent and a pH regulator.
Description
Technical Field
The invention belongs to the technical field of pharmacy, and particularly relates to a compound ketoconazole suspension spray and a preparation method thereof.
Background
Contact dermatitis is an inflammatory response that occurs at the site of contact, even to an external site, after a single or multiple exposure of the skin or mucosa to an exogenous substance. The clinical symptoms comprise skin red swelling, pimple, blister, itching, pain, burning sensation and the like, and the common complication is infection. The clinical treatment mainly comprises drug treatment, and avoids allergen and irritation.
Most of the existing ketoconazole suspensions or compound ketoconazole suspensions for treating contact dermatitis still have the problems of poor stability, low bioavailability or poor effect of treating contact dermatitis.
Disclosure of Invention
The embodiment of the invention provides a compound ketoconazole suspension spray, aiming at solving the problems of poor stability, low bioavailability or poor effect of treating contact dermatitis of most of the existing ketoconazole suspensions or compound ketoconazole suspensions for treating contact dermatitis.
The embodiment of the invention is realized in such a way that the compound ketoconazole suspension spray comprises the following components in parts by weight: 8-12 parts of ketoconazole, 4-6 parts of levofloxacin hydrochloride, 3-5 parts of chlorphenamine maleate, 5.5-11 parts of a suspending agent, 0.1-1 part of a stabilizer and 650-1150 parts of a pH regulator.
The embodiment of the invention also provides a preparation method of the compound ketoconazole suspension spray, which comprises the following steps:
weighing the components according to the formula of the compound ketoconazole suspension spray;
dissolving the crushed and sieved ketoconazole by using a pH regulator, stirring and shearing to obtain a solution A;
dissolving levofloxacin hydrochloride and chlorphenamine maleate in pure water, adding suspending agent and stabilizer, and stirring to obtain solution B;
and adding the solution B into the solution A, and homogenizing under high pressure to obtain the compound ketoconazole suspension spray.
The compound ketoconazole suspension spray provided by the embodiment of the invention adopts the synergistic administration of ketoconazole, levofloxacin hydrochloride and chlorphenamine maleate, and can obviously improve the treatment effect on contact dermatitis; the suspension spray prepared can obviously improve the bioavailability of the medicine and is very convenient for the application of skin mucosa; in addition, the stability of the spray can be obviously improved by adding a suspending agent, a stabilizing agent and a pH regulator.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The compound ketoconazole suspension spray provided by the embodiment of the invention adopts the synergistic administration of ketoconazole, levofloxacin hydrochloride and chlorphenamine maleate, and can obviously improve the treatment effect on contact dermatitis; the suspension spray prepared can obviously improve the bioavailability of the medicine and is very convenient for the application of skin mucosa; in addition, the stability of the spray can be obviously improved by adding a suspending agent, a stabilizing agent and a pH regulator.
The embodiment of the invention provides a compound ketoconazole suspension spray which comprises the following components in parts by weight: 8-12 parts of ketoconazole, 4-6 parts of levofloxacin hydrochloride, 3-5 parts of chlorphenamine maleate, 5.5-11 parts of a suspending agent, 0.1-1 part of a stabilizer and 650-1150 parts of a pH regulator.
Ketoconazole, a pyrrole antifungal agent, has antibacterial effects against deep infection fungi such as Candida, Coccomydia, Coccidioides, Histoplasma, Sporotrichum, etc., and also has antibacterial activity against Trichophyton trichophyton, etc. Levofloxacin hydrochloride is one of quinolone drugs, has broad-spectrum antibacterial action and strong antibacterial action, and has strong antibacterial activity on most enterobacteriaceae bacteria, such as gram-negative bacteria, such as escherichia coli, klebsiella, proteus, salmonella, shigella, haemophilus influenzae, legionella pneumophila, neisseria gonorrhoeae and the like. Chlorpheniramine maleate (also called chlorpheniramine maleate) is an antihistamine drug. The product of the invention has antiallergic effect by antagonizing H1 receptor, and is mainly used for rhinitis, skin mucosa allergy and relieving cold symptoms such as lacrimation, sneeze, watery nasal discharge and the like. Clinical tests prove that the three medicines can effectively treat the contact dermatitis by combined administration.
In a preferred embodiment of the invention, the suspending agent is sodium carboxymethylcellulose and glycerol. The stabilizing agent is tween 80. The pH regulator comprises 0.1moL/L hydrochloric acid and 1moL/L sodium hydroxide.
In the preferred embodiment of the invention, the composition comprises the following components in parts by weight: 9-11 parts of ketoconazole, 5-6 parts of levofloxacin hydrochloride, 4-5 parts of chlorphenamine maleate, 8-11 parts of a suspending agent, 0.1-0.5 part of a stabilizer and 850-1100 parts of a pH regulator.
More preferably, the paint comprises the following components in parts by weight: 10-11 parts of ketoconazole, 5-6 parts of levofloxacin hydrochloride, 4-5 parts of chlorphenamine maleate, 9-11 parts of a suspending agent, 0.1-0.5 part of a stabilizer and 975-1100 parts of a pH regulator.
Preferably, the paint comprises the following components in parts by weight: 8-12 parts of ketoconazole, 4-6 parts of levofloxacin hydrochloride, 3-5 parts of chlorphenamine maleate, 5.5-11 parts of a suspending agent, 0.1-1 part of a stabilizing agent, 650-1150 parts of a pH regulator and 0.065-0.16 part of a coloring agent.
Wherein the colorant is one or more of amaranth pigment, lemon yellow pigment or bright melanin.
Preferably, the average particle size of insoluble particles in the compound ketoconazole suspension spray prepared by the embodiment of the invention is 280-350 nm. More preferably, the average particle size of insoluble particles in the compound ketoconazole suspension spray is 280 nm.
The embodiment of the invention also provides a preparation method of the compound ketoconazole suspension spray, which comprises the following steps:
step 101, weighing the components according to the formula of the compound ketoconazole suspension spray.
And step 102, dissolving the crushed and sieved ketoconazole by using a pH regulator, stirring and shearing to obtain a solution A.
103, dissolving levofloxacin hydrochloride and chlorphenamine maleate in pure water, adding a suspending agent and a stabilizing agent, and uniformly stirring to obtain solution B.
And step 104, adding the solution B into the solution A, and homogenizing under high pressure to obtain the compound ketoconazole suspension spray. And specifically, adding the solution B into the solution A for homogenizing for 2 times by adopting an ATS high-pressure homogenizer at the normal temperature and 1200bar to obtain the compound ketoconazole suspension spray.
In step 102, the ketoconazole may be pulverized by a particle pulverizer and then sieved by a 200-mesh sieve, and then the ketoconazole with the formula amount is weighed for use.
In step 104, a high-pressure homogenizer may be used to homogenize the solution a and the solution B.
The compound ketoconazole suspension spray prepared by the pH-dependent dissolution-precipitation method and the high-pressure homogenization technology is a nano suspension, wherein the average particle size of insoluble particles is 280-350 nm, the stability is high, the bioavailability of insoluble drugs can be obviously improved, and the treatment effect of treating contact dermatitis is improved.
Examples of certain embodiments of the invention are given below, which are not intended to limit the scope of the invention.
In addition, it should be noted that the numerical values given in the following examples are as precise as possible, but those skilled in the art will understand that each numerical value should be understood as a divisor rather than an absolutely exact numerical value due to measurement errors and experimental operational problems that cannot be avoided. For example, due to errors in weighing the apparatus, it should be understood that the weight values of the components in the compound ketoconazole suspension spray of each example may have errors of ± 2% or ± 1%.
Example 1
The formula of the compound ketoconazole suspension spray of the embodiment is as follows:
11 parts of ketoconazole, 5.3 parts of levofloxacin hydrochloride, 5 parts of chlorpheniramine maleate, 2 parts of sodium carboxymethylcellulose, 5 parts of glycerol, 801 parts of tween, 900 parts of 0.1moL/L hydrochloric acid and 100 parts of 1moL/L sodium hydroxide.
The preparation process of the compound ketoconazole suspension spray of the embodiment is as follows:
swelling sodium carboxymethylcellulose with pure water, and standing overnight for use.
The ketoconazole is crushed by a particle crusher and then sieved by a 200-mesh sieve, and 200-mesh fine powder in the prescription amount is taken for standby.
Dissolving ketoconazole with 0.1moL/L hydrochloric acid, stirring until the solution is clear, adding 1moL/L sodium hydroxide, and rapidly stirring and shearing to obtain solution A.
Dissolving levofloxacin hydrochloride and chlorphenamine maleate in pure water, adding glycerol, sodium carboxymethylcellulose and tween 80, and stirring to obtain solution B.
And adding the solution B into the solution A, and homogenizing under high pressure to obtain the compound ketoconazole suspension spray.
Example 2
The formula of the compound ketoconazole suspension spray of the embodiment is as follows:
8 parts of ketoconazole, 6 parts of levofloxacin hydrochloride, 3 parts of chlorpheniramine maleate, 2 parts of sodium carboxymethylcellulose, 8 parts of glycerol, 800.1 parts of tween, 800 parts of 0.1moL/L hydrochloric acid and 100 parts of 1moL/L sodium hydroxide.
The preparation process of the compound ketoconazole suspension spray of the embodiment is the same as that of the embodiment 1.
Example 3
The formula of the compound ketoconazole suspension spray of the embodiment is as follows:
12 parts of ketoconazole, 4 parts of levofloxacin hydrochloride, 5 parts of chlorpheniramine maleate, 3 parts of sodium carboxymethylcellulose, 7 parts of glycerol, 800.5 parts of tween, 1000 parts of 0.1moL/L hydrochloric acid and 150 parts of 1moL/L sodium hydroxide.
The preparation process of the compound ketoconazole suspension spray of the embodiment is the same as that of the embodiment 1.
Example 4
The formula of the compound ketoconazole suspension spray of the embodiment is as follows:
10 parts of ketoconazole, 4.5 parts of levofloxacin hydrochloride, 3.5 parts of chlorpheniramine maleate, 2.5 parts of sodium carboxymethylcellulose, 6.5 parts of glycerol, 800.8 parts of tween, 900 parts of 0.1moL/L hydrochloric acid and 90 parts of 1moL/L sodium hydroxide.
The preparation process of the compound ketoconazole suspension spray of the embodiment is the same as that of the embodiment 1.
Example 5
The formula of the compound ketoconazole suspension spray of the embodiment is as follows:
9.5 parts of ketoconazole, 5.5 parts of levofloxacin hydrochloride, 4.8 parts of chlorpheniramine maleate, 1.8 parts of sodium carboxymethylcellulose, 7.5 parts of glycerol, 800.9 parts of tween, 850 parts of 0.1moL/L hydrochloric acid and 80 parts of 1moL/L sodium hydroxide.
The preparation process of the compound ketoconazole suspension spray of the embodiment is the same as that of the embodiment 1.
Example 6
The formula of the compound ketoconazole suspension spray of the embodiment is as follows:
11.5 parts of ketoconazole, 4.8 parts of levofloxacin hydrochloride, 4.5 parts of chlorphenamine maleate, 2.3 parts of sodium carboxymethylcellulose, 6.7 parts of glycerol, 800.7 parts of tween, 650 parts of 0.1moL/L hydrochloric acid, 100 parts of 1moL/L sodium hydroxide and 0.065 part of a colorant (amaranth pigment).
The preparation process of the compound ketoconazole suspension spray of this example is the same as that of example 1 except that "after levofloxacin hydrochloride and chlorpheniramine maleate are dissolved by pure water, glycerin, sodium carboxymethylcellulose, tween 80 and a coloring agent are added and uniformly stirred to obtain solution B" and the coloring agent is dissolved by a small amount of hot water for injection before use, the other steps are the same as those of example 1.
Example 7
The formula of the compound ketoconazole suspension spray of the embodiment is as follows:
10.5 parts of ketoconazole, 6 parts of levofloxacin hydrochloride, 3.5 parts of chlorpheniramine maleate, 2.8 parts of sodium carboxymethylcellulose, 8 parts of glycerol, 800.5 parts of tween, 900 parts of 0.1moL/L hydrochloric acid, 100 parts of 1moL/L sodium hydroxide and 0.16 part of a colorant (bright melanin).
The preparation process of the compound ketoconazole suspension spray of the embodiment is the same as that of the embodiment 6.
Example 8
The formula of the compound ketoconazole suspension spray of the embodiment is as follows:
12 parts of ketoconazole, 5.7 parts of levofloxacin hydrochloride, 5 parts of chlorpheniramine maleate, 2 parts of sodium carboxymethylcellulose, 6 parts of glycerol, 801 parts of tween, 600 parts of 0.1moL/L hydrochloric acid, 50 parts of 1moL/L sodium hydroxide and 0.1 part of a colorant (lemon yellow pigment).
The preparation process of the compound ketoconazole suspension spray of the embodiment is the same as that of the embodiment 6.
Example 9
The formula of the compound ketoconazole suspension spray of the embodiment is as follows:
8.5 parts of ketoconazole, 6 parts of levofloxacin hydrochloride, 4 parts of chlorpheniramine maleate, 3 parts of sodium carboxymethylcellulose, 5 parts of glycerol, 801 parts of tween, 900 parts of 0.1moL/L hydrochloric acid, 90 parts of 1moL/L sodium hydroxide and 0.15 part of colorant (amaranth pigment and bright melanin).
The preparation process of the compound ketoconazole suspension spray of the embodiment is the same as that of the embodiment 6.
Example 10
The formula of the compound ketoconazole suspension spray of the embodiment is as follows:
11 parts of ketoconazole, 5.5 parts of levofloxacin hydrochloride, 5 parts of chlorpheniramine maleate, 2 parts of sodium carboxymethylcellulose, 8 parts of glycerol, 800.5 parts of tween, 1000 parts of 0.1moL/L hydrochloric acid, 150 parts of 1moL/L sodium hydroxide and 0.12 part of a colorant (bright melanin).
The preparation process of the compound ketoconazole suspension spray of the embodiment is the same as that of the embodiment 6.
Comparative example 1
The formulation of the compound ketoconazole suspension of comparative example 1 is as follows:
11 parts of ketoconazole, 5.3 parts of levofloxacin hydrochloride, 5.5 parts of chlorpheniramine maleate, 10 parts of sodium carboxymethylcellulose, 250 parts of glycerol and 0.3 part of ethylparaben.
The preparation process of the compound ketoconazole suspension of the comparative example 1 is as follows:
1) the prescribed amount of sodium carboxymethylcellulose was taken and swollen with 500mL of purified water overnight.
2) And (3) crushing the ketoconazole by using a particle crusher, sieving by using a 200-mesh sieve, and taking 200-mesh fine powder according to the prescription amount for later use.
3) Taking the ethylparaben according to the prescription amount, adding a proper amount of purified water, and heating until the ethylparaben is completely dissolved.
4) Taking prescribed amounts of levofloxacin hydrochloride and chlorphenamine maleate, adding the levofloxacin hydrochloride and the chlorphenamine maleate into the solution obtained in the step 3), and stirring until the levofloxacin hydrochloride and the chlorphenamine maleate are completely dissolved for later use.
5) And (3) uniformly mixing the glycerol with the ketoconazole fine powder in the step 2), adding the mixture into the sodium carboxymethylcellulose aqueous solution in the step 1), and uniformly stirring.
6) And step 4), adding the solution in the step 5) into the solution, and uniformly stirring to obtain the compound ketoconazole suspension.
Comparative example 2
Compared with the above example 1, except that the same amount of tween 80 in the example 1 is replaced by polyethylene glycol 400, the rest raw materials and the preparation process are the same as those in the example 1, and the compound ketoconazole suspension spray is prepared.
Comparative example 3
Compared with the above example 1, the comparative example 3 has the same raw materials and preparation process as the example 1 except that the same amount of tween 80 in the example 1 is replaced by hypromellose, and the compound ketoconazole suspension spray is prepared.
Comparative example 4
Comparative example 4 compared with the above example 1, except that the ketoconazole in example 1 is removed and the amount of the ketoconazole is supplemented with 1moL/L sodium hydroxide, the rest raw materials and the preparation process are the same as those in example 1, and the compound ketoconazole suspension spray is prepared.
Comparative example 5
Comparative example 5 compared with the above example 1, except that levofloxacin hydrochloride in the example 1 is removed, and pure water is used to complement the amount of levofloxacin hydrochloride, the rest raw materials and the preparation process are the same as the example 1, and the compound ketoconazole suspension spray is prepared.
Comparative example 6
Comparative example 6 compared with the above example 1, except that the chlorpheniramine maleate in the example 1 is removed, and the amount of the chlorpheniramine maleate is supplemented with pure water, the rest raw materials and the preparation process are the same as those in the example 1, and the compound ketoconazole suspension spray is prepared.
Test 1: spray Effect test
By carrying out a spraying effect test on the above examples 1-10 and comparative example 1, the test method is as follows: and (3) bottles of each group of test samples are respectively taken, 20mL of each bottle is continuously sprayed in a ventilated showcase at uniform pressure until the liquid in the bottles is completely sprayed, the spraying times are recorded, the average value is taken, and the spraying effect is observed. The test results are shown in table 1 below.
TABLE 1
| Test sample | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 |
| Number of injections (times) | 197 | 196 | 194 | 195 | 194 | 193 |
| Spray effect | Fog like | Fog like | Fog like | Fog like | Fog like | Fog like |
| Test sample | Example 7 | Example 8 | Example 9 | Example 10 | Comparative example 1 | |
| Number of injections (times) | 191 | 190 | 193 | 192 | 179 | |
| Spray effect | Fog like | Fog like | Fog like | Fog like | Column shape of water |
As can be seen from table 1 above, the spraying effect of the compound ketoconazole suspension of comparative example 1 is inferior to that of the compound ketoconazole suspension spray prepared in the embodiment of the present invention, and the main reasons are that the amount of the suspension aid of comparative example 1 is large, and the viscosity of the solution is high, so that the compound ketoconazole suspension cannot be effectively sprayed into a mist, and the spraying times and the spraying effect of the compound ketoconazole suspension are affected.
And (3) testing 2: stability test
The compound ketoconazole suspension spray prepared in the example 1 and the comparative examples 2 and 3 is tested, and the test method comprises the following steps: three parallel samples of the three groups of test samples are respectively stored at room temperature, after the three groups of test samples are stored for 1 month and 3 months, the average particle size of insoluble particles of each group of test samples is respectively tested by a Malvern dynamic light scattering particle size analyzer, the average value is taken, and the test result is shown in the following table 2.
TABLE 2
As can be seen from table 2 above, when tween 80 is used, compared with when polyethylene glycol 400 or hypromellose is used as a stabilizer of the compound ketoconazole suspension spray, the prepared compound ketoconazole suspension spray has the highest stability, and the average particle size of the insoluble particles can be maintained at about 280nm after 3 months.
And (3) testing: skin irritation test
1. Test samples: the compound ketoconazole suspension spray prepared in the embodiments 1-10 and the comparative examples 1-6 provided by the embodiment of the invention.
2. The test method comprises selecting 34 volunteers from a certain region, wherein the volunteers are 20-45 years old, healthy, and non-lactating women or pregnant women, and non-constitutional sensitive people who do not take medicines recently. Volunteers were randomly divided into an average of 17 groups of two persons each. Wherein, the group 1 is a blank control group, no substance is placed in the chamber of the spot tester, the spot tester is pasted on the back or the bent side of the forearm of the volunteer by using a hypoallergenic adhesive tape, and the hypoallergenic adhesive tape is lightly pressed by hands to be evenly pasted on the skin; the processing methods of the groups 2 to 17 are the same as those of the group 1, except that: respectively putting the compound ketoconazole suspension spray which is added with 0.025mL and provided by the embodiments 1-10 of the invention into a chamber of a spot tester; that is, group 2 corresponds to the compound ketoconazole suspension spray provided in example 1 of the present invention, group 3 corresponds to the compound ketoconazole suspension spray provided in example 2 of the present invention, group 4 corresponds to the compound ketoconazole suspension spray … … provided in example 3 of the present invention, and so on, and group 17 corresponds to the compound ketoconazole suspension spray provided in comparative example 6. After the test of each group lasts for 24 hours and 48 hours, 30min after the spot tester is removed, and after the indentation disappears, the reaction condition of the skin at the application position is observed and recorded.
Among them, the skin reaction grading criteria of the skin-enclosed patch test are shown in table 3 below.
TABLE 3
| Extent of reaction | Grade of rating | Skin reactions |
| - | 0 | Negative reaction |
| ± | 1 | Suspicious reaction, only weak erythema. |
| + | 2 | Weak yang reaction (erythema reaction: erythema, infiltration, edema, possibly papules). |
| ++ | 3 | Strong positive reaction (herpes reaction): erythema, infiltration, edema, pimples, herpes; the reaction may be beyond the test area. |
| +++ | 4 | Very strong positive reaction (fusogenic herpes reaction): obvious erythema, severe infiltration, edema, and fusional herpes; the reaction goes beyond the test area. |
The skin reactions at the test sites of the subjects of groups 1 to 17 were negative throughout the test. Therefore, the compound ketoconazole suspension spray provided by the embodiment of the invention does not cause skin allergy and irritation, and has good safety.
And (4) testing: therapeutic test for contact dermatitis
The compound ketoconazole suspension spray prepared in the above examples 1-10 and comparative examples 1-6 is subjected to a curative effect test of contact dermatitis, and the test method comprises the following steps:
120 patients are selected from the skin clinic department for clinical test, and the compound ketoconazole suspension spray of the invention 1-10 and the comparative examples 1-6 are taken for local spraying medication treatment on the dermatitis part of the patients.
Acute and chronic eczema 60 cases: the selection criteria are local skin thickening, infiltration, rough surface, lichenification, dark red or grey brown, which may be accompanied by pigmentation, secondary changes such as slight scales, scratches and scabs, scattered pimples or papules on the periphery, and chapping at the joint and active site. The drug effect judgment standard is that the drug effect is cured: local inflammation disappears, the skin lesion surface is smooth, and subjective symptoms disappear; the effect is shown: the skin lesion and the inflammation are basically eliminated, and the subjective symptoms are obviously relieved; the method has the following advantages: partial regression of lesions or inflammation; and (4) invalidation: there was no change before and after treatment.
Dermatitis in 60 cases: the selection criteria are skin peeling, thickening, discoloration, and itching when touched. The drug effect judgment standard is that the drug effect is cured: local inflammation disappears, the skin lesion surface is smooth, and subjective symptoms disappear; the effect is shown: the skin lesion and the inflammation are basically eliminated, and the subjective symptoms are obviously relieved; the method has the following advantages: partial regression of lesions or inflammation; and (4) invalidation: there was no change before and after treatment.
The clinical effect observation results are shown in the following 4-5 [ c1 ].
TABLE 4
TABLE 5
| Examples | Number of people (human) | Display effect (human) | Effective (human) | Invalid (human) | Total effective rate (%) |
| Example 1 | 60 | 49 | 8 | 3 | 95.00% |
| Example 2 | 60 | 45 | 10 | 5 | 91.67% |
| Example 3 | 60 | 41 | 14 | 5 | 91.67% |
| Example 4 | 60 | 40 | 16 | 4 | 93.33% |
| Example 5 | 60 | 46 | 9 | 5 | 91.67% |
| Example 6 | 60 | 45 | 10 | 5 | 91.67% |
| Example 7 | 60 | 48 | 8 | 4 | 93.33% |
| Example 8 | 60 | 45 | 11 | 4 | 93.33% |
| Example 9 | 60 | 48 | 8 | 4 | 93.33% |
| Example 10 | 60 | 48 | 7 | 5 | 91.67% |
| Comparative example 1 | 60 | 37 | 8 | 15 | 75.00% |
| Comparative example 2 | 60 | 38 | 10 | 12 | 80.00% |
| Comparative example 3 | 60 | 40 | 12 | 8 | 86.67% |
| Comparative example 4 | 60 | 34 | 10 | 16 | 73.33% |
| Comparative example 5 | 60 | 35 | 10 | 15 | 75.00% |
| Comparative example 6 | 60 | 36 | 7 | 17 | 71.67% |
As can be seen from tables 4 and 5 above, the compound ketoconazole suspension spray provided by the embodiment of the invention has the effective rate of treating acute and chronic eczema of over 90%, and the effective rate of treating dermatitis of over 91%. And the comparison results of comparative examples 4-6 and example 1 show that the synergistic administration of ketoconazole, levofloxacin hydrochloride and chlorphenamine maleate can obviously improve the treatment effect on dermatitis. Compared with the polyethylene glycol 400 or hydroxypropyl methylcellulose serving as a stabilizer, the prepared spray has an improved dermatitis treatment effect, and the reason that the stability of the spray can be remarkably improved and the effective components of the spray can better play the roles of the spray can be probably because the tween 80 is added. In addition, the ketoconazole is treated by hydrochloric acid and sodium hydroxide, and the effect of treating dermatitis by the spray is also influenced to a certain extent.
In conclusion, the compound ketoconazole suspension spray provided by the embodiment of the invention adopts the synergistic effect of ketoconazole, levofloxacin hydrochloride and chlorphenamine maleate, and can significantly improve the treatment effect on contact dermatitis; the suspension spray prepared can obviously improve the bioavailability of the medicine and is very convenient for the application of skin mucosa; in addition, the stability of the spray can be obviously improved by adding a suspending agent, a stabilizing agent and a pH regulator.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
The inventors were asked to confirm whether the test data of tables 4 and 5 below meet the conventional and logical rules in the art so as not to cause unusual test data. If any data which do not accord with the laws and logics are required to be directly corrected in the document.
Claims (10)
1. The compound ketoconazole suspension spray is characterized by comprising the following components in parts by weight:
8-12 parts of ketoconazole, 4-6 parts of levofloxacin hydrochloride, 3-5 parts of chlorphenamine maleate, 5.5-11 parts of a suspending agent, 0.1-1 part of a stabilizer and 650-1150 parts of a pH regulator.
2. The compound ketoconazole suspension spray according to claim 1, wherein the suspending agent is sodium carboxymethylcellulose and glycerol.
3. The compound ketoconazole suspension spray according to claim 1, wherein the stabilizer is tween 80.
4. The compound ketoconazole suspension spray according to claim 1, wherein the pH regulator is 0.1moL/L hydrochloric acid and 1moL/L sodium hydroxide.
5. The compound ketoconazole suspension spray according to claim 1, which comprises the following components in parts by weight:
9-11 parts of ketoconazole, 5-6 parts of levofloxacin hydrochloride, 4-5 parts of chlorphenamine maleate, 8-11 parts of a suspending agent, 0.1-0.5 part of a stabilizer and 850-1100 parts of a pH regulator.
6. The compound ketoconazole suspension spray according to claim 1, which comprises the following components in parts by weight:
10-11 parts of ketoconazole, 5-6 parts of levofloxacin hydrochloride, 4-5 parts of chlorphenamine maleate, 9-11 parts of a suspending agent, 0.1-0.5 part of a stabilizer and 975-1100 parts of a pH regulator.
7. The compound ketoconazole suspension spray according to claim 1, which comprises the following components in parts by weight:
8-12 parts of ketoconazole, 4-6 parts of levofloxacin hydrochloride, 3-5 parts of chlorphenamine maleate, 5.5-11 parts of a suspending agent, 0.1-1 part of a stabilizing agent, 650-1150 parts of a pH regulator and 0.065-0.16 part of a coloring agent.
8. The compound ketoconazole suspension spray according to claim 1, wherein the mean particle size of insoluble particles in the compound ketoconazole suspension spray is 280-350 nm.
9. The compound ketoconazole suspension spray according to claim 1, wherein the mean particle size of the insoluble particles in the compound ketoconazole suspension spray is 280 nm.
10. The preparation method of the compound ketoconazole suspension spray according to any one of claims 1 to 9, which comprises the following steps:
weighing the components according to the formula of the compound ketoconazole suspension spray as claimed in any one of claims 1 to 9;
dissolving the crushed and sieved ketoconazole by using a pH regulator, stirring and shearing to obtain a solution A;
dissolving levofloxacin hydrochloride and chlorphenamine maleate in pure water, adding suspending agent and stabilizer, and stirring to obtain solution B;
and adding the solution B into the solution A, and homogenizing under high pressure to obtain the compound ketoconazole suspension spray.
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