CN115531312A - Preparation process of terbinafine hydrochloride spray - Google Patents
Preparation process of terbinafine hydrochloride spray Download PDFInfo
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- CN115531312A CN115531312A CN202210685477.2A CN202210685477A CN115531312A CN 115531312 A CN115531312 A CN 115531312A CN 202210685477 A CN202210685477 A CN 202210685477A CN 115531312 A CN115531312 A CN 115531312A
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- terbinafine hydrochloride
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- aqueous solution
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- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 title claims abstract description 59
- 229960000699 terbinafine hydrochloride Drugs 0.000 title claims abstract description 53
- 239000007921 spray Substances 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000003756 stirring Methods 0.000 claims abstract description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000010438 heat treatment Methods 0.000 claims abstract description 24
- 239000008213 purified water Substances 0.000 claims abstract description 22
- 239000002994 raw material Substances 0.000 claims abstract description 22
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229960003639 laurocapram Drugs 0.000 claims abstract description 20
- 239000007864 aqueous solution Substances 0.000 claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 claims abstract description 18
- 239000000203 mixture Substances 0.000 claims abstract description 18
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 16
- 229940040526 anhydrous sodium acetate Drugs 0.000 claims abstract description 16
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims abstract description 13
- 239000004299 sodium benzoate Substances 0.000 claims abstract description 13
- 235000010234 sodium benzoate Nutrition 0.000 claims abstract description 13
- 239000006184 cosolvent Substances 0.000 claims abstract description 8
- 238000005303 weighing Methods 0.000 claims abstract description 4
- 238000002844 melting Methods 0.000 claims abstract description 3
- 230000008018 melting Effects 0.000 claims abstract description 3
- 239000003814 drug Substances 0.000 claims description 21
- 101000656751 Haloarcula marismortui (strain ATCC 43049 / DSM 3752 / JCM 8966 / VKM B-1809) 30S ribosomal protein S24e Proteins 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 19
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- 229960003885 sodium benzoate Drugs 0.000 claims description 4
- 229960002722 terbinafine Drugs 0.000 claims description 4
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000012982 microporous membrane Substances 0.000 claims description 3
- 238000005259 measurement Methods 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- 238000005352 clarification Methods 0.000 claims 1
- 125000004957 naphthylene group Chemical group 0.000 claims 1
- 239000004615 ingredient Substances 0.000 abstract description 4
- 210000003491 skin Anatomy 0.000 description 23
- 241000700159 Rattus Species 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000012360 testing method Methods 0.000 description 16
- 210000000434 stratum corneum Anatomy 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 210000004207 dermis Anatomy 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000002504 physiological saline solution Substances 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000002390 adhesive tape Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
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- 230000001886 ciliary effect Effects 0.000 description 4
- 238000009792 diffusion process Methods 0.000 description 4
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 230000003187 abdominal effect Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
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- 231100000419 toxicity Toxicity 0.000 description 3
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- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010017533 Fungal infection Diseases 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229960003964 deoxycholic acid Drugs 0.000 description 2
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 2
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- 206010067484 Adverse reaction Diseases 0.000 description 1
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- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
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Images
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
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- 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 discloses a preparation process of terbinafine hydrochloride spray, which comprises the following steps: weighing: according to the weight ratio of 0.2kg of terbinafine hydrochloride, 0.03kg of anhydrous sodium acetate, 0.4kg of laurocapram,
0.007kg of sodium benzoate, 20L of purified water and the raw materials are weighed for standby application, (II) configuration: taking the above weights first
Heating the mixture to a proper temperature, completely melting the mixture to be clear and transparent, then stopping heating the heating system, adding 50% of purified water in the mixture ratio of the raw materials, stirring the mixture to be dissolved, then adding terbinafine hydrochloride into a cosolvent aqueous solution according to the load of the raw materials, and stirring the mixture to completely dissolve the terbinafine hydrochloride to obtain a secondary dissolved aqueous solution. The preparation process of the terbinafine hydrochloride spray effectively controls the proportion of each ingredient in the preparation process, thereby reducing the overall preparation cost, realizing the function of mass production and solving the problem that the mass production cannot be realized due to higher cost.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation process of terbinafine hydrochloride spray.
Background
Terbinafine hydrochloride is an allylamine medicine with broad-spectrum antifungal activity, has double functions of killing and inhibiting fungi, is first marketed under the trade name Lamisil (Lamisil) developed by Sandoz corporation in 20 th century in 90 years, and is approved for production of raw materials, tablets and ointments to market in 1997 in China. Because of its advantages of short treatment course, good curative effect, low recurrence rate, good tolerance and high safety, it is widely used for treating various mycosis clinically. Years of clinical use data show that terbinafine hydrochloride is a common medicament with definite and safe clinical curative effect, wide application range and low adverse reaction for resisting superficial fungal infection at present, and is a safe and effective medicament for resisting dermatophytosis at present.
After being applied to the skin topically, the terbinafine hydrochloride can penetrate through the stratum corneum to be tightly combined with the skin horny cells and stored in the stratum corneum and sebaceous glands of the dermis layer, so that the concentration of the terbinafine hydrochloride in the skin, the hair and the nail plate is higher, and the storage time is long. Considering that the small animal fungi are usually dispersed in the whole body and hair, the external preparation has good treatment effect on local epidermis, and the external preparation is applied aiming at the characteristic that the diseased region is the skin, the liquid medicine is quickly absorbed, and the medicine effect can be quickly exerted, so the invention decides to develop the preparation suitable for external application on the skin.
Terbinafine hydrochloride contains a secondary amine group, is weakly basic, slightly soluble in water, soluble in isopropanol, methanol, ethanol, etc., and is almost insoluble in diethyl ether. Compared with other formulations, the skin external formulation is commonly used in creams, sprays, gels and the like, the administration is carried out in the form of spray, and no direct mechanical friction exists between the skin external formulation and the administration part during the administration, so that the skin external formulation reduces the damage or stimulation to the skin and has the advantages of convenient use, quick absorption, uniform spraying and the like, thereby being the preferred spray formulation in the invention.
The existing terbinafine hydrochloride spray cannot effectively control the cost during production and preparation, so that the overall production cost is higher and mass production cannot be carried out.
Disclosure of Invention
The invention aims to provide a preparation process of a terbinafine hydrochloride spray, so as to solve the problems that the cost cannot be effectively controlled, the overall production cost is higher and mass production cannot be carried out when the existing terbinafine hydrochloride spray provided by the invention is produced and prepared.
In order to achieve the purpose, the invention provides the following technical scheme: a preparation process of terbinafine hydrochloride spray comprises the following steps:
weighing: according to the weight ratio of 0.2kg of terbinafine hydrochloride, 0.03kg of anhydrous sodium acetate, 0.4kg of laurocapram,
HS15, 0.007kg of sodium benzoate, 20L of purified water and the raw materials were weighed for use.
(II) configuration: taking the above weights first
HS15, heating the spray to a proper temperature to completely melt the spray until the spray is clear and transparent, stopping heating a heating system, adding 50% of purified water in the raw material ratio, stirring to dissolve the purified water, adding terbinafine hydrochloride into a cosolvent aqueous solution according to the load of the raw materials, stirring to completely dissolve the terbinafine hydrochloride to obtain a secondary dissolved aqueous solution, adding sodium benzoate, anhydrous sodium acetate and laurocapram into the secondary dissolved aqueous solution according to the raw material ratio, stirring to dissolve the sodium benzoate, the anhydrous sodium acetate and the laurocapram to obtain a tertiary dissolved aqueous solution, finally adding the residual purified water after the raw materials are used in the heating process into the tertiary dissolved aqueous solution according to the raw material ratio, and uniformly stirring to obtain the terbinafine hydrochloride spray liquid.
(III) filtering: the prepared liquid medicine is roughly filtered by a G3 titanium rod, then conveyed to a high-level tank, finely filtered by a 0.4 mu m microporous membrane and then conveyed to a filling and sealing room by a pipeline.
(IV) filling and sealing: checking the clarity of the liquid medicine to be qualified, filling the liquid medicine by a spray filling machine, wherein the filling amount is 100ml, and movably screwing a cover after the filling is finished.
And (V) packaging: and packaging the filled sprayer through an automatic packaging machine.
Preferably, in the configuration process of the step (two), the stirring speed of the stirring blade of the dosing tank is fixed at 60 revolutions per minute.
Preferably, the step (two) is carried out in pairs
During the heating of the HS15, the heating was carried out,
the heating temperature of HS15 is controlled to be 55-60 ℃.
Preferably, 50% of purified water is added in the step (two) for the first time, and when stirring is started, observation is carried out for 10min, 15min and 20min, wherein the mixed solution has no floccules or particles visible to naked eyes and keeps clear.
Preferably, in the step (two), when the prescription amount of terbinafine is dissolved in the solubilizing aqueous solution and stirred, the mixed solution is observed at 10min, 15min and 20min, no floccule or particle can be seen by naked eyes, and the clarity is kept.
Preferably, in the step (II), when the sodium benzoate, the anhydrous sodium acetate and the laurocapram are added and stirred, the mixture is observed at 5min, 10min and 15min, the mixture has no visible floccule or particle, the clarity is kept, and the sample is taken for measurement after the stirring,
the content of HS15 is 90-110% of the whole weight.
Compared with the prior art, the invention has the beneficial effects that: the preparation process of the terbinafine hydrochloride spray effectively controls the proportion of each ingredient in the preparation process, thereby reducing the overall preparation cost, realizing the function of mass production and solving the problem that the mass production cannot be realized due to higher cost.
Drawings
FIG. 1 is a schematic view of a process flow of the present invention;
figure 2 is a schematic diagram of the time comparison of ciliary movement according to the present invention;
FIG. 3 is a schematic view of the observation of the pathological section of the rat mucous membrane of the present invention;
FIG. 4 is a schematic view of a drug specification according to the present invention;
FIG. 5 is a schematic diagram of the apparatus of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The first embodiment is as follows:
the preparation process of terbinafine hydrochloride spray includes the following steps:
weighing: according to the weight ratio of 0.2kg of terbinafine hydrochloride, 0.03kg of anhydrous sodium acetate, 0.4kg of laurocapram,
HS15, 0.007kg of sodium benzoate, 20L of purified water and the raw materials were weighed for use.
(II) configuration: taking the above weights first
HS15, heating to a proper temperature, completely melting to be clear and transparent, stopping a heating system, adding 50% of purified water in the raw material ratio, stirring to dissolve, then bearing the weight of the raw materials, and mixingAdding terbinafine hydrochloride into a cosolvent aqueous solution, stirring to completely dissolve the terbinafine hydrochloride to obtain a secondary dissolved aqueous solution, then adding sodium benzoate, anhydrous sodium acetate and laurocapram into the secondary dissolved aqueous solution according to the proportion of the raw materials, stirring to dissolve the terbinafine hydrochloride to obtain a tertiary dissolved aqueous solution, finally adding the residual purified water after the raw materials are used in heating into the tertiary dissolved aqueous solution according to the proportion of the raw materials, and uniformly stirring to obtain the terbinafine hydrochloride spray liquid medicine.
(III) filtering: the prepared liquid medicine is roughly filtered by a G3 titanium rod, then conveyed to a high-level tank, finely filtered by a 0.4 mu m microporous membrane and then conveyed to a filling and sealing room by a pipeline.
(IV) filling and sealing: checking the clarity of the liquid medicine to be qualified, filling the liquid medicine by a spray filling machine, wherein the filling amount is 100ml, and movably screwing a cover after the filling is finished.
And (V) packaging: and packaging the filled sprayer by an automatic packaging machine.
In the configuration process of the step (II), the stirring speed of the stirring paddle of the batching tank is fixed at 60 revolutions per minute.
Step (two) is to
During the heating of the HS15, the heat is removed,
the heating temperature of HS15 is controlled to be 55-60 ℃.
And (II) adding 50% of purified water for the first time, and observing for 10min, 15min and 20min when stirring is started, wherein the mixed solution is free of floccules or particles visible to naked eyes and keeps clear.
And (II) when the terbinafine with the prescription dose is dissolved in the solubilizing water solution and stirred, the observation is carried out for 10min, 15min and 20min, and the mixed solution has no floccules or particles visible to naked eyes and keeps clear.
Step two, after sodium benzoate, anhydrous sodium acetate and laurocapram are added, the step two is carried outStirring for 5min, 10min, and 15min, observing the mixture without visible floccule or granule, keeping clarity, sampling after stirring, measuring,
the content of HS15 is 90-110 wt% of the whole.
The second embodiment:
on the basis of the first embodiment, the invention carries out experiments on the research on the cilium toxicity and the mucous membrane irritation of the cosolvent, and comprises the following steps:
step (one): adopting in-vivo Bufo siccus experimental method, selecting sodium deoxycholate with serious ciliate toxicity recognized in literature as positive control, and physiological saline as blank control, and adding 10% of the total amount of the above materials
Cilia toxicity studies with HS15 solutions.
Step (II): referring to the study of mucosa irritation, rat nasal mucosa was selected as the experimental subject, and 10% of the test subjects were used respectively
HS15 solution and normal saline are treated, the thickness of the mucous epithelium is measured after seven days, and whether the two solutions are irritant to the long-term nasal mucosa of the rat is examined.
The test result of the step (I) is shown in figure 2, and the test result shows that the ciliary continuous movement time of the 1% sodium deoxycholate test group is obviously different from that of the normal saline (P)<0.01 Indicating that it is highly toxic to cilia, consistent with literature reports; 10% of
The cilia continuous movement time of the HS15 solution group is not significantly different from that of the normal saline group (P)>0.05 Indicating that it has essentially no effect on ciliary action, i.e., no ciliary toxicity.
The experimental result section in the step (II) is shown in FIG. 3, the test result of the thickness of the mucosal epithelium is shown in Table 1, and the test result shows that 10% of the total
After the HS15 solution and the normal saline are respectively treated for 7 days, the rat mucous membrane tissue slices have no obvious difference, the surface of the rat mucous membrane tissue slices and the surface of the rat mucous membrane tissue slices do not cause the loss of the mucous membrane,
the thickness of the mucosal epithelium after seven days of administration of HS15 was (0.183. + -. 0.013) mm, respectively, and there was no significant difference (P) from the thickness of the mucosa after seven days of administration of the normal saline group (0.169. + -. 0.011) mm>0.05 Account for 0%
HS15 is not irritating to the mucosa.
TABLE 1
The test results show that the preparation adopts
HS15 is used as a cosolvent, has obvious dissolving assisting effect on terbinafine hydrochloride serving as a main drug, and has small irritation, so purified water is primarily selected as a solvent,
HS15 co-solvent to increase the solubility of the drug in water.
Example three:
on the basis of the first embodiment, the experiment for screening the cosolvent dosage comprises the following steps:
taking the same amount of the ingredients according to the ratio of one of the embodiments
HS15 can be completely melted to be clear and transparent when heated to 55-60 ℃, at the moment, the heating system is stopped, and the addition of the HS15 is equivalent to the addition of the HSIn example one, 50% of purified water was added, 1g of terbinafine hydrochloride was added according to Table 2, and dissolved by ultrasonic wave, and the volume was adjusted to 100ml with purified water, and the properties of the solution were observed.
TABLE 2
The test results are shown in Table 3 and show
When the dosage of HS15 is 5%, the solubilizing effect is poor, the terbinafine hydrochloride can not be completely dissolved, when the dosage is 10% and 15%, the solubilizing effect is good, the terbinafine hydrochloride can be completely dissolved, the production cost and the quality of the finished product are comprehensively considered, and the initial determination is carried out
TABLE 3
Example four:
on the basis of the first embodiment, the method for testing the dosage of laurocapram comprises the following steps:
step (one): taking the same amount according to the ratio of the ingredients of the first embodiment
HS15, heating to 55-60 ℃ to completely melt to be clear and transparent, stopping heating the temperature raising system, adding purified water which is 50% of the mixture in the first embodiment, adding 1g of terbinafine hydrochloride after ultrasonic or stirring dissolution, adding laurocapram with different amounts according to the table 4, fixing the volume to 100ml by using purified water, and uniformly stirring for later use.
TABLE 4
Step (II): taking male SD rats into a closed transparent box, dipping a proper amount of diethyl ether by absorbent cotton, throwing the rats into the closed box, anesthetizing the rats, taking the rats in a half-hemp state, wetting the abdominal rat feathers of the rats with soap water, removing the rat feathers completely, removing the neck of the rats after normal feeding drinking water is 24 hours after the physical signs of the rats are recovered to be normal, peeling the abdominal skin, removing subcutaneous adipose tissues and blood vessels, washing the rats with normal-temperature physiological saline solution, sucking water by using a piece of mirror wiping paper, flatly spreading and wrapping the rat wiping paper, covering the outer layer with tinfoil paper, putting the rat wiping paper into a sealing bag, freezing and storing the rat wiping paper at the temperature of-20 ℃ for standby use within two weeks, naturally placing the completely packaged skin into normal-temperature physiological saline for incubation during experimental use, inspecting whether the skin is complete after 15 minutes, and transferring the rat wiping paper into the normal-temperature physiological saline for incubation for 30 minutes after the skin is complete for use.
Step (III): transdermal tests were carried out using a drug transdermal diffusion tester (yellow sea drug test type RYJ-12B) having a total of 12 diffusion cells, so that 3 replicates of 4 formulations were tested per test, 2 replicates were conducted. Transdermal diffusion test devices used in the tests are shown in fig. 1-3 and mainly comprise a modified vertical Franz diffusion cell and rat abdominal skin. The skin is held between the delivery chamber and the receiving chamber with the stratum corneum facing the delivery chamber and clamped with iron clamps. Adding physiological saline solution with bubbles removed and preheated to 37 deg.C into receiving pool (volume of receiving pool is 6.5 ml), allowing skin to contact completely with receiving liquid surface, and magnetically stirring the receiving liquid at 300 r/min.
Step (IV): the skin penetrated for 12 hours (n = 3) was removed, the surface of the skin was uniformly rinsed with 15ml of physiological saline, wiped dry with a mirror-wiping paper, excess skin was cut off, the skin was placed in an area of about 2.8cm2 in contact with the test solution, the stratum corneum and the epidermal dermis were separated, and the retention of terbinafine hydrochloride in the stratum corneum and epidermal dermis was measured.
Step (V): flow rate of tetramethylammonium hydroxide (25% tetramethylammonium hydroxide 5.8ml, water 800ml, pH adjusted to 7.8 with 0.7mol/L phosphoric acid solution, water diluted to 1000 ml) -tetrahydrofuran-acetonitrile (20: 1ml/min; detection wavelength: 280nm; sample introduction amount: 20ul; column temperature: normal temperature; the theoretical plate number is not lower than 2000 calculated according to terbinafine hydrochloride peak.
Step (six): the receiver medium in the receiver tank was taken out by 0.5mL at 12h while quickly being replenished with the same volume of blank receiver medium at the same temperature. The obtained sample was filtered through a 0.45 μm organic filter and then measured under the above-mentioned chromatographic conditions.
Step (seven): one side of the horny layer of the rat skin is tightly adhered by a medical adhesive tape, after uniform pressure is applied, the adhesive tape is removed, the horny layer is seen to be stripped off in a repeated way, the adhesion and the tearing are repeated for 3 to 5 times, and new adhesive tape is used each time until the skin surface is smooth and uniform, so that the horny layer can be regarded as being completely adhered by the adhesive tape. Shearing the adhered adhesive tape into pieces, placing in a 10ml centrifuge tube, adding 4ml methanol, performing ultrasonic extraction for 1h, cooling at room temperature, and adding methanol to dilute to scale. Centrifuging for 15min at 5000r/min, collecting supernatant, blowing with nitrogen blower for 2 hr to volatilize, re-dissolving with 4ml methanol, ultrasonic treating for 5min, vortex for 2min, centrifuging for 15min at 5000r/min, collecting filtrate, measuring according to the above chromatographic conditions, and calculating retention of terbinafine hydrochloride in stratum corneum per unit area.
And (eight): the epidermis dermis layer after the cuticle layer is removed is cut into pieces and is fully ground in a mortar. Adding 1ml of methanol into a mortar by using a liquid transfer gun, grinding the mixture into a chyle state, transferring the chyle state into a 10ml centrifuge tube, repeatedly adding the chyle state into the mortar in the way, transferring the mixture into the centrifuge tube for 5 times, and adding the methanol into the centrifuge tube for 5ml cumulatively. And (f) the rest of the operations are carried out in the same step (seven), and the retention amount of terbinafine hydrochloride in the epidermal dermis of unit area is calculated.
The test results are shown in table 5, and the results show that the receiving solution in each prescription does not detect terbinafine hydrochloride, the concentration of terbinafine hydrochloride in the receiving solution is lower than the detection limit (0.06 mug/ml) of terbinafine in the receiving solution, the stratum corneum retention is increased in the prescription added with laurocapram compared with the prescription without the addition, no obvious rule is found among different addition concentrations, and the dermis retention is obviously increased in the prescriptions added with 2% and 3% of laurocapram compared with the prescriptions without the addition and 1% of laurocapram.
TABLE 5
And (4) conclusion: terbinafine hydrochloride solutions of different prescriptions can not penetrate through the skin to enter the receiving liquid; the prescription of adding laurocapram can promote terbinafine hydrochloride to enter the stratum corneum, but the test error is larger, which is probably related to the more complex stratum corneum sample treatment method; the prescription added with 2 percent and 3 percent of laurocapram has equivalent penetration promoting effect on terbinafine hydrochloride entering stratum corneum and is obviously superior to the prescription which is not added and the addition amount of which is 1 percent. In conclusion, the dosage of laurocapram was finally determined to be 2% in combination with cost considerations in production.
Example five:
on the basis of the first embodiment, the selection of the bacteriostatic agent is tested, and the method comprises the following steps:
preparing samples according to the prescription design in Table 6, taking about 50ml of purified water, adding
HS15, after ultrasonic dissolution, adding 1g of terbinafine hydrochloride, ultrasonic dissolution, adding sodium benzoate and different amounts of anhydrous sodium acetate, stirring to dissolve, fixing the volume to 100ml with purified water, observing the properties of the solution and measuring the pH value.
The test results are shown in table 6, and the results show that the pH value of the terbinafine hydrochloride solution tends to decrease along with the prolonging of the standing time, the pH value of the solution is ensured to be between 3.5 and 4.5, the drug effect is better, the pH value of the solution cannot be adjusted to a specified range when the dosage of the anhydrous sodium acetate is between 0.08 and 0.1 percent, the pH value of the solution is better adjusted when the dosage of the anhydrous sodium acetate is between 0.15 and 0.23 percent, and the dosage of the anhydrous sodium acetate is finally selected to be 0.15 percent in combination with the cost consideration on production.
TABLE 6
It should also be noted that the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation, an element defined by the phrases "comprising one of 8230; \8230;" 8230; "does not exclude the presence of additional like elements in a process, method, article, or apparatus that comprises the element.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments described in the foregoing embodiments, or equivalents may be substituted for elements thereof.
Claims (6)
1. A preparation process of terbinafine hydrochloride spray is characterized by comprising the following steps:
weighing: according to the weight ratio of 0.2kg of terbinafine hydrochloride, 0.03kg of anhydrous sodium acetate, 0.4kg of laurocapram and 2kg of
HS15, 0.007kg of sodium benzoate, 20L of purified water and the raw materials are weighed for later use.
(II) configuration: taking the above weights first
HS15, heating to a proper temperature, completely melting to be clear and transparent, stopping a heating system, adding 50% of purified water in the raw material ratio, stirring to dissolve, then bearing the weight of the raw materials, and adding the hydrochloric acid to the specific ratioAdding the naphthylene into a cosolvent aqueous solution, stirring to completely dissolve the terbinafine hydrochloride to obtain a secondary dissolved aqueous solution, then adding sodium benzoate, anhydrous sodium acetate and laurocapram into the secondary dissolved aqueous solution according to the proportion of the raw materials, stirring to dissolve the sodium benzoate, the anhydrous sodium acetate and the laurocapram to obtain a tertiary dissolved aqueous solution, finally adding the purified water left after the raw materials are used in heating into the tertiary dissolved aqueous solution according to the proportion of the raw materials, and uniformly stirring to obtain the terbinafine hydrochloride spray liquid medicine.
(III) filtering: the prepared liquid medicine is roughly filtered by a G3 titanium rod, then conveyed to a high-level tank, finely filtered by a 0.4 mu m microporous membrane and then conveyed to a filling and sealing room by a pipeline.
(IV) filling and sealing: checking the clarity of the liquid medicine to be qualified, filling the liquid medicine by a spray filling machine, wherein the filling amount is 100ml, and movably screwing a cover after the filling is finished.
And (V) packaging: and packaging the filled sprayer by an automatic packaging machine.
2. The process for preparing terbinafine hydrochloride spray according to claim 1, wherein: and in the configuration process of the step (II), the stirring speed of the stirring paddle of the batching tank is fixed at 60 revolutions per minute.
3. The process for preparing terbinafine hydrochloride spray according to claim 1, wherein: the step (two) is in pair
During the heating of the HS15, the heating was carried out,
the heating temperature of HS15 is controlled to be 55-60 ℃.
4. The process for preparing terbinafine hydrochloride spray according to claim 1, wherein: and (II) adding 50% of purified water for the first time, and observing for 10min, 15min and 20min when stirring is started, wherein the mixed solution is free of floccules or particles visible to naked eyes and keeps clear.
5. The process for preparing terbinafine hydrochloride spray according to claim 1, wherein: and in the step (II), when the terbinafine in the prescription amount is dissolved in the solubilizing water solution and stirred, observation is carried out for 10min, 15min and 20min, and the mixed solution does not have floccules or particles visible to naked eyes and keeps clear.
6. The process for preparing terbinafine hydrochloride spray according to claim 1, wherein: the step (II) is that when the sodium benzoate, the anhydrous sodium acetate and the laurocapram are added and stirred, the mixture is observed for 5min, 10min and 15min, the mixed solution has no visible floccule or particle, the clarification is kept, and the sample is taken for measurement after the stirring,
the content of HS15 is 90-110% of the whole weight.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120114574A1 (en) * | 2009-01-30 | 2012-05-10 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Compositions for nail and skin treatment |
| CN109453116A (en) * | 2017-09-06 | 2019-03-12 | 北京中医药大学 | A kind of terbinafine HCl spray and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120114574A1 (en) * | 2009-01-30 | 2012-05-10 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Compositions for nail and skin treatment |
| CN109453116A (en) * | 2017-09-06 | 2019-03-12 | 北京中医药大学 | A kind of terbinafine HCl spray and preparation method thereof |
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| Title |
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| 刁长林 等: "改进输液滤过系统 有效控制输液中的微粒", 《西北药学杂志》, vol. 18, no. 2, pages 77 * |
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