CN108066279A - A kind of medicinal external emulsifiable paste composition containing benzene alkene not moral - Google Patents
A kind of medicinal external emulsifiable paste composition containing benzene alkene not moral Download PDFInfo
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- CN108066279A CN108066279A CN201810032954.9A CN201810032954A CN108066279A CN 108066279 A CN108066279 A CN 108066279A CN 201810032954 A CN201810032954 A CN 201810032954A CN 108066279 A CN108066279 A CN 108066279A
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- moral
- benzene alkene
- emulsifiable paste
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- alkene
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- BECOTCIRZWIXJB-MDZDMXLPSA-N CC(C)C1C([O]=C)=CC(/C=C/C2=CC=CCC2)=CC1=O Chemical compound CC(C)C1C([O]=C)=CC(/C=C/C2=CC=CCC2)=CC1=O BECOTCIRZWIXJB-MDZDMXLPSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- 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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
Abstract
The invention discloses a kind of benzene alkene not moral medicinal external emulsifiable pastes, the defects of oxidative degradation easy for the agent not made in Germany of benzene alkene, inventor intends by way of adding in antioxidant in preparation system, reduce the generation of oxidation reaction, and pass through addition transdermal enhancer, using liposome and alcohol plastid technology, increase the percutaneous abilities of benzene alkene not moral external preparation, enhance curative effect of medication.Experiment proves that the every detection of gained cream complies with standard, the generation of simultaneous oxidation degradation impurity is suppressed significantly, and is greatly increased and the stability of product, and percutaneous abilities are due to adding transdermal enhancer, it is also significantly improved, achieved the purpose that of the invention initial using liposome and alcohol plastid technology.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of medicinal external emulsifiable paste composition and its system containing benzene alkene not moral
Preparation Method and purposes.
Background technology
Psoriasis is a kind of common chronic inflammation disease, and characteristic lesions are to be covered with multilayer on red papules or patch
The silvery white scales of skin that peel off.The main pathological change of its skin lesion includes keratinocyte hyperplasia with parakeratosis, inflammatory cell leaching
Profit and new vessels are formed.Psoriasis is clinically divided into slight (skin lesion area is less than according to the size of skin lesion area
10%), moderate (skin lesion area is between 10%~30%) and severe (skin lesion area is more than 30%).In, severe patient need whole body
It treats (methotrexate (MTX), ciclosporin A), local application is as auxiliary treatment.
The common external used medicine of clinical treatment psoriasis has glucocorticoids, vitamin A acid analog derivative, dimension at present
Raw element D3 analogs, immunosupress analog derivative and salicylic acid etc., there is no the externally applied drug of target spot specificity to list.
Moral to extract isolated natural products out of nematode infections insect bodies, not can inhibit human peripheral to benzene alkene
Mononuclear cell proliferation induces its apoptosis, has negative regulation effect to T cell nuclear factor (NF)-κ B accesses.I phase clinical research knot
Fruit shows that moral external application better tolerance, adverse reaction be not slight for benzene alkene.II phase clinical study results are shown, evident in efficacy, 12 weeks
Moral group does not fully assess target improvement rate (62.8%) apparently higher than placebo (13.0%, P to benzene alkene afterwards<0.000 1).
Moral (English name, benvitimod) is not small molecule stilbene compound to benzene alkene, entitled 5- (the 2- styrene of chemistry
Base) -2- isopropyls-Resorcinol.Initially from the symbiotic bacteria of soil nematodes (Heterorhabditissp.) a kind of
It is extracted in the metabolite of (Photorhabdus luminescence), artificial synthesized, structure is as follows：
Moral can not significantly inhibit multiple inflammatory cytokines such as interferon (IFN-γ), interleukin 2 to benzene alkene
(IL-2) and tumor necrosis factor-alpha (TNF-α) etc., and the vigor and wetting capacity of T cell can be inhibited.In addition, it by
Proof can inhibit mouse allergic contact dermatitis.These prompting benzene alkene not moral can be used for treating multiple autoimmune diseases and
Inflammation.
Above-claimed cpd structure is benzene alkene not moral, there are two phenolic hydroxyl groups in structure, is easily oxidized to form as quinones substance,
And aobvious red, temporarily become impurity X, Y, structure is as follows：
Liposome (liposome) is a kind of pharmaceutical carrier.It is by having the phospholipid bilayer structure of similar biofilm structure
Into vesicles.Drug can be embedded in a diameter of sub-micron or nano level lipid particles by it, and this particle has class
, in vivo can be biodegradable like biological cell membrane structure, non-immunogenicity.Encapsulated drug can be changed after into human body
Distribution in vivo, makes drug be mainly distributed in the histoorgans such as liver, spleen, lung and lymph, thus has certain organ targeting.Fat
Plastid extends the half-life period of drug, improves the therapeutic index of drug, reduce the poison of drug with that can protect pharmaceutical activity group
The features such as side reaction.Liposome still solves the another sharp weapon that insoluble drug plays its bioactivity, and application field includes
Drug, gene therapy, medical material, vaccine, biological agent, pesticide, cosmetics and health products etc..Simultaneously because double points of liposome
Sublayer structure is similar with cell membrane, therefore it can promote the effect of Medicated Permeation as external medicament carrier.
Alcohol plastid is used exclusively for a kind of special liposome vectors of Drug Percutaneous Absorption, is carried first by touitou etc.
Go out, the cholesterol in liposome is replaced with the alcohol of higher concentration.Compared with conventional liposome, there is grain size smaller, envelop rate is high,
The advantages of drugloading rate is big, there is better flexibility, transdermal efficient, and skin hold-up is big, therefore alcohol plastid is administered in New Percutaneous
It gets most of the attention in system research.
The cuticula of dense regular is the barrier of Drug Percutaneous Absorption, and alcohol plastid promotes drug transdermal to inhale as pharmaceutical carrier
There are mainly two types of the mechanism of receipts：1. penetrate mechanism：The imitated vesicle structure that alcohol plastid is formed carries drug and is directed through cuticula, due to
There is (ethyl alcohol, isopropanol, propylene glycol etc.) in the alcohol of phospholipid layer middle and high concentration (20%~45%), alcohol plastid has more preferably than liposome
Flexibility and film mobility, therefore penetration depth is deeply more many than liposome, and drug transdermal efficiency significantly improves；2. merge machine
System：The phosphatide of alcohol plastid is merged with Stratum corneum lipids, and the structure of cuticula dense regular is disturbed, while drug is released from vesica
It releases, penetrates skin alone.
The addition of alcohol is the main reason for transdermal efficiency of alcohol plastid enhances.On the one hand, alcohol, which inherently has, promotees infiltration work
With can reduce the critical-temperature of Stratum corneum lipids, increase its mobility；On the other hand, the addition of alcohol makes the grain size of alcohol plastid
Smaller, the mobility of imitated vesicle structure is stronger, and the variation beneficial to infiltration also has occurred in zeta current potentials.
Terpene compound is widely present in traditional medicine volatile oil, is the sensible middle the effective elements of the medicine of many wind dispellings.In recent years
Come, terpene compound has obtained widely studied and application as natural percutaneous transdermal enhancer in external preparation, due to this kind of
The secondary irritation of ingredient poison is very small, part by U.S. FDA be known as GRAS compounds (generally regarded as safe,
Generally acknowledged safe material), therefore, the percutaneous transdermal enhancer of terpenes has become the hot research field in transdermal delivery system.Big portion
Divide terpene compound that can promote the Transdermal absorption of opposed polarity effective ingredient as percutaneous transdermal enhancer, show good
Promote effect.
The most widely used master for being menthol (menthol), being Herba Menthae Haplocalycis volatile oil in terpenes dermal penetration enhancer
Want ingredient, levo form is also known as " menthol ", there is refrigerant and weak anesthetic effect to skin and mucous membrane, available for ease pain, it is antipruritic, anti-
Rotten and sterilization.The study found that menthol, which has the transdermal penetration of multi-medicament, remarkably promotes effect, and with outstanding security
It is included by FDA into GRAS (generally regarded as safe by the FDA).
Moral water solubility is not poor for benzene alkene, it is more difficult to water soluble preparation, such as spray, solution etc. be made.
Therefore benzene alkene agent, the especially external preparation not made in Germany that a kind of anxious property to be developed is stablized, it is same in preparation research
When pay close attention to preparation in bulk pharmaceutical chemicals oxidative degradation and enhancing Cutaneous permeation effect, so as to greatly enhance the stability of preparation and medicine
Effect.
The content of the invention
To reduce the generation of bulk pharmaceutical chemicals oxidative degradation impurity in preparation and enhancing the effect of its Cutaneous permeation.Inventor is by grinding
Study carefully, obtain a kind of medicinal external emulsifiable paste composition containing benzene alkene not moral, by main ingredient benzene alkene not moral, transdermal enhancer menthol, antioxygen
Agent Butylated Hydroxyanisole, oil phase solvent propylene glycol, emulsifier polyoxyethylene sorbitan monoleate, assistant for emulsifying agent glycerin monostearate, thickener 18
Alcohol, aqueous phase solvent purified water composition, said composition are further prepared into cream as follows：
Step 1：Benzene alkene not moral bulk pharmaceutical chemicals ultramicro grinding is taken, average grain diameter is spare less than 10 μm；
Step 2：Oil phase solvent propylene glycol is taken, heating water bath takes recipe quantity antioxidant Butylated Hydroxyanisole, benzene alkene is not successively to 60 DEG C
Moral, transdermal enhancer menthol, thickener octadecyl alcolol, the stirring of assistant for emulsifying agent glycerin monostearate, dissolving are oil phase；
Step 3：It fetches water phase solvent purified water, heating water bath is to 60 DEG C, stirring and dissolving emulsifier polyoxyethylene sorbitan monoleate, with 0.1M
NaOH or HCl adjusts pH value to 6.0-7.0, is water phase；
Step 4：Under vacuum, stirring, water is added in oil phase, is cooled down, it is lasting to stir, until system temperature drops
Down to room temperature, the emulsifiable paste containing benzene alkene not moral is obtained；
Step 5：The not moral emulsifiable paste of benzene alkene obtained by step 4 is taken, it is filling in aluminum ointment tube, obtain finished product.
The medicinal external emulsifiable paste composition containing benzene alkene not moral, unit formulation composition are as follows：
The above-mentioned medicinal external emulsifiable paste composition containing benzene alkene not moral, adds in liposome technology, is further prepared into external application lipid
Body cream, by main ingredient benzene alkene not moral, transdermal enhancer menthol, antioxidant Butylated Hydroxyanisole, lipid solvent ethyl alcohol, soybean lecithin
Fat, oil phase solvent propylene glycol, emulsifier polyoxyethylene sorbitan monoleate, assistant for emulsifying agent glycerin monostearate, thickener octadecyl alcolol, water mix
Agent purified water forms, and said composition is further prepared into medicinal external emulsifiable paste agent as follows：
Step 1：Benzene alkene not moral bulk pharmaceutical chemicals ultramicro grinding is taken, average grain diameter is spare less than 10 μm；
Step 2：Oil phase solvent propylene glycol is taken, heating water bath takes recipe quantity thickener octadecyl alcolol, assistant for emulsifying agent successively to 60 DEG C
Glycerin monostearate stirs, dissolving, is oil phase；
Step 3：Fetch water phase solvent, heating water bath is to 60 DEG C, stirring and dissolving emulsifier polyoxyethylene sorbitan monoleate, with 0.1M NaOH or
HCl adjusts pH value to 6.0-7.0, is water phase；
Step 4：Under vacuum conditions, water is added in oil phase, cooled down, it is lasting to stir, until system temperature is reduced to room
Temperature obtains blank emulsifiable paste matrix；
Step 5：Take recipe quantity soybean lecithin, benzene alkene not moral bulk pharmaceutical chemicals, antioxidant Butylated Hydroxyanisole, transdermal enhancer menthol
It is dissolved in appropriate absolute ethyl alcohol, is lipid soln, it is spare；
Step 6：Purified Water q. s are taken, pH value is adjusted to 6.0-7.0 with 0.1M NaOH or HCl, are liposome water phase, 40 DEG C,
Under agitation, it is reversed along water phase direction of rotation to match somebody with somebody the syringe of No. 25 syringe needles by lipid soln obtained by step 5, it is pasting
It is injected at nearly chamber wall in liposome water phase, is evaporated under reduced pressure, flings to ethyl alcohol, obtain benzene alkene not moral liposome turbid liquor；
Step 7：The not moral liposome turbid liquor of benzene alkene obtained by step 6 is taken, with step 4 gained blank emulsifiable paste matrix, mixing is stirred
It mixes uniformly, obtains benzene alkene not moral lipidosome cream；
Step 8：The not moral lipidosome cream of benzene alkene obtained by step 7 is taken, it is filling in aluminum ointment tube, obtain finished product.
The external-use liposome antiperspirant cream compositions containing benzene alkene not moral, unit formulation composition are as follows：
Further, the above-mentioned medicinal external emulsifiable paste containing benzene alkene not moral, adds in alcohol plastid technology, is further prepared into external application
Alcohol plastid cream, by main ingredient benzene alkene, moral, transdermal enhancer menthol, antioxidant Butylated Hydroxyanisole, soybean lecithin, lipid be not molten
Agent propylene glycol, emulsifier polyoxyethylene sorbitan monoleate, assistant for emulsifying agent glycerin monostearate, thickener octadecyl alcolol, aqueous phase solvent purified water
Composition, said composition are further prepared into cream as follows：
Step 1：Benzene alkene not moral bulk pharmaceutical chemicals ultramicro grinding is taken, average grain diameter is spare less than 10 μm；
Step 2：Recipe quantity thickener octadecyl alcolol, assistant for emulsifying agent glycerin monostearate are taken successively, and heating water bath is stirred to 60 DEG C
It mixes, dissolves, be oil phase；
Step 3：Fetch water phase solvent, heating water bath is to 60 DEG C, stirring and dissolving emulsifier polyoxyethylene sorbitan monoleate, with 0.1M NaOH or
HCl adjusts pH value to 6.0-7.0, is water phase；
Step 4：Under vacuum conditions, water is added in oil phase, cooled down, it is lasting to stir, until system temperature is reduced to room
Temperature obtains blank emulsifiable paste matrix；
Step 5：Take recipe quantity soybean lecithin, benzene alkene not moral bulk pharmaceutical chemicals, antioxidant Butylated Hydroxyanisole, transdermal enhancer menthol
It is dissolved in recipe quantity propylene glycol, is lipid soln, it is spare；
Step 6：Purified Water q. s are taken, pH value is adjusted to 6.0-7.0 with 0.1M NaOH or HCl, are alcohol plastid water phase, 40 DEG C,
Under agitation, by lipid soln obtained by step 5, to match somebody with somebody the syringe of No. 25 syringe needles along water phase direction of rotation direction, pasting
It is injected at nearly chamber wall in alcohol plastid water phase, obtains benzene alkene not moral alcohol plastid suspension；
Step 7：The not moral alcohol plastid suspension of benzene alkene obtained by step 6 is taken, with step 4 gained blank emulsifiable paste matrix, mixing is stirred
It mixes uniformly, obtains benzene alkene not moral alcohol plastid emulsifiable paste；
Step 8：The not moral lipidosome cream of benzene alkene obtained by step 7 is taken, it is filling in aluminum ointment tube, obtain finished product.
The external application alcohol plastid antiperspirant cream compositions containing benzene alkene not moral, unit formulation composition are as follows：
。
Patent application is further illustrated the present invention by testing as follows
The defects of oxidative degradation easy for the agent not made in Germany of benzene alkene, inventor intends the side by adding in antioxidant in preparation system
Formula, reduces the generation of oxidation reaction, and passes through addition transdermal enhancer, using liposome and alcohol plastid technology, increases benzene alkene not
The percutaneous abilities of moral external preparation enhance curative effect of medication.
Experiment proves that the every detection of gained cream complies with standard, and the generation of simultaneous oxidation degradation impurity is significantly pressed down
System, greatly increases and the stability of product, and percutaneous abilities are due to adding transdermal enhancer, using liposome and alcohol plastid skill
Art also significantly improves, and has achieved the purpose that of the invention initial.
Experiment one：Under different antioxygen agent concentrations, the degree of oxidation of drug and soybean lecithin.
This experiment is mainly investigated in ethanol solution, and under different antioxidant and antioxygen agent concentration, 4 is interior when small, antioxidant pair
Benzene alkene not moral and the stabilization of soybean lecithin, after testing benzene alkene used not oxidative degradation impurity, i.e. impurity X in moral bulk pharmaceutical chemicals
With the total amount of impurity Y, content 0.002%, soybean lecithin peroxide value POV is determined as 4 in usp40 methods.Experimental condition
And oxidative impurity levels are as follows under respective conditions：
Under 1 different condition of table, protective effect of the antioxidant to benzene alkene not moral
。
Under 2 different condition of table, (soybean lecithin degree of oxidation is with peroxide for protective effect of the antioxidant to soybean lecithin
Change value POV is counted)
。
As above data can be seen that Butylated Hydroxyanisole to benzene alkene not moral and soybean lecithin oxidation protection effect, hence it is evident that
Better than other three kinds of antioxidant, and i.e. to benzene alkene, moral and soybean lecithin oxidation do not have the Butylated Hydroxyanisole of 0.01%-0.05%
There is apparent inhibitory action.
Experiment two：Benzene alkene not test by moral emulsifiable paste prescription screening
Design following composition：
。
Preparation process：
Step 1：Benzene alkene not moral bulk pharmaceutical chemicals ultramicro grinding is taken, average grain diameter is spare less than 10 μm；
Step 2：Oil phase solvent propylene glycol is taken, heating water bath takes recipe quantity antioxidant Butylated Hydroxyanisole, benzene alkene is not successively to 60 DEG C
Moral, transdermal enhancer menthol, thickener octadecyl alcolol, the stirring of assistant for emulsifying agent glycerin monostearate, dissolving are oil phase；
Step 3：Fetch water phase solvent, heating water bath is to 60 DEG C, stirring and dissolving emulsifier polyoxyethylene sorbitan monoleate, with 0.1M NaOH or
HCl adjusts pH value to 6.0-7.0, is water phase；
Step 4：Under vacuum conditions, water is added in oil phase, cooled down, it is lasting to stir, until system temperature is reduced to room
Temperature obtains the emulsifiable paste containing benzene alkene not moral；
Step 5：The not moral emulsifiable paste of benzene alkene obtained by step 4 is taken, it is filling in aluminum ointment tube, obtain finished product.
Test result analysis：Above-mentioned prescription 1-4 emulsifiable pastes shaping is preferable, and uniform color, quality is fine and smooth, has appropriate toughness,
It is easy to apply on skin, no sand type.
Experiment three：Benzene alkene not test by moral lipidosome cream prescription screening
Design following composition：
。
Preparation process is as follows：
Step 1：Benzene alkene not moral bulk pharmaceutical chemicals ultramicro grinding is taken, average grain diameter is spare less than 10 μm；
Step 2：Oil phase solvent propylene glycol is taken, heating water bath takes recipe quantity thickener octadecyl alcolol, assistant for emulsifying agent successively to 60 DEG C
Glycerin monostearate stirs, dissolving, is oil phase；
Step 3：Fetch water phase solvent, heating water bath is to 60 DEG C, stirring and dissolving emulsifier polyoxyethylene sorbitan monoleate, with 0.1M NaOH or
HCl adjusts pH value to 6.0-7.0, is water phase；
Step 4：Under vacuum conditions, water is added in oil phase, cooled down, it is lasting to stir, until system temperature is reduced to room
Temperature obtains blank emulsifiable paste matrix；
Step 5：Take recipe quantity soybean lecithin, benzene alkene not moral bulk pharmaceutical chemicals, antioxidant Butylated Hydroxyanisole, transdermal enhancer menthol
It is dissolved in appropriate absolute ethyl alcohol, is lipid soln, it is spare；
Step 6：Purified Water q. s are taken, pH value is adjusted to 6.0-7.0 with 0.1M NaOH or HCl, are liposome water phase, 40 DEG C,
Under agitation, it is reversed along water phase direction of rotation to match somebody with somebody the syringe of No. 25 syringe needles by lipid soln obtained by step 5, it is pasting
It is injected at nearly chamber wall in liposome water phase, is evaporated under reduced pressure, flings to ethyl alcohol, obtain benzene alkene not moral liposome turbid liquor；
Step 7：The not moral liposome turbid liquor of benzene alkene obtained by step 6 is taken, with step 4 gained blank emulsifiable paste matrix, mixing is stirred
It mixes uniformly, obtains benzene alkene not moral lipidosome cream；
Step 8：The not moral lipidosome cream of benzene alkene obtained by step 7 is taken, it is filling in aluminum ointment tube, obtain finished product.
Test result analysis：Above-mentioned prescription 1-4 emulsifiable pastes shaping is preferable, and uniform color, quality is fine and smooth, has appropriate toughness,
It is easy to apply on skin, no sand type.
Experiment four：Benzene alkene not test by moral alcohol plastid emulsifiable paste prescription screening
Design following composition：
。
Preparation process is as follows：
Step 1：Benzene alkene not moral bulk pharmaceutical chemicals ultramicro grinding is taken, average grain diameter is spare less than 10 μm；
Step 2：Recipe quantity thickener octadecyl alcolol, assistant for emulsifying agent glycerin monostearate are taken successively, and heating water bath is stirred to 60 DEG C
It mixes, dissolves, be oil phase；
Step 3：Fetch water phase solvent, heating water bath is to 60 DEG C, stirring and dissolving emulsifier polyoxyethylene sorbitan monoleate, with 0.1M NaOH or
HCl adjusts pH value to 6.0-7.0, is water phase；
Step 4：Under vacuum conditions, water is added in oil phase, cooled down, it is lasting to stir, until system temperature is reduced to room
Temperature obtains blank emulsifiable paste matrix；
Step 5：Take recipe quantity soybean lecithin, benzene alkene not moral bulk pharmaceutical chemicals, antioxidant Butylated Hydroxyanisole, transdermal enhancer menthol
It is dissolved in recipe quantity propylene glycol, is lipid soln, it is spare；
Step 6：Purified Water q. s are taken, pH value is adjusted to 6.0-7.0 with 0.1M NaOH or HCl, are alcohol plastid water phase, 40 DEG C,
Under agitation, by lipid soln obtained by step 5, to match somebody with somebody the syringe of No. 25 syringe needles along water phase direction of rotation direction, pasting
It is injected at nearly chamber wall in alcohol plastid water phase, obtains benzene alkene not moral alcohol plastid suspension；
Step 7：The not moral alcohol plastid suspension of benzene alkene obtained by step 6 is taken, with step 4 gained blank emulsifiable paste matrix, mixing is stirred
It mixes uniformly, obtains benzene alkene not moral alcohol plastid emulsifiable paste；
Step 8：The not moral lipidosome cream of benzene alkene obtained by step 7 is taken, it is filling in aluminum ointment tube, obtain finished product.
Test result analysis：Above-mentioned prescription 1-4 emulsifiable pastes shaping is preferable, and uniform color, quality is fine and smooth, has appropriate toughness,
It is easy to apply on skin, no sand type.
Experiment five：It tests three gained liposomes and tests the envelop rate of four gained alcohol plastids
Taking three gained benzene alkene of experiment, moral liposome and four gained alcohol plastid samples of experiment are not appropriate, free with the separation of centrifugal ultrafiltration method
Drug calculates free drug and wrapped medication amount respectively, to be wrapped medication amount/(being wrapped medication amount+free drug amount) *
100% is envelop rate, and acquired results are as follows：
。
To test benzene alkene prepared by three prescriptions and technique not moral liposome and alcohol plastid it can be seen from upper table data
Envelop rate is good, more than 95%, close to 100%, it is seen that although water-soluble water solubility is not bad for moral molecule for benzene alkene, but fat-soluble
Well, and with phospholipid bilayer there is good compatibility, can be present in mosaic mode in bilayer, therefore lipid
The envelop rate of body and alcohol plastid is very high.
Experiment six：Liposome and alcohol plastid droplet measurement
Taking three gained benzene alkene of experiment, moral liposome and four gained alcohol plastid samples of experiment are not appropriate, with dynamic light scattering determination grain
Footpath, acquired results are as shown in the table：
。
Because prepared by use injection method, when lipid mixture and water are in contact in the process, great shearing force is have passed through, therefore
Gained liposome and alcohol plastid grain size are smaller.
Experiment seven：Usual cream, liposome and alcohol plastid medicinal external emulsifiable paste release in vitro：
Two gained medicinal external emulsifiable pastes of experiment are taken, test three gained liposomes and the appropriate (sample of four alcohol plastid medicinal external emulsifiable paste samples of experiment
Number A1-A4, B1-B4, C1-C4), it separately takes by not adding in the benzene alkene of skin penetration enhancer and antioxidant obtained by example IV not
Moral usual cream is control sample D, and the film through performance of three is evaluated using molecular cut off as 3500 semi-permeable membrane.Method is such as
Under：Extracorporeal releasing experiment cuts off the bag filter of molecular cut off 3500 for dialysis membrane, and dialysis membrane is placed in 2% (m/V) carbonic acid
In hydrogen sodium and 1mmol/L natrium adetates (pH=8.0), 10min is boiled, is let cool, then thoroughly float dialysis membrane with distilled water
It washes, it is spare.Using Franz diffusion cells as release device.Dialysis membrane is fixed between supply pool and reception tank, precision weighs 1.0g
Sample is spread evenly across on semi-permeable membrane, spreading area, 1cm2, release receiving liquid is 0.5% lauryl sodium sulfate physiological saline
Solution, volume 6.4mL, temperature be (37 ± 1) DEG C, magnetic stirring speed 300r/min.Respectively at 15min, 30min, 1h, 2h,
4h, 6h, 8h, 12h, 16h are sampled, and per sub-sampling 1mL, while add 1mL physiological saline.Sample is with 0.45um filtering with microporous membrane
HPLC is carried out afterwards and measures content of drug, calculates drug release percentage.It is as shown in the table：
。
Skin penetration enhancer and the common benzene alkene of antioxidant are not added in example IV gained as upper table data can be seen that
Moral emulsifiable paste sample D is not compared, and sample A, B, C transmission rates increased, and be sequentially C>B>A, i.e. alcohol plastid emulsifiable paste>Liposome
Emulsifiable paste>Add transdermal enhancer emulsifiable paste>Usual cream.
Experiment four：Usual cream, liposome and the in-vitro percutaneous release of alcohol plastid medicinal external emulsifiable paste
Two gained medicinal external emulsifiable pastes of experiment are taken, test three gained liposomes and the appropriate (sample of four alcohol plastid medicinal external emulsifiable paste samples of experiment
Number A1-A4, B1-B4, C1-C4), separately take by example IV prepare benzene alkene not moral usual cream be control sample D, with sucking pig skin
Skin evaluates the film through performance of three.
Method is as follows：By sucking pig arteria carotis sacrificed by exsanguination, with electric razor unhairing, skin is stripped, is prepared into dermatotome
Homogeneous thickness, -80 DEG C save backup.
The transdermal penetration burst size of sample is investigated using vertical Franz diffusion tests instrument.Suckling pig skin is taken to be placed in physiology salt
It is cleaned in water.Its cuticula is fixed between the supply pool of diffusion cell and acceptance pool upward, drains bubble, recirculated water is kept
(37±0.5)℃.The accepting medium to deaerate in advance is added in acceptance pool, is 0.5% lauryl sodium sulfate physiological saline of 35ml
Solution adds stirrer with 300rmin-1Speed stirring.Precision weighs 1.0g samples and is spread evenly across on skin, spreading area
For 3.3cm2, respectively at 2,4,8,18,20,22 and sampling 1mL for 24 hours, and supplement the receiving liquid of equivalent equality of temperature.Sample is with 0.45um
HPLC is carried out after filtering with microporous membrane and measures content of drug, drug is calculated and adds up to discharge percentage.It is as shown in the table：
。
From upper table data, transdermal enhancer menthol, liposome, the introducing of the technology of alcohol plastid gradually increased common
The 24 of emulsifiable paste it is small when skin add up transit dose, i.e. alcohol plastid emulsifiable paste>Lipidosome cream>Add transdermal enhancer emulsifiable paste>Usual cream.
Experiment five：Product irritation test：
Two gained medicinal external emulsifiable pastes of experiment are taken, test three gained liposomes and the appropriate (sample of four alcohol plastid medicinal external emulsifiable paste samples of experiment
Number A1-A4, B1-B4, C1-C4).
New zealand rabbit 24, is divided into normal skin group and damaged skin group, every group 1.It is right using androgynous left and right sides itself
Compare method.Depilation processing, each one piece of left and right, unhairing scope 3cm*3cm are carried out to administration area for 24 hours before experiment.Damaged skin group with
" well " word is drawn at medicine position, to ooze out blood as degree.Sample A1-A4, B1-B4, C1-C4 emulsifiable paste 0.5g is smeared at the depilation of left side respectively,
Right side applies equivalent blank control emulsifiable paste.Application time 4h, once a day, continuous 28 days.After sticking, remove test sample and be used in combination
Warm water or nonirritant solvent cleaning medicine-feeding part.It examines skin at coating whether there is erythema or oedema before each coating, stops
Continue observation 3 days after medicine.
Result of the test：In administration phase and observation period.Rabbit medicine-feeding part and comparing part are visually observed under full spectrum light
Position skin is showed no erythema and is formed.Also the lesions such as erosion, ulcer are had no.It is checked under mirror.Normal skin group and damaged skin group are empty
White control position epidermis is complete.Surface is without parakeratosis.Stratum granulosum, spinous layer thickness are normal.Cell has no denaturation, necrosis.Corium
Blood vessel is without apparent expansion or congested.Interstitial is without oedema.The adnexal structures such as hair follicle, sebaceous glands understand.Normal skin group and
Damaged skin group gives position epidermis each layer tissue structural integrity.Corium is without blood vessel dilatation, hyperemia and inflammatory cell infiltration.
Test six heat-resisting low temperature resistant tests：
Two gained medicinal external emulsifiable pastes of experiment are taken, test three gained liposomes and the appropriate (sample of four alcohol plastid medicinal external emulsifiable paste samples of experiment
Number A1-A4, B1-B4, C1-C4) in right amount, be respectively placed in 55 DEG C of constant temperature 6 it is small when and -15 DEG C place 24 it is small when, see whether point
Layer, it is as a result as follows：
。
Experiment seven：Accelerated stability experiment in 12 months
Two gained medicinal external emulsifiable pastes of experiment are taken, test three gained liposomes and the appropriate (sample of four alcohol plastid medicinal external emulsifiable paste samples of experiment
Number A1-A4, B1-B4, C1-C4), another four gained of Example does not add in skin penetration enhancer and the common benzene alkene of antioxidant not
Moral emulsifiable paste sample D (containing packaging), puts 40 DEG C ± 2 DEG C, is stored 12 months under the conditions of 75% ± 5%RH, respectively respectively at 0 month, 1
Month, relevant nature is measured by sampling, obtains corresponding data December in June in March, it is as shown in the table：
5 four kinds of formulation samples stability of table compare
。
It can be seen from upper table data according to it is of the present invention experiment two gained medicinal external emulsifiable pastes, test three gained liposomes and
Four alcohol plastid medicinal external emulsifiable paste samples are tested, at 40 DEG C ± 2 DEG C, under 75% ± 5%RH acceleration environments, after storage in 12 months, are contained
Amount, related substance are varied from, but content is more than 98.5%, oxidation impurities total amount and maximum single contaminant no more than
0.05%, total impurities is below 1.0%；It corresponds, skin penetration enhancer and antioxidant is not added in obtained by example IV
Moral emulsifiable paste sample D is not after accelerating storage in 12 months for common benzene alkene, and content falls to approximately 95%, and oxidation impurities total amount is more than
1.5%, maximum single contaminant is more than 1.5%, and total impurities is then close to 5.0%.
Based on as above analyzing, according to two gained medicinal external emulsifiable pastes of experiment of the present invention, three gained liposomes and experiment four are tested
Under acceleration conditions, the data after storing 12 months are shown alcohol plastid medicinal external emulsifiable paste sample, and stability is significantly better than embodiment
Four gained do not add in skin penetration enhancer and the common benzene alkene of antioxidant not moral emulsifiable paste sample D, i.e., by the prescription of the present invention and
The stability of benzene alkene not moral emulsifiable paste is remarkably reinforced in technique, and oxidation and the generation of hydrolysis impurity are significantly inhibited, from
And cause the present invention that there is prominent substantive distinguishing features and marked improvement, and with practicability.
Specific embodiment
The advantageous effect further illustrated the present invention is tested by following.But it is not limited to following embodiments, this field
Technical staff made on the basis of the present invention, equivalent substitute or the conversion of substantive content of the present invention are not departed from, also at this
Within the protection domain of invention.
Moral cream does not prepare (unit to 1 benzene alkene of embodiment：g)
Composition：
。
Preparation process：
Step 1：Benzene alkene not moral bulk pharmaceutical chemicals ultramicro grinding is taken, average grain diameter is spare less than 10 μm；
Step 2：Oil phase solvent propylene glycol is taken, heating water bath takes recipe quantity antioxidant Butylated Hydroxyanisole, benzene alkene is not successively to 60 DEG C
Moral, transdermal enhancer menthol, thickener octadecyl alcolol, the stirring of assistant for emulsifying agent glycerin monostearate, dissolving are oil phase；
Step 3：Fetch water phase solvent, heating water bath is to 60 DEG C, stirring and dissolving emulsifier polyoxyethylene sorbitan monoleate, with 0.1M NaOH or
HCl adjusts pH value to 6.0-7.0, is water phase；
Step 4：Under vacuum conditions, water is added in oil phase, cooled down, it is lasting to stir, until system temperature is reduced to room
Temperature obtains the emulsifiable paste containing benzene alkene not moral；
Step 5：The not moral emulsifiable paste of benzene alkene obtained by step 4 is taken, it is filling in aluminum ointment tube, obtain finished product.
Not prepared by the agent of moral lipidosome cream for 2 benzene alkene of embodiment
Composition：
。
Preparation process is as follows：
Step 1：Benzene alkene not moral bulk pharmaceutical chemicals ultramicro grinding is taken, average grain diameter is spare less than 10 μm；
Step 2：Oil phase solvent propylene glycol is taken, heating water bath takes recipe quantity thickener octadecyl alcolol, assistant for emulsifying agent successively to 60 DEG C
Glycerin monostearate stirs, dissolving, is oil phase；
Step 3：Fetch water phase solvent, heating water bath is to 60 DEG C, stirring and dissolving emulsifier polyoxyethylene sorbitan monoleate, with 0.1M NaOH or
HCl adjusts pH value to 6.0-7.0, is water phase；
Step 4：Under vacuum conditions, water is added in oil phase, cooled down, it is lasting to stir, until system temperature is reduced to room
Temperature obtains blank emulsifiable paste matrix；
Step 5：Take recipe quantity soybean lecithin, benzene alkene not moral bulk pharmaceutical chemicals, antioxidant Butylated Hydroxyanisole, transdermal enhancer menthol
It is dissolved in appropriate absolute ethyl alcohol, is lipid soln, it is spare；
Step 6：Purified Water q. s are taken, pH value is adjusted to 6.0-7.0 with 0.1M NaOH or HCl, are liposome water phase, 40 DEG C,
Under agitation, it is reversed along water phase direction of rotation to match somebody with somebody the syringe of No. 25 syringe needles by lipid soln obtained by step 5, it is pasting
It is injected at nearly chamber wall in liposome water phase, is evaporated under reduced pressure, flings to ethyl alcohol, obtain benzene alkene not moral liposome turbid liquor；
Step 7：The not moral liposome turbid liquor of benzene alkene obtained by step 6 is taken, with step 4 gained blank emulsifiable paste matrix, mixing is stirred
It mixes uniformly, obtains benzene alkene not moral lipidosome cream；
Step 8：The not moral lipidosome cream of benzene alkene obtained by step 7 is taken, it is filling in aluminum ointment tube, obtain finished product.
Not prepared by moral alcohol plastid cream for 3 benzene alkene of embodiment
Composition：
。
Preparation process is as follows：
Step 1：Benzene alkene not moral bulk pharmaceutical chemicals ultramicro grinding is taken, average grain diameter is spare less than 10 μm；
Step 2：Recipe quantity thickener octadecyl alcolol, assistant for emulsifying agent glycerin monostearate are taken successively, and heating water bath is stirred to 60 DEG C
It mixes, dissolves, be oil phase；
Step 3：Fetch water phase solvent, heating water bath is to 60 DEG C, stirring and dissolving emulsifier polyoxyethylene sorbitan monoleate, with 0.1M NaOH or
HCl adjusts pH value to 6.0-7.0, is water phase；
Step 4：Under vacuum conditions, water is added in oil phase, cooled down, it is lasting to stir, until system temperature is reduced to room
Temperature obtains blank emulsifiable paste matrix；
Step 5：Take recipe quantity soybean lecithin, benzene alkene not moral bulk pharmaceutical chemicals, antioxidant Butylated Hydroxyanisole, transdermal enhancer menthol
It is dissolved in recipe quantity propylene glycol, is lipid soln, it is spare；
Step 6：Purified Water q. s are taken, pH value is adjusted to 6.0-7.0 with 0.1M NaOH or HCl, are alcohol plastid water phase, 40 DEG C,
Under agitation, by lipid soln obtained by step 5, to match somebody with somebody the syringe of No. 25 syringe needles along water phase direction of rotation direction, pasting
It is injected at nearly chamber wall in alcohol plastid water phase, obtains benzene alkene not moral alcohol plastid suspension；
Step 7：The not moral alcohol plastid suspension of benzene alkene obtained by step 6 is taken, with step 4 gained blank emulsifiable paste matrix, mixing is stirred
It mixes uniformly, obtains benzene alkene not moral alcohol plastid emulsifiable paste；
Step 8：The not moral lipidosome cream of benzene alkene obtained by step 7 is taken, it is filling in aluminum ointment tube, obtain finished product.
Moral cream does not prepare (unit to 4 benzene alkene of embodiment：g)
。
Preparation process：
Step 1：Benzene alkene not moral bulk pharmaceutical chemicals ultramicro grinding is taken, average grain diameter is spare less than 10 μm；
Step 2：Oil phase solvent propylene glycol is taken, heating water bath takes recipe quantity benzene alkene not moral successively to 60 DEG C, thickener octadecyl alcolol,
Assistant for emulsifying agent glycerin monostearate stirs, dissolving, is oil phase；
Step 3：Fetch water phase solvent, heating water bath is to 60 DEG C, stirring and dissolving emulsifier polyoxyethylene sorbitan monoleate, with 0.1M NaOH or
HCl adjusts pH value to 6.0-7.0, is water phase；
Step 4：Under vacuum conditions, water is added in oil phase, cooled down, it is lasting to stir, until system temperature is reduced to room
Temperature obtains the emulsifiable paste containing benzene alkene not moral；
Step 5：The not moral emulsifiable paste of benzene alkene obtained by step 4 is taken, it is filling in aluminum ointment tube, obtain finished product.
Claims (10)
1. a kind of medicinal external emulsifiable paste composition containing benzene alkene not moral, by main ingredient benzene alkene not moral, transdermal enhancer menthol, antioxidant
Butylated Hydroxyanisole, oil phase solvent propylene glycol, emulsifier polyoxyethylene sorbitan monoleate, assistant for emulsifying agent glycerin monostearate, thickener octadecyl alcolol,
Aqueous phase solvent purified water forms, and unit formulation composition is as follows：
Said composition is further prepared into cream as follows：
Step 1：Benzene alkene not moral bulk pharmaceutical chemicals ultramicro grinding is taken, average grain diameter is spare less than 10 μm；
Step 2：Oil phase solvent propylene glycol is taken, heating water bath takes recipe quantity antioxidant Butylated Hydroxyanisole, benzene alkene is not successively to 60 DEG C
Moral, transdermal enhancer menthol, thickener octadecyl alcolol, the stirring of assistant for emulsifying agent glycerin monostearate, dissolving are oil phase；
Step 3：It fetches water phase solvent purified water, heating water bath is to 60 DEG C, stirring and dissolving emulsifier polyoxyethylene sorbitan monoleate, with 0.1M
NaOH or HCl adjusts pH value to 6.0-7.0, is water phase；
Step 4：Under vacuum, stirring, water is added in oil phase, is cooled down, it is lasting to stir, until system temperature drops
Down to room temperature, the emulsifiable paste containing benzene alkene not moral is obtained；
Step 5：The not moral emulsifiable paste of benzene alkene obtained by step 4 is taken, it is filling in aluminum ointment tube, obtain finished product.
2. a kind of external-use liposome cream containing benzene alkene not moral, by main ingredient benzene alkene not moral, transdermal enhancer menthol, antioxygen
Agent Butylated Hydroxyanisole, lipid solvent ethyl alcohol, soybean lecithin, oil phase solvent propylene glycol, emulsifier polyoxyethylene sorbitan monoleate, assistant for emulsifying agent list
Tristerin, thickener octadecyl alcolol, aqueous phase solvent purified water composition, unit formulation composition are as follows：
。
Said composition is further prepared into medicinal external emulsifiable paste agent as follows：
Step 1：Benzene alkene not moral bulk pharmaceutical chemicals ultramicro grinding is taken, average grain diameter is spare less than 10 μm；
Step 2：Oil phase solvent propylene glycol is taken, heating water bath takes recipe quantity thickener octadecyl alcolol, assistant for emulsifying agent successively to 60 DEG C
Glycerin monostearate stirs, dissolving, is oil phase；
Step 3：Fetch water phase solvent, heating water bath is to 60 DEG C, stirring and dissolving emulsifier polyoxyethylene sorbitan monoleate, with 0.1M NaOH or
HCl adjusts pH value to 6.0-7.0, is water phase；
Step 4：Under vacuum conditions, water is added in oil phase, cooled down, it is lasting to stir, until system temperature is reduced to room
Temperature obtains blank emulsifiable paste matrix；
Step 5：Take recipe quantity soybean lecithin, benzene alkene not moral bulk pharmaceutical chemicals, antioxidant Butylated Hydroxyanisole, transdermal enhancer menthol
It is dissolved in appropriate absolute ethyl alcohol, is lipid soln, it is spare；
Step 6：Purified Water q. s are taken, pH value is adjusted to 6.0-7.0 with 0.1M NaOH or HCl, are liposome water phase, 40 DEG C,
Under agitation, it is reversed along water phase direction of rotation to match somebody with somebody the syringe of No. 25 syringe needles by lipid soln obtained by step 5, it is pasting
It is injected at nearly chamber wall in liposome water phase, is evaporated under reduced pressure, flings to ethyl alcohol, obtain benzene alkene not moral liposome turbid liquor；
Step 7：The not moral liposome turbid liquor of benzene alkene obtained by step 6 is taken, with step 4 gained blank emulsifiable paste matrix, mixing is stirred
It mixes uniformly, obtains benzene alkene not moral lipidosome cream；
Step 8：The not moral lipidosome cream of benzene alkene obtained by step 7 is taken, it is filling in aluminum ointment tube, obtain finished product.
3. benzene alkene as described in claim 1 not moral medicinal external emulsifiable paste agent, which is characterized in that composition is as follows：
4. benzene alkene as described in claim 1 not moral medicinal external emulsifiable paste agent, which is characterized in that composition is as follows：
5. benzene alkene as described in claim 1 not moral medicinal external emulsifiable paste agent, which is characterized in that composition is as follows：
6. benzene alkene as described in claim 1 not moral medicinal external emulsifiable paste agent, which is characterized in that composition is as follows：
7. benzene alkene as claimed in claim 2 not moral external-use liposome cream, which is characterized in that composition is as follows：
8. benzene alkene as claimed in claim 2 not moral external-use liposome cream, which is characterized in that composition is as follows：
9. benzene alkene as claimed in claim 2 not moral external-use liposome cream, which is characterized in that composition is as follows：
10. benzene alkene as claimed in claim 2 not moral external-use liposome cream, which is characterized in that composition is as follows：
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113797159A (en) * | 2021-10-22 | 2021-12-17 | 冠昊生物科技股份有限公司 | Vatinuomod cream and preparation method and application thereof |
| CN114569586A (en) * | 2022-01-28 | 2022-06-03 | 鲁奕诗 | Bendanimod enema and preparation method thereof |
| CN116265421A (en) * | 2021-12-17 | 2023-06-20 | 上海泽德曼医药科技有限公司 | Compounds for preventing or treating central nervous system related diseases |
| WO2023109859A1 (en) * | 2021-12-15 | 2023-06-22 | 上海泽德曼医药科技有限公司 | Stilbene compound and application thereof in prevention and/or treatment for central nervous system-related diseases |
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| CN113797159A (en) * | 2021-10-22 | 2021-12-17 | 冠昊生物科技股份有限公司 | Vatinuomod cream and preparation method and application thereof |
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| CN114569586B (en) * | 2022-01-28 | 2023-12-05 | 鲁奕诗 | Benzenimod enema and preparation method thereof |
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Application publication date: 20180525 |