CN107137352B

CN107137352B - Novel foaming agent

Info

Publication number: CN107137352B
Application number: CN201710398045.2A
Authority: CN
Inventors: 李鹏飞; 李春娟; 吴龙昊; 张严源
Original assignee: Do Pharma Tech Co ltd
Current assignee: Beijing Xingyuanxiang Biotechnology Group Co ltd
Priority date: 2017-05-31
Filing date: 2017-05-31
Publication date: 2020-05-22
Anticipated expiration: 2037-05-31
Also published as: CN107137352A

Abstract

Provides a preparation method of a novel aerosol foaming agent. The foaming agent contains 0.001-0.04% (w/w) of surfactant for foaming.

Description

Novel foaming agent

Technical Field

The invention relates to a novel preparation method of a foaming agent, wherein the foaming agent is prepared by using a trace amount of a surfactant.

Background

The foaming agent is a formulation product which is prepared by dispersing a solution, an emulsion, a suspension or a gel in a propellant, storing the mixture by using a pressure-resistant container and finally spraying the mixture in a solid foam form for use. Foreign application to the medical field is called foam, and application to the daily chemical field is called mouse (mousse). The external preparation is characterized by convenient use, small density, small shearing stress, good body feeling, easy distribution on the epidermis and the cavity compared with other external preparations, no contamination, better absorption, capability of ensuring the adsorption and action time of the product, easy washing and strong compliance, and can form a thin medicine film after being used.

The foaming agent can be divided into a non-rapid elimination foaming agent and a rapid elimination foaming agent, wherein the prior art of the rapid elimination foaming agent generally adopts an alcohol-water system, namely ethanol and water as carrier media. When the quick-elimination foam is used on the surface of a human body, the foam can be quickly defoamed under the action of the body temperature to form a liquid state and is automatically dispersed on an action part. The surfactant plays a major role in foaming, and can be used for solubilization, emulsification, etc., when necessary. When the main purpose is foaming, a surfactant having a certain foaming ability, that is, the surfactant for foaming mentioned in the present invention, should be selected.

US2678147 proposes the idea that aerosols behave as foams, but no very detailed embodiment has been given at this time.

US3092555, US3144386 propose specific foaming agent preparation methods and gradually lead to preparation methods of general foaming agents, including general surfactant use methods. In the research and implementation throughout the years, people are used to set the dosage of the surfactant in the range of 0.1-15%. US 397884 explicitly proposes to prepare the foam in an emulsified manner, but its surfactant is also a common amount falling within the above range.

Similar obvious problems with the use of surfactants have long been the subject of extensive research on foaming agents, which has been to place the surfactant at greater than 0.1%. In fact, it is not uncommon to use surfactants in very small proportions in addition to the foaming agent. The inventors have surprisingly found, by experimental studies, that foam formulations of good quality can be prepared when the amount of surfactant used is reduced by a large amount, e.g. less than 0.04%

Surfactants are widely used in industry for dispersion, wetting, penetration, solubilization, emulsification, air bubbling, lubrication, sterilization, and the like. The surfactant is difficult to be effectively treated, and the use of a large amount of surfactant can inevitably discharge the surfactant into water and soil in the forms of waste water, waste residue and the like, and finally influences the whole ecological environment.

Surfactants affect soil primarily its water retention properties, particle aggregation ability, and soil pH. The surfactant mainly influences the gas exchange capacity between the water body and the air, and directly causes the increase of the dissolved amount of harmful pollutants in water, and the like. When the content of the surfactant in the water body is high, the growth of algae and other primary organisms in the water body is influenced, so that the food chain of aquatic organisms in the water body is damaged. In addition, the surfactant has different effects on animals, such as increase of animal poisoning phenomenon, sex ratio change and the like, and especially, the artificially synthesized surfactant has accumulation effect and larger harm degree.

The conventional foaming agent preparation process has the condition of common surfactant abuse, and the inventor finds that the use of the surfactant in the conventional process is unreasonable through experiments, and most products can achieve the ideal preparation effect by using a trace amount of the surfactant. Greatly reduces the use of the surfactant, can effectively reduce the influence of the industry on the environment, and reduces the production cost and the social cost.

The formulation characteristics of the foaming agent determine that the foaming agent has relatively poor physical stability under the conditions of overhigh temperature or overlow temperature, namely, incomplete foaming state or no foaming easily occurs under the temperature conditions. The disadvantageous physical stability is also more pronounced in terms of the cold-forming effect, since the foaming agent itself is present in the pressure vessel and is not allowed to be stored at too high a temperature. This effect is relatively weak for non-quick-release foams and is more pronounced for quick-release foams. The micro-surfactant technology used in the invention can obviously improve the physical stability of the foaming agent in the aspect, and achieve the preparation effect which is often difficult to achieve by the traditional process.

AU463216 mentions the concept of rapid foam elimination (quick breaking foam) in which the foam solution is anhydrous. WO8501876 describes a chlorhexidine acetate composition, which is essentially a rapid defoaming composition, wherein the technical characteristic of rapid defoaming is that the content of aliphatic alcohol is 40% -90%, and the best is 60%; the water content is 10% -40%; 5% -10% of aliphatic alcohol; the surfactant is preferably polysorbate 0.1-15%. WO8801863 relates to a series of processes for the preparation of minoxidil foams, among which there is a rapid elimination foam based on high ethanol. The technical system mainly disclosed by the patent is adopted for subsequent mass quick-elimination type foaming agent products. The fast-eliminating foam established in the system has the core technical characteristics that the fast-eliminating foam contains 30-75% of ethanol, 0.5-10% of emulsifier, 10-50% of water and 2.5-25% of chlorofluoroalkane (CFC) serving as a propellant. This technical process was subsequently developed into a technical system using short-chain gaseous alkanes, such as propane, butane, isobutane, etc., as propellants. For example, CN96192817.4 provides a typical solution for a fast-release foam formulation, wherein ethanol, emulsifier, water are added in accordance with WO8801863, except that CN96192817.4 uses propane and butane as propellants. The foaming agent development in the last decades of the world is along with or applied to or derived from the technical scheme of CN 96192817.4. Products that have been developed by this technology include ROGAINE, EXTINA, OLUX, EVOCLIN, and the like.

The use of chlorofluoroalkanes has been limited internationally due to the significant damaging effect on the ozone layer. The widely adopted technical scheme of short-chain alkane at present has great potential safety hazard. The problems of flammability and explosiveness of propane, butane, isobutane or other short-chain alkanes cause that the conventional foaming agent has different safety hazards in material storage, production control, inspection, transportation, daily use and the like. These limit the development of a large number of foam products as an excellent formulation.

Tetrafluoroethane is also called HFC134a as a novel hydrofluoroalkane which can meet the requirement of throwing and is safe and environment-friendly, and has been popularized in the field of aerosol for many years as a substitute product of chlorofluoroalkane. However, tetrafluoroethane as a foaming agent propellant has a high technical threshold, and no mature foaming agent product is active on the market so far. Through a large number of researches, under the condition that the technical range of WO8801863 contains 30-75% of ethanol, 0.5-10% of emulsifier and 10-50% of water, when the dosage of the ethanol reaches or exceeds 45%, the tetrafluoroethane is used as a propellant, so that an ideal foam effect is difficult to obtain, and a complete foam form cannot be presented at a relatively low temperature such as 15 ℃. When the ethanol dosage is less than 45 percent, the prepared foam is difficult to meet the requirement of quick elimination. The reason for this is that the inside of the good and uniform foaming agent is uniform aerosol, and the propellant in the pressure-resistant tank is well dissolved or uniformly dispersed with other contents. The aerosol balance of the content of the foaming agent is greatly changed at low temperature, the integrity of the foam is obviously influenced, and the influence of a system with tetrafluoroethane as a propellant is particularly remarkable.

The good foam form is maintained at 15-25 ℃, and the foam is considered as a basic requirement for meeting daily use requirements. In the foam elimination experiment, it was considered that 50ml of the foaming agent at 37 ℃ completely eliminated as a liquid in 2 minutes was sufficient for quick elimination. The quick-release foaming agent has a poor foaming state at a high temperature, for example, 30 ℃.

The inventor focuses on the research work of novel propellant in the field of foaming agent, and applies tetrafluoroethane as propellant to foaming agent smoothly in CN200910081689.4, and applies the technology thereof to industrialization through complete and detailed research, and the product becomes the first foaming agent product which uses tetrafluoroethane as propellant and obtains clinical permission in China. However, CN200910081689.4, although successfully applied tetrafluoroethane, did not have the property of rapid elimination. The inventors have conducted studies. The process method provided by the invention is applied to the preparation of the quick elimination type foaming agent and also applied to the preparation of the quick elimination type foaming agent taking tetrafluoroethane as a propellant. The quick elimination type foaming agent prepared by the technical method of the invention, for example, tetrafluoroethane is used as a propellant, can meet the basic low-temperature use requirement of the product on the basis of meeting the quick elimination at higher temperature. If the quick elimination type foaming agent prepared by the technology of the invention is used, the foaming agent using other propellants is better in a low-temperature state.

The preparation of the foaming agent realizes the fundamental improvement of the preparation of the foaming agent, greatly reduces the use of the surfactant and protects the environment. The quick elimination type foaming agent prepared by the invention solves the problem of preparing the quick elimination type foaming agent by using tetrafluoroethane as a propellant. The obtained product has good advantages in the field of low-temperature storage, and can solve the problem that the prepared foaming agent is difficult to store or use at lower temperature when tetrafluoroethane is used as a propellant.

The invention creates the idea of preparing the medicinal preparation by using a trace amount of surfactant, and the medicinal preparation is successfully applied to the foaming agent, and the product has obvious stability advantage, and particularly has outstanding advantage on the low-temperature use or storage stability of the quick-elimination type foaming agent using tetrafluoroethane as a propellant.

Disclosure of Invention

The invention relates to a preparation method of a novel foaming agent, wherein the core is to prepare the foaming agent by using a trace amount of surfactant. Where trace amounts refer to the use of surfactant added in a unit formulation at levels significantly below the usual use range. The surfactant for foaming action is used in a trace amount, and the surfactant having no foaming ability is not essential for the foaming agent itself.

The surfactant for foaming is used in a trace amount of 0.001-0.04%, wherein the effect is the best when the surfactant for foaming is used in an amount of 0.01-0.03%. The amount of the foaming surfactant is 0.005-0.04% (w/w), and the total amount of the foaming surfactant can be in the range of a single surfactant or a combination of several foaming surfactants. When the surfactant is used in the dosage range, the preparation effect of the foaming agent is good, and the foaming agent is not inferior to that when the dosage of the surfactant is more than 0.1%, and often has better physical stability. When the foaming surfactant is used in the dosage range, the tetrafluoroethane can be used for preparing the foaming agent, and the low-temperature foam stability of the quick-extinguishing foaming agent for preparing the alcohol-water system is obviously superior to that when the dosage of the surfactant is more than 0.1 percent.

The foaming surfactant used in the present invention is preferably selected from the group consisting of tweens, polyoxyethylene stearate, alkyl sulfate, sulfonate, alcohol ether, polyoxyethylene ether, and ethanolamine, and most preferably selected from the group consisting of tweens and polyoxyethylene stearate. The invention is also suitable for preparing the foaming agent by other foaming surfactants.

The invention often selects some viscosity regulators when preparing the foaming agent, the viscosity regulators are dissolved in an organic phase or a water phase, and the viscosity regulators are not precipitated and are uniformly distributed in the whole system after the viscosity regulators are mixed. The viscosity regulator plays a role in regulating the viscosity of a system and simultaneously plays a supporting role as a skeleton component of the foam. Part of active ingredients in the medicinal foaming agent or the cosmetic foaming agent can play a role in adjusting viscosity or supporting, and the viscosity adjusting agent does not need to be added independently.

The viscosity regulator is organic phase soluble substance such as fatty alcohol such as cetyl alcohol and stearyl alcohol, or stearic acid with similar effect. When the fatty alcohol is used, the total usage amount of the substances is 0.5-10%. One is water soluble or water dispersible material, such as gelatin, carbomer, alginic acid and alginate, water soluble cellulose and water soluble cellulose salt or water soluble cellulose derivative. And the other part is that alcohol or water system can be dissolved well, such as polyethylene glycol with certain molecular weight section. When the viscosity regulator is dissolved in a solvent, the viscosity regulator is dissolved in the solvent and then the preparation is carried out.

Some additives are not required in all of the foams of the present invention, such as pH adjusters, perfumes, and the like. When the used pressure container is a metal can and the content is isolated by an unplated layer, an acid-base regulator is often required to be added to regulate the pH value of the content to be neutral, and the general tolerance requirement of human skin is considered to be 5-7.5. Because the dosage of alcohol and ester is relatively high, and the pressure-resistant container is a closed high-pressure system, it does not need to add preservative.

The preparation of the quick-eliminating foaming agent at least comprises a propellant and surface activity

Agent, water, low boiling point alcohol. Often ethanol, isopropanol or other volatile alcohols with boiling points below 100 ℃. The amount is usually 30% to 90% (w/w), preferably 45% to 65%.

In view of the drying effect of volatile alcohols on the skin, humectants should be added to the system as needed. The humectant generally uses nonvolatile substances compatible with an alcohol phase and a water phase, preferably glycerin, the use range of the glycerin is 0.1-25%, and according to specific facts, the humectant has certain influence on the excellent foam forming condition. Other optional humectants include propylene glycol, liquid polyethylene glycols, panthenol, sorbitol, and the like.

The invention can use fluorochloroalkane, short-chain fatty alkane, hydrofluoroalkane and the like as propellants to prepare various types of foaming agents. Short-chain aliphatic alkanes, hydrofluoroalkanes, are recommended. The preparation of the foaming agent by the tetrafluoroethane can meet the requirement of environmental protection, can reduce the safety risk of combustion or explosion, and the pressure in the pipe is generally 0.3-0.6 mPa after the pressurization.

In the present invention, a metal is used as a material of the pressure-resistant container, and generally, iron or aluminum is used, and in order to prevent the container from being rusted, it is often necessary to coat the inner surface of the container with a film to isolate the container from the contents. The pH value is adjusted to 5-8, so that the corrosion of the pressure-resistant container can be effectively prevented, and the purpose can be effectively achieved by using a buffer system. Common buffer systems include acetic acid and acetates, phosphoric acid and phosphates, citric acid and citrates, sorbic acid and sorbates, benzoic acid and benzoates, and the like.

The invention can adopt a two-phase process and a single-phase process. When a two-phase process is used, the components dissolved in the organic solvent are first dissolved in the solvent to form an organic phase. The ingredients dissolved in water are dissolved in water to form a water phase. The prepared two phases are uniformly mixed to form a uniform system after mixing, and the system has certain viscosity and is uniform white liquid, white gel or colorless liquid and colorless gel. In individual cases some suspended materials are present as suspended liquids or suspended colloids. The two-phase mixing process can be carried out at normal temperature or by proper heating, and the whole process can be carried out in various modes such as automatic permeation, stirring, shearing, collision and the like. The single-phase process is to prepare all materials except the propellant by a one-tank dispersing or dissolving mode.

The invention mainly solves the abuse problem of the surfactant in the preparation of the foaming agent, and is remarkably reflected in the great reduction of the use of the surfactant. By applying the technology, the environmental protection benefit is increased, the improvement of the product stability is important and good, and especially, the rapid elimination type foaming agent prepared by using tetrafluoroethane can be reasonably stored at a lower temperature while the rapid elimination efficiency is ensured. In the same technical scheme, if tetrafluoroethane is not used as a propellant and old propellants such as mixed alkane are used, the effects of enhancing the stability and improving the rapid elimination capability can be achieved.

The invention can be applied to the improvement of the existing foaming agent products including quick-elimination type foaming agents, such as terbinafine foaming agent, hydrocortisone foaming agent, calcipotriol foaming agent, mesalazine foaming agent, nonoxynol foaming agent, minoxidil foaming agent, ketoconazole foaming agent, betamethasone valerate foaming agent, clobetasol propionate foaming agent, clindamycin phosphate foaming agent and the like. Can also be used for the development of brand-new foam preparations, and the fields comprise disinfection medicines, analgesic medicines, acne treatment medicines, antifungal medicines, hormone medicines, antiviral medicines and other skin medicines. Representative drugs include chlorhexidine acetate, benzalkonium chloride, benzalkonium bromide, nanosilver, lidocaine, procaine, prilocaine, felbinac, ibuprofen, diclofenac, miconazole, econazole, clotrimazole, fluconazole, terbinafine hydrochloride, triamcinolone acetonide, liranaftate, tretinoin, isotretinoin, tazarotene, halomethasone, fluticasone propionate, mometasone furoate, hydrocortisone, fluocinolone acetonide, formoterol, tulobuterol, ciprofloxacin, lomefloxacin, mupirocin, ribavirin, tacrolimus, acyclovir, and the like. Besides the field of medicines, the invention can also be applied to the field of daily chemicals.

Example 1

Components	In an amount% (w/w)
		Betamethasone valerate	0.12
Ethanol	57.79
		Propylene glycol	2.00
Cetyl alcohol	1.10
		Octadecanol	0.50
Tween 60	0.025
		Citric acid anhydrous	0.073
Potassium citrate	0.027
		Water (W)	33.69
Propane/butane	4.675

Mixing ethanol and propylene glycol. Adding betamethasone valerate, cetyl alcohol and stearyl alcohol, stirring until the betamethasone valerate, the cetyl alcohol and the stearyl alcohol are dissolved and clarified to prepare an alcohol phase. Dissolving Tween 60, citric acid and potassium citrate in water, stirring to dissolve and clarify, injecting into the same container, and filtering to obtain the content. Filling the content into a pressure-resistant aluminum bottle, and filling a propane and butane mixed propellant to finish the preparation.

Example 2

%（w/w）	1	2	3	4	5	6	7	8	9
										Clobetasol propionate	0.05	0.05	0.05	0.05	0.05	0.05	0.05	0.05	0.05
Anhydrous ethanol	50.1	48.39	50.1	53.1	56.1	49.1	56.1	56.1	50.1
										Glycerol	3	3	3	3	3	13	3	3	3
Cetyl alcohol	0.9	0.9	0.9	0.9	0.9	0.9	0.9	0.9	0.9
										Octadecanol	0.4	0.4	0.4	0.4	0.4	0.4	0.4	0.4	0.4
Tween 60	0	0.01	0.01	0.02	0.02	0.02	0.05	1	1
										Citric acid	0.07	0.07	0.07	0.07	0.07	0.07	0.07	0.07	0.07
Potassium citrate	0.03	0.03	0.03	0.03	0.03	0.03	0.03	0.03	0.03
										Water (W)	40.44	42.15	40.44	37.43	34.43	31.43	34.4	33.45	39.45
Tetrafluoroethane	5	5	5	5	5	5	5	5	5

Preparation of organic phase

Heating ethanol to about 50 deg.C, adding glycerol, cetyl alcohol, stearyl alcohol, and tween 60, and stirring to dissolve and clarify. Clobetasol propionate was added to the solution and stirred to clarify the solution.

Preparation of aqueous phase

Dissolving citric acid and potassium citrate with water, and clarifying.

Mixing the organic phase and the water phase, stirring to be uniform, filling into a pressure-resistant tank body, and sealing by a valve. And pressurizing the tetrafluoroethane. And (5) installing a trigger to finish preparation.

The foam quality was evaluated by the discharge foam.

Investigation item

1

2

3

4

5

6

7

8

9

Defoaming time of 37 ℃ foam

——

＞10min

3′47″

1′37″

1′08″

1′45″

46″

54″

1′03″

Foam character at 25 DEG C

Liquid, method for producing the same and use thereof

Good effect

Diluted foam

Is slightly poor

Foam character at 15 DEG C

Liquid, method for producing the same and use thereof

Good effect

Is slightly poor

Diluted foam

Foam character at 5 DEG C

Liquid, method for producing the same and use thereof

Good effect

Diluted foam

Liquid, method for producing the same and use thereof

Diluted foam

Method for measuring defoaming time at 37 ℃: pressing the trigger to eject about 50ml of foam from the foaming agent into a thermostatic container which is pre-insulated to 37 ℃, immediately timing till the foam is completely eliminated to liquid, and ending timing. If the timing time exceeds 10min, the foam can not be completely eliminated into liquid, and the foam is considered not to be easily eliminated and can not meet the requirement of quick elimination, and the recording is not continued.

The foam character observation method comprises the following steps: placing the foaming agent in water bath at 25 deg.C/15 deg.C/5 deg.C, and keeping the temperature until the water level is 1/2 deg.C for 30 min. The foam was taken out, rapidly discharged, and the foam properties were visually observed.

Good foam properties should satisfy: the foam is fine and complete and can continuously exist in the shape of the sprayed foam after being sprayed.

And (3) investigating the physical stability of the foaming agent at high and low temperatures in experiments 3 and 9.

The temperature is reduced to 2-8 ℃ for 20 hours, the temperature is restored to room temperature for 4 hours, the temperature is increased to 30 ℃ for 20 hours, the temperature is restored to room temperature for 4 hours, and the cycle is one. Experiment was continued for 5 cycles.

Example 3

Components	In an amount% (w/w)
		Terbinafine hydrochloride	1
Ethanol (96%)	54
		Propylene glycol	6
Cetyl alcohol	1.1
		Octadecanol	0.4
Stearic acid polyoxyethylene 40 ester	0.02
		Citric acid	0.06
Potassium citrate	0.04
		Water (W)	29.38
Tetrafluoroethane	8

Ethanol and propylene glycol were mixed and heated to about 50 ℃. Adding terbinafine hydrochloride, hexadecanol and octadecanol, stirring to dissolve and clarify, filtering, and filling the filtrate into a pressure-resistant metal can. Dissolving polyoxyethylene 40 stearate, citric acid and potassium citrate in water, stirring to dissolve and clarify, filtering, injecting the filtrate into the same container, and automatically mixing to obtain the content. And filling the content into a pressure-resistant aluminum bottle, and filling tetrafluoroethane to finish the preparation.

Claims

1. A fast-release foaming agent, said foaming agent having the following composition:

。