Sterile liquid droplet ophthalmic gel preparation and the method of its production


(57) Abstract:

New gel product can be used in ophthalmology as an artificial tear fluid for the treatment of "dry eye". Drip gel preparation has a viscosity of from 2000 to 6000 mPas and a pH value of 6-8. It contains a water continuous phase and a liquid hydrophobic phase. The latter consists of droplets dispersed in the aqueous phase, the droplets do not contain emulsifiers. The aqueous phase contains at least one polymeric gelling component, such as polymers of acrylic acid. Preferably, it is contained in an amount of 0.1-3 weight. %. The hydrophobic phase contains acceptable organic oil. Preferably the oil contains triglyceride of medium chain length. The drug is produced by dispersing a hydrophobic phase in a continuous aqueous phase, preferably in a pre-prepared sterile hydrogel. New drug prevents mechanical irritation of the eyes, is sterile. It is durable during storage, even when further comprises legkorazdrazhimoy substances such as vitamin a and its derivatives. 2 C. and 13 C. p. F.-ly.

The objects of this invention is the drip-liquid sterile ophthalmic is hidcote and for the treatment of dry eye, and method of manufacturing such a gel preparation.

It is known that long as substitutes for the natural tear fluid, and also for processing of dry eye are applied aqueous preparations which contain, for example, film-forming components on the basis of polyvinyl alcohol (PVOH), polyvinyl pyrrolidone (PVP), cellulose derivatives or dextran. The review of these drugs (authors - Sucker, Fuchs, Speiser) can be found, for example, in "Pharmazeutische Technologie" ("Pharmaceutical technology") for 1978. We consider systems in which there is only one liquid phase is typically an aqueous solution of the other components. In those cases, when these components are sparingly soluble or insoluble in water, they are suspended in the aqueous phase in the form of a fine mist.

The production of semi-synthetic drugs, for example, is made on the basis of cellulose derivatives or dextran, is complicated by the fact that these substances are difficult to separate insoluble components. Therefore, the need to prevent mechanical irritation of the eyes makes the process of preparation of solutions of these drugs are very expensive. In addition, these drugs are very difficult sterilization is but autoclaving these medicines without losing their quality. So, autoclaving preparations based on cellulose derivatives leads to an irreversible decrease in their viscosity, autoclaving preparations based on dextran leads to partial decomposition.

Polyvinyl alcohol also can be sterilized only by heating using very pure saponified form, because otherwise it depolymerization PVOH component. As PVOH and PVP components provide a relatively small concentration, the share of these components in the product to achieve the desired viscosities should be great. This entails increasing the concentration of ophthalmic drugs, such as drugs based on polyvinyl alcohol concentration exceeds 10%.

To date, from DE 3440352 and DE 4303818, as well as from US 5252318 already know the use of polyacrylic acid and its derivatives, such as Carbopol("Carbopol" 940 issued by company B. F. Goodrich Company), as a gel base for drip-liquid sterile eye gels. In the US 5441732, published after the priority date of the present application, describes a combination of two special gel components, one of Kotor as a thermosetting gel polymer are various derivatives of cellulose, and as a polymer, gelatinizing by changing the hydrogen ion exponent pH mention polyacrylates, in particular polyacrylates with cross links. The gel formation in this case, apparently (due to changes in hydrogen ion exponent pH), should occur in the eye. This mixture of polymers should be applied together with organic oils which can dissolve a variety of active substances. Vitamin a is not mentioned.

To ophthalmic drugs that are used as film-forming and lubrication, must be made very high demands in terms of portability, lack of irritants and stability during storage. In particular, if the ophthalmological drugs are supposed to be used for a long period of time, which is typical of the treatment of "dry eye", even temporary irritation of the type of burning sensation in the eye is a very unpleasant feeling, which makes it impossible for prolonged therapy. Needless to say that the application of such ophthalmic funds are not allowed impaired vision, the veil before the eyes, or other acute irritation.

When processing Mina A. So, after the priority date of this application was mass production of drip gel preparations on the basis of Carbopolcontaining, along with other conventional components palmitate vitamin A. In this case we are talking about single-phase gels with one continuous aqueous liquid phase, not containing any other hydrophobic liquid phase. The shelf life of such products during storage (more than 40% of the initial excess vitamin a in the product) is about one year. As shown by experimental studies, six months vitamin a is reduced by approximately 20%, so 40% saturation of the drug in vitamin a guarantee for one year maintaining its minimum content in the product.

Part of the natural tear fluid, inter alia, include fatty components, containing triglycerides and phospholipids. Research has already been conducted on the use of triglycerides in synthetic tear fluid, which, however, was possible only with the addition of the emulsifier and an emulsion for topical application to the eye. The disadvantage of this approach is that the desired residual quantity of the natural tear fluid Gogo invention is to provide ophthalmic preparations in particular gel preparations differ significantly increased durability during storage, especially if these drugs contain legkorazdrazhimoy substances such as vitamin a and its derivatives.

Another important object of the present invention is to provide such drugs that do not cause acute irritation and visual impairments, especially if provided by the long-term storage of such drugs.

Another task of great importance is the creation of such drugs, which can again be used for an extended period of time and/or provide a long lasting effect on the eyes after each individual use, without causing drug intolerance, irritation and other discomforts.

The basis of the invention lies some unexpected discoveries.

On the one hand, it has been unexpectedly found that in the artificial tear fluids and drugs for the treatment of "dry eye" relatively rapid destruction of vitamin a and its derivatives, in particular palmitate vitamin a, can be drastically slowed down when the product is two-component and consists of Jidai continuous liquid aqueous phase, in which the hydrophobic liquid phase is distributed in the form of small droplets. A simple explanation of this effect is not found. The most likely factors of destruction of vitamin a are oxygen and/or light, and, with regard to these two factors, not matter, is whether the preparation of one liquid phase or in two separate phases. Moreover, if the component-based vitamin a dissolved in a hydrophobic liquid phase, it seems logical that vitamin a is more susceptible to the effects of oxygen from the air and/or light.

Perhaps some influence on these drugs provides simultaneous addition of antioxidants, such as vitamin E and its derivatives, in particular the acetate of vitamin E. In any case, as proposed by the present invention products vitamin And is preferably used together with such antioxidants.

Following an unexpected effect of the invention is that it allows to produce drugs with water and a hydrophobic liquid phase, whose composition is very close to natural lacrimal fluids and, in particular, correspond to them according to the content of triglycerides, not requiring the use of emulsifiers. This is century Unlike drugs, is not done in a gel base, the triglycerides in the proposed gel preparations can also be in the form of small droplets for a long time, and these droplets are stably retained without the introduction of gel emulsifiers. These drugs can easily be sterile and have an excellent tolerability.

Proposed in the invention of drugs, including gel preparations are characterized by a refractive index almost identical with the refractive index of the natural tear fluid, and, in addition, have on eye long action.

Proposed in the invention of drugs, apparently, reduce the surface tension of water eye gel that helps them better distribution on the cornea. This also achieves a more uniform distribution of suspended or dissolved in an oil (hydrophobic) phase active substances. Improved wettability placed on the cornea of the eye items such as contact lenses or the front lens ophthalmic instruments.

The results of extensive studies show that the proposed invention medications, raspaculo humidity 45%), but in the conditions of the Mediterranean subtropical climate (temperature 26oC, relative humidity 60%) and even in very hot and humid climatic conditions (temperature 31oC, relative humidity 70%) are very stable, remaining practically without changes or with minor changes to the content of vitamin a (if it is provided in the composition), pH pH, osmoticnosti, viscosity and appearance.

Basically, as a liquid hydrophobic components in the composition proposed in the invention of two-phase preparations, in particular gels, suitable acceptable for use in ophthalmology organic oils that can dispersing in the aqueous phase in the form of droplets without the addition of emulsifiers. Examples of these oils are derivatives of fatty acids as esters of fatty acids, triglycerides and esters of phthalic acid. Presently particularly preferred hydrophobic component are triglycerides, in particular homogeneous or mixed triglycerides, composed mainly or entirely of fatty acids class C8- C12. Most preferred in this sense srednezerny Treaty component of such triglycerides are presented in the form of a mixture of n-octanoic acid and n-decanoas acids, component of at least 95%, and the remainder are short-chained fatty acids.

Such srednezerny triglycerides derived semi-synthetic in the way from the oil firm and dry part of the endosperm of Cocos nucifera L. by hydrolysis of coconut oil, obtained from the endosperm, its decomposition into fractions with the release of fatty acids and their re-esterification.

Such srednezerny triglycerides are already being used as foundations in cosmetics, as additives and fillers in the pharmaceutical industry, as well as for production of high quality food products. Despite the known advantages of such medium chain triglycerides, about the potential for and extent of their use in ophthalmic preparations to date, very little is known.

Proposed invention the preparations made, in particular, in a gel base containing, in General, from 0.1 to 3.0%, and in particular is approximately 0.2% by weight of polyacrylic acid, which plays the role of a gel in the aqueous phase contain such srednezerny triglycerides in the amount of usually from 0.5 to 10%, particularly about 1% by weight.

Proposed invention gel preparations preferably imagazine in the invention, the preparations preferably contain preservatives, in particular, such as cetrimide, chloride benzalkonium or thiomersal. In addition, it is preferable introduction the preparation of at least one of isotonic, which is the most suitable sorbitol.

The content of component-based vitamin a, in particular palmitate vitamin a, in the most preferred embodiment of the invention is from about 500 international units per gram of the drug. It is also preferable for stabilizing component-based vitamin a in the presence of the drug at least one antioxidant, for which the most suitable vitamin E and acetate vitamin E.

The production method proposed in the invention is a sterile preparation, in particular - gel preparation consists of several stages. Preferably for the preparation of the gel are sterile suspension polyacrylic acid as described in DE 4300818, i.e. autoclave at a temperature of approximately 120oC and a gauge pressure of 1 bar (0.1 MPa) for 20 minutes. Simultaneously prepare an aqueous solution containing a preservative and isotonic, i.e., preferably cetrimide and sorbitol. This aqueous solution is mixed with the received autoclaved suspension polyacrylic and - in a simpler variant of compressed air. Then, by careful injection of a sterile solution of sodium hydroxide is neutralized mixture, thus begins the formation of the gel. After neutralization in the composition of the resulting gel no longer remains unreacted base. Then in antiseptic conditions in sterile gel is injected hydrophobic liquid component, i.e., preferably srednezerny triglyceride. This hydrophobic liquid component are mixed to obtain a completely homogeneous dispersion. The magnitude of the resulting oil droplets in the dispersion according to the invention is at most 100 μm and corresponds to the droplet sizes in conventional emulsion obtained without additives strong emulsifiers.

After you complete these steps sterile gel can be packaged in the usual way.

In another embodiment, in thus obtained a sterile gel type active substance, such as palmitate vitamin A. For this component based on vitamin a, and preferably much smaller amount of the antioxidant is dissolved in a neutral oil, which is then filtered to a sterile state. After this oil solution, stirring, said gel base, for example in the form of drip solution.

Used in accordance with the invention geleobrazovanie are preferably polyacrylic acid with a molecular weight comprising about 3 to 5 million. Particular preference is given to well-known products, such as polymer acid Carbopol(manufactured by B. F. Goodrich Chemicals Co.). The most preferred Carbopol 980. The concentration of geleobrazovanie in the preparations is preferably about 0.2% by weight.

Neutralization required for gel formation, are generally performed using sterile dilute sodium hydroxide solution, with the greatest effect brings the use of 1-N sodium hydroxide. However, it is possible to use other inorganic bases, alkali carbonates or organic bases, such as amines, in particular triethylamine and Diisopropylamine.

Thus obtained gels have a viscosity in the range 2000 to 6000 mPas at a temperature of 20oC.

Used according to the invention the preservative conventional type, such as cetrimide, chloride benzalkonium or thiomersal, is contained in the usual concentrations. For example, cetrimide is mannitol, dextrose, glycerin, propylene glycol or sorbitol (the latter is especially preferred), are used in their usual concentrations. The use of sorbitol is most effective when its concentration 4,85% by mass.

The invention is explained in more detail below with two examples.

Example 1

In a special device through the fibrous filter with a cell size of 25 to 40 μm impose a homogeneous suspension containing about 375 kg of water intended for injection, and 2000 kg of polyacrylic acid (Carbopol 980). This suspension autoclave with stirring for 20 minutes under conditions of a temperature of 121oC and a gauge pressure of 1 bar (0.1 MPa), and then cooled to room temperature under free ventilation through sterilized air filter.

In parallel, approximately 469 kg of water intended for injection, place in a suitable container, then in the water by stirring the dissolved first 0,100 kg cetrimide, and then 48,510 kg of sorbitol. This solution is added to already autoclaved suspension of polyacrylic acid, applying steam sterilized membrane filter cartridge type with a cell size of 0.2 mcgranaham the device several times in a vacuum.

In sterile conditions in about 20 kg of water intended for injection, mixing, dissolving 0,832 kg caustic soda. Dissolved sodium hydroxide by filtration through steam sterilized membrane filter cartridge type added to a suspension of polyacrylic acid with cetrimide and sorbitol, then to this suspension add the remainder of water intended for injection. The resulting gel was stirred circulation way until smooth.

Then in sterile gel after filtration through a sterile filter with a cell size of 0.2 μm add srednezerny triglycerides, stirring to obtain a completely homogeneous. Next, measure the hydrogen ion exponent pH of the thus obtained gel, which is at a temperature of 20oC should be 6 - 8. The osmotic pressure of the drug according to the invention should be in the range of 260 - 320 mOsm/kg, Then this gel is sterile Packed in 5 g tubes.

Example 2

In 9,37 g neutral oil (Myritol) dissolved 0.6 g of vitamin a palmitate and 0.03 g of the acetate of vitamin E.

This solution is filtered to sterile condition by means of a filter (Millipor 1, add 10 g of the aforementioned neutral oil solution and stirred using a paddle stirrer. After 20 minutes of mixing the finished product packaging 10 g in tubes. In one gram of gel contains 500 international units of vitamin a, the vitamin a is characterized by a 20% excess.

Opposable example

The gel of carbopol is manufactured by the method described in example 1 but without adding the component sredizemnogo triglycerides.

Comparative test

As in example 2, the gel obtained in opposable example, is saturated with vitamin a palmitate in the same concentration.

Sample preparation with vitamin a, obtained without adding the component of the triglyceride, and the corresponding samples of the preparation obtained in example 2 were stored under standard conditions. After a total of six months of storage the content of vitamin a in the drug samples received in opposition to the example, without the use of a component of triglycerides, decreased in total by 20%. The sample preparation obtained in example 2, the content of vitamin a remained unchanged within the measurement accuracy.

2. The drug under item 1, characterized in that the aqueous phase contains at least one polymeric gelling component, mainly in the form of a polyacrylic acid or a polymer of a derivative of acrylic acid in a quantity sufficient to provide the ability to gelation.

3. The drug under item 2, characterized in that the preparation contains polyacrylic acid in an amount of from 0.1 to 3 wt.% preferably about 0.2 wt.%.

4. The drug according to any one of paragraphs.1-3, characterized in that the hydrophobic phase contains ophthalmologist acceptable organic oil, especially oil, which can be dispersed and supported in dispergirovannom state in the form of droplets in an aqueous medium without the addition of emulsifier.

5. The drug under item 4, wherein the oil contains at least one derivative of a fatty acid, one triglyceride and/or one ester of phthalic acid.

6. The drug under item 5, characterized in that the oil contains triglyceride, especially triglyceride sny fatty acids (C8- C12.

7. The drug under item 4 or 6, characterized in that the oil contains medium-chain triglyceride.

8. The drug according to any one of paragraphs.5-7, characterized in that the preparation contains medium-chain triglycerides in an amount of from 0.5 to 10 wt.%, preferably 1 wt.%.

9. The drug according to any one of paragraphs.5-8, characterized in that the preparation contains at least one ophthalmologist active agent in a therapeutically effective amount.

10. The drug under item 9, wherein the drug includes a component that contains vitamin a, in particular ester of palmitic acid, and particularly preferably in combination with an antioxidant, such as vitamin E or acetate of vitamin E.

11. The drug according to any PP.1-10, characterized in that the preparation contains a preserving agent, in particular isotherwise agent.

12. The drug under item 11, wherein the preservative agent is centrimide, benzalkonium or thiomersal, and isotherwise agent, in this case, sorbitol.

13. Method of production of the preparation according to any one of paragraphs.1-12, characterized in that the hydrophobic phase, especially a component of the medium-chain triglyceride, uniformly dispersed in n is on p. 13, characterized in that it uses a component of polyacrylic acid, which reacts with a suitable base, in particular sodium hydroxide solution for gel formation by neutralizing the carboxylic acid groups.

15. The method according to p. 14, characterized in that the active substance is added to sterile drug under aseptic conditions and evenly mixed with the drug.


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SUBSTANCE: invention describes sterile anesthetic composition for parenteral administration of propofol emulsified in water for injection. The composition comprise above 3 wt.-% but 6 wt.-% of less of solvent not mixing with water. Propofol is dissolved in indicated solvent. The composition is stabilized with 0.2-1.0 wt.-% of surface-active substance and has pH value level in the range 5.0-7.5. The composition with reduced pH value level allows preventing above 10-fold elevating growth of microorganisms for at least 24 h after random external pollution. Reduced fat content in composition also provides the stable analgetic effect for prolonged time and with reduced risk for the blood fat content exceeding.

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15 cl, 4 dwg, 4 tbl, 3 ex