RU2600863C2 - Ophthalmic composition, containing phenylephrine - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine, namely to ophthalmology. Ophthalmic composition contains water, phenylephrine, highly flexible substance, osmotic substance and buffer substance. Highly flexible substance is represented by hydroxypropyl methylcellulose in concentration range of 0.1-3 %. Osmotic substance is selected from group, consisting of salt and sugar. PH of composition makes 4-5.5. Osmolarity of composition is within 300-400 mosm. Method of producing said composition is also provided, which involves addition of phenylephrine to water solution, containing hydroxypropyl methylcellulose, buffer substance and osmotic substance.

EFFECT: usage of group of inventions allows to increase stability of composition at extended storage life.

16 cl, 3 tbl, 3 ex

Description

FIELD OF THE INVENTION

The present invention provides for the creation of an ophthalmic composition for topical use containing a mydriatic substance and a viscoelastic polymer, as well as methods for making such a composition for administration to humans and animals.

BACKGROUND OF THE INVENTION

Dilatation of the pupil (mydriasis) has various indications, for example, studies of the eyeball, improvement of visual acuity with age-related refraction, improvement of vision in the treatment of cataracts, etc. (Mydriasis-use of phenylephrine (a dose-response concept), Chawdhary S, Angra SK, Zutshi R, Sachdev MS, Indian Journal of Ophthamology, 1984, vol 32, issue 4, 213-16).

Phenylephrine is recommended as a vasoconstrictor, decongestant, and mydriatic agent for a wide range of ophthalmic conditions and procedures. Mydriatic agent is a substance that induces dilatation of the pupil. A mydriatic agent is used to dilate the pupils during uveitis, during a number of surgical procedures and for refraction without cycloplegia. The specified tool can also be used for ophthalmoscopy and other diagnostic procedures, such as a reactivity provocation test in patients with a narrow profile of the anterior chamber angle, for differential diagnosis and pupil dilatation in ophthalmic surgery for preoperative preparation.

Phenylephrine is an extremely unstable compound in solution and, as you know, decomposes in the light and in contact with atmospheric oxygen. Phenylephrine hydrochloride and solutions containing the drug are oxidized and should be stored in a sealed and opaque package. Drug solutions should not be used if they are brown in color or contain a precipitate. However, oxidation of the drug, leading to a loss of activity, can occur without a color change. In accordance with the information on known technical solutions in this field, known compositions containing phenylephrine were obtained, however, none of the known technical solutions provides a solution to the oxidation problem.

Given all the disadvantages of the prior art, the applicant has developed a simple and industrially viable composition with a longer shelf life.

The purpose of the invention

An object of the present invention is to provide an ophthalmic composition comprising phenylephrine, a mydriatic substance and a viscoelastic substance.

An additional objective of the present invention is to provide a method for the manufacture of an ophthalmic drug.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an ophthalmic composition comprising phenylephrine, a viscoelastic substance, an osmotic substance, an ophthalmologically acceptable salt, a buffering agent, and water. The phenylephrine content in the composition may be in the range of 0.15% -10% weight to volume ratio. Phenylephrine may be in the form of a pharmaceutically acceptable salt of an inorganic acid, such as hydrochloride, bicarbonate, sulfate, nitrate, etc., or a salt of an organic acid, such as tartarate, acetate, etc.

The composition contains a viscoelastic material, preferably selected from the group consisting of carboxymethyl cellulose, polyvinyl alcohol, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, povidone, dextran, etc. In general, the amount of viscoelastic material, for example, such as hydroxypropyl methylcellulose, contained in the composition is 0.1-3%, preferably 0.2-1% and most preferably 0.2-0.5%.

The viscosity of the composition in accordance with the present invention may be 0.1-10 cP, preferably 0.5-5 cP and most preferably 1-3 cP. The specified relatively low viscosity provides a comfortable use of the drug, prevents the occurrence of blurred vision and provides ease of processing of the composition during manufacturing, transportation and filling of the package.

The composition optionally further includes at least one ophthalmologically acceptable salt in an amount necessary to bring the osmolality of the composition to an ophthalmologically acceptable range. Such a salt includes a salt containing a sodium, potassium or ammonium cation, and an anion of chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfate; a preferred salt includes sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfate and ammonium sulfate, with sodium chloride being extremely preferred. Other solutions suitable for controlling osmolality include sugar, for example, dextrose, lactose, xylitol, mannitol and glycerol.

The composition in accordance with the description given above in this patent contains a buffering agent and / or a substance for adjusting osmolality in an amount in which the solution is substantially isotonic and has a physiologically acceptable pH.

The composition also includes a substance for normalizing osmolality, such as sodium citrate. Ophthalmologically acceptable osmolality is in the range of 150-1150 milliosmol, preferably in the range of 250-450 milliosmol, and most preferably in the range of 300-400 milliosmol.

The composition in accordance with the present invention additionally optionally includes at least one ophthalmologically acceptable pH regulator and / or a buffer substance comprising an acid such as acetic, boric, citric, lactic, phosphoric and hydrochloric acid; a base such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane, triethanolamine; and a buffering agent such as citrate / dextrose, sodium bicarbonate and ammonium chloride, or an amino acid. Such an acid, base and / or buffer are preferably included in the composition in an amount necessary to maintain the pH in an ophthalmologically acceptable range.

The pH of the composition in accordance with the present invention may be in the range of 3-8, preferably in the range of 4-7, and most preferably in the range of 4.0-5.5.

The amount of salt and buffer substance necessary to control the osmolality and pH, respectively, is well known to those skilled in the art.

The composition in accordance with the present invention is preferably packaged in an opaque plastic package, the composition may be in the form of eye drops packaged in a glass bottle, preferably amber, a plastic, preferably opaque, blow-fill-seal bottle or a three-component , preferably an opaque plastic bottle.

In another embodiment of the present invention, the composition in accordance with the present invention can be prepared by a method comprising the following steps:

a) the preparation of an aqueous solution of hydroxypropyl methylcellulose, a buffer substance and an osmotic substance;

b) adding phenylephrine to the solution prepared in step a).

A solution of hydroxypropyl methylcellulose, a buffer substance and an osmotic substance can be prepared by simple mixing, by mixing the components, if necessary. Buffer substances and osmolality control substances can be added at any stage, but they should preferably be present in a solution with hydroxypropyl methylcellulose before phenylephrine is added. First, an aqueous solution is prepared containing hydroxypropylmethyl cellulose, a buffer substance and an osmotic substance, and phenylephrine is added to this solution with stirring until it is completely dissolved. The processes for preparing the ophthalmic composition in accordance with the present invention are preferably carried out in a sterile environment in order to ensure the production of a sterile preparation.

Benefits

It was found that a composition of this type in accordance with the present invention is generally stable and effective compared to compositions not containing a viscoelastic substance.

Examples

A detailed description of the present invention is given below with reference to the following examples, which are illustrative only and in no way limit the scope of the present invention. Any examples of implementation that may be obvious to a person skilled in the art are considered to be within the scope of the present invention.

Example 1: Preparation of a composition

post number Components Units rev. mg / ml one Phenylephrine hydrochloride 25.0 2 Benzalkonium chloride 0.1 3 Ethylenediaminetetraacetic acid disodium salt 1,0 four Sodium metabisulfite 2.0 5 Sodium citrate 7.5 6 Lemon acid 1.16 7 Hydroxypropyl methylcellulose 3.0 8 Sodium hydroxide to adjust pH In sufficient quantity 9 Water for injections In sufficient quantities up to 1 ml

Procedure:

Water for injection was heated to 70-80 ° C, hydroxypropyl methyl cellulose was dissolved by slow addition and constant stirring until it was completely dissolved. The temperature was lowered to 25-30 ° C and then, in turn, disodium salt of ethylenediaminetetraacetic acid, citric acid, sodium citrate and benzalkonium chloride were added. Before the addition of sodium metabisulfite, the solution was bubbled with bubbles of nitrogen passed through a 0.22 micron filter. Phenylephrine was then dissolved, and the pH was adjusted with a dilute sodium hydroxide solution. The contents were mixed for 30 minutes, filtered using a 0.22 micron filter and packaged in plastic vials under sterile conditions.

Example 2: Effect of the composition on pupil dilatation in rabbits.

The composition was prepared in accordance with the procedure described in example 1. Prepared another composition similar to the composition in example 1, but not containing hydroxypropylmethyl cellulose. The effects of a composition containing hydroxypropyl methylcellulose were compared with the effects of a composition not containing hydroxypropyl methylcellulose. The mydriatic effect of the composition was studied by examining pupil dilatation activity in New Zealand albino rabbits weighing approximately 2.5-3 kg, and the results of the study are presented in Table 1.

Rabbits were divided into two groups of 6 animals each. The left eye of each rabbit was a control and one drop of isotonic saline 0.9% sodium chloride was instilled into it. One drop of the composition according to the present invention containing a viscoelastic substance and not containing a viscoelastic substance was instilled into the right eye. The observation was carried out and recorded at 0 minute (control value), 15 minutes, 30 minutes, 45 minutes, 60 minutes, and then after every hour for 6 hours the pupil size. The results are presented in table 1.

Table 1 Sample Maximum dilatation Maximum Dilation Time Maximum dilatation remaining for: Recovery time Composition in accordance with the present invention (containing a viscoelastic substance) 7.8 ± 0.6 1 hour 1 hour 4 hours A composition not containing a viscoelastic substance (control composition) 6.5 ± 1.2 2 hours 1 hour 0 hours

Table 1 above shows data on dilatation of the pupil and on the time required for dilatation of the pupil. An increase in the dilatation value and a reduction in the period of time required for dilatation indicates a higher composition efficiency. The period of maximum dilatation indicates the duration of the effectiveness of the drug, while the time to achieve maximum dilatation is indicated by the time of maximum dilatation. The shorter the maximum dilatation period, the higher the efficiency.

The results allow us to draw the following conclusions:

- The maximum dilatation of the pupil observed when using a composition containing a viscoelastic substance in accordance with the present invention was 7.8 ± 0.6 mm, while the maximum dilatation of the pupil observed when using a composition not containing a viscoelastic substance was 6, 5 ± 1.2.

- The time for maximum dilatation was 1 hour when using a composition containing a viscoelastic substance, while the time for maximum dilatation when using a composition not containing a viscoelastic substance was 2 hours.

- The maximum dilatation when using both compositions was 1 hour.

- Recovery was faster (time to restore pupil size to normal values) when using the composition in accordance with the present invention.

The data indicate that when using the composition in accordance with the present invention, the maximum dilatation of the pupil (7.8 ± 0.6 mm) is greater with a shorter period of time, and recovery is faster, which indicates a higher efficiency of the composition in accordance with the present invention. This also indicates that the composition prepared by the method in example 1, acts synergistically compared to a composition that does not contain hydroxypropylmethyl cellulose.

Example 3

It was found that the addition of hydroxypropyl methylcellulose improves the appearance, reduces the content of impurities and, therefore, increases the overall shelf life of the drug, based on the data shown in table 2 below.

table 2 post number Temperature / humidity / shelf life Composition containing viscoelastic substance Viscoelastic-Free Composition Solution color Impurity content Sodium metabisulfite PH value of the solution Solution color Impurity content Sodium metabisulfite PH value of the solution Source Colorless 0.1% 1.37 mg / ml 4.7 Colorless 0.1% 1.37 mg / ml 4.7 one. 40 ° C / 20% /
1 month Colorless 0.2% 1.25 mg / ml 4,5 Colorless 0.15% 1.25 mg / ml 4.6 2. 40 ° C / 20% /
3 months Colorless 0.3% 1.00 mg / ml 4.0 Colorless 0.18% 1.24 mg / ml 4,5 3. 40 ° C / 20% /
6 months Light yellow 0.5% 0.8 mg / ml 3.8 Colorless 0.20% 1.22 mg / ml 4,5

The results allow us to draw the following conclusions:

- The solution remained colorless after 6 months with an accelerated stability test method with a composition containing a viscoelastic substance compared to a composition not containing a viscoelastic substance.

- In the solution, a decrease in the level of impurities was observed during the accelerated method of stability tests with a composition containing a viscoelastic substance, compared with a composition not containing a viscoelastic substance.

- In the solution, an increase in the level of sodium metabisulfite was observed after 6 months with the accelerated stability test method with a composition containing a viscoelastic substance compared with a composition not containing a viscoelastic substance.

- In the solution, increased stability of the pH value was observed during the accelerated method of stability tests with a composition containing a viscoelastic substance, compared with a composition not containing a viscoelastic substance.

Claims (16)

1. An ophthalmic composition containing water, phenylephrine, a viscoelastic substance, an osmotic substance, a buffer substance, characterized in that as a viscoelastic substance contains hydroxypropyl methylcellulose in a concentration range of 0.1-3%, the osmotic substance is selected from the group comprising salt and sugar, the pH of the composition is 4-5.5, the osmolality of the composition is in the range of 300-400 mosm. 2. The composition according to claim 1, in which the content of phenylephrine is in the range of concentration from 0.15% to 10% weight to volume ratio. 3. The composition according to claim 1, in which phenylephrine is a salt selected from the group comprising hydrochloride, bicarbonate, sulfate, nitrate, tartarate and acetate. 4. The composition according to claim 1, in which the content of hydroxypropylmethyl cellulose is in the range of 0.2-1% and most preferably 0.2-0.5%. 5. The composition according to claim 1, in which the viscosity of the composition is in the range of 0.1-10 cP. 6. The composition according to claim 1, in which the viscosity of the composition is in the range of 0.5-5 cP. 7. The composition according to claim 1, in which the viscosity of the composition is in the range of 1-3 cP. 8. The composition according to claim 1, in which the salt is selected from the group comprising a cation of sodium, potassium or ammonium, and the anion of chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfate. 9. The composition according to claim 1, in which the sugar is selected from the group comprising dextrose, lactose, xylitol, mannitol and glycerin. 10. The composition according to claim 1, in which the osmotic substance is selected from the group comprising sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfate and ammonium sulfate. 11. The composition according to claim 1, in which the buffer substance is selected from the group comprising acid, such as acetic, boric, citric, lactic, phosphoric and hydrochloric acid. 12. The composition according to claim 1, in which the buffer substance is selected from the group comprising a base, such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate and sodium lactate. 13. The composition according to claim 1, in which the buffer substance is selected from the group comprising tris-hydroxymethylaminomethane, triethanolamine, dextrose, sodium bicarbonate, ammonium chloride and amino acid. 14. A method of manufacturing a composition according to claim 1, comprising the following steps:
- preparation of an aqueous solution containing hydroxypropylmethyl cellulose, an osmotic substance and a buffer substance,
- adding phenylephrine to the prepared solution, characterized in that the pH and osmolality of the composition are regulated. 15. The method according to 14, characterized in that the regulation of pH and osmolality of the composition is carried out by adding a buffer substance and substances to regulate the osmolality in a solution with hydroxypropyl methylcellulose. 16. The method according to clause 15, wherein the addition of a buffer substance and substances for regulating osmolality is carried out in a solution with hydroxypropyl methylcellulose before the addition of phenylephrine.