Storage of stable preparation of prostaglandin

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to ophthalmology. A method for increasing the stability of a prostaglandin composition comprising prostaglandin, a preserving agent and pharmaceutically acceptable excipients, wherein the method comprises a stage whereat: the prostaglandin composition specified in a group consisting of Travoprost, Latanoprost, Bimatoprost and Tafluprost is packaged in a reusable low-density polyethylene container made of a low-density polyethylene wherein said low-density polyethylene container represents a low-density polyethylene bottle prepared with the use of blow-fill-seal technology, wherein low-density polyethylene resin is specified in a group consisting of Purell PE 1810 E, Purell PE 1840 H, Purell PE 3020 D, Purell PE 3040 D, Purell PE 3220 D.

EFFECT: group of inventions provides the local reusable ocular administration, the stability of the composition at room temperature up to 25°C for more than twelve months.

18 cl, 5 tbl, 1 ex

 

Technical field of invention

This invention provides a stable method of storage of the pharmaceutical composition comprising a prostaglandin(s), where the method includes the step of storing the composition of prostaglandin in a plastic container, preferably low density polyethylene (LDPE), preferably LDPE container having Purell PE 3020 D resin, applying a Blow Fill Seal (blowing-filling-sealing) (BFS) technology.

Background of the invention

Glaucoma, an eye disorder that affects a variety of mammals, including primates, characterized by elevated intraocular pressure (ocular hypertension). People such ocular hypertension caused by an imbalance between the degree of secretion of intraocular fluid ciliated epithelium in the anterior and posterior chamber of the eye and the degree of leakage or drainage of intraocular fluid from the front and rear cameras, mainly through the channel of Lemma. It is usually assumed that the obstruction of the drainage of intraocular fluid is the primary cause of the imbalance.

Chronic glaucoma is typically leads to a slow, progressive loss of visual fields and, if left unchecked, eventually goes blind. Various active compounds available for the treatment of glaucoma, including various prostaglandins.

Prostaglandins them who have low solubility in water and generally not stable. Attempts have been made to dissolution and stabilization of various prostaglandins by complexing them with various cyclodextrins. See, for example: EP A (Ueno et al.) and EP A (Wheeler). These attempts have had varying success.

Containers for ophthalmic products are used for several purposes; facilitate production; support protection of the product, including sterility and the absence of pyrogen; allow inspection of the contents; allow loading and storage; and provide convenient application.

The components of the container for eye products should be considered as an integral part of products, because they can have a strong influence on product stability, efficacy, toxicity and safety, and, therefore, should be carefully evaluated different tests before choosing for a particularly active composition contained.

Widely used components of the container for eye products are glass and plastic, however, the use of glass containers decreased, and favour the use of plastic containers, because they weigh less, are more resistant to shock and other mechanical influences, cost less and offer more design capabilities. Polyethylene, preferably LDPE, which is a low density polyethylene, with or without additives, and polypropylene are the camping plastics, required by the European Pharmacopoeia.

It is known that polypropylene is durable, strong and more resistant to temperature than low density polyethylene. However, polypropylene has a lower resistance to oxidizing media such as oxygen and acid, which can lead to cracking and yellowing of the plastic. The polypropylene does not provide the best flexibility and the ability to process compared with polyethylene and, therefore, is not the first choice as containers for sterile compositions, especially for technology-blowing-filling-sealing. Also, polypropylene is not cost-effective option compared with polyethylene.

U.S. patent No. 6235781 (Weiner) ['781] discloses pharmaceutical products containing the aqueous prostaglandin composition, Packed in polypropylene containers. According to the '781 aqueous prostaglandin composition, Packed in polypropylene containers are more stable than those Packed in plastic containers. '781 further indicates that the stability of the prostaglandin compounds is subjected to the influence of polyethylene containers (LDPE) compared with polypropylene containers under different stability conditions.

Further, PCT application WO 2002/022106 (Wong) reveals that in addition to refrigerated (2-8°C), soluble derivatives of simple is pandina and analogues exhibit undesirable stability in standard containers of low-density polyethylene (LDPE). The requirement for eye drug was cooled, significantly reduces the suitability of treatment for people in less developed parts of the world. In addition, even if suitable cooling of the drug increases the cost of treatment for the patient and, therefore, further reduces its suitability for needing it.

Therefore, there is a need in the prior art method of storing a prostaglandin, using cost-effective components of the container for a longer period of time.

A brief description of the invention

The invention therefore provides a method of increasing the stability of the pharmaceutical composition comprising an active compound selected from prostaglandin-derived prostaglandin or prostaglandin analog, where the method includes a stage on which provide a pharmaceutical composition, especially the ophthalmic composition in a container made of polyethylene, preferably LDPE, also preferably LDPE container having Purell PE 3020 D resin.

This invention, moreover, provides a container, the method of increasing the stability of the ophthalmic composition, comprising travoprost, latanoprost, bimatoprost, tafluprost, where the container is made of polyethylene, preferably LDPE, also preferably LDPE container with Purell PE 3020 D see the Lu, prepared using BFS technology.

A detailed description of the invention

Prostaglandins that can be used in this invention include all pharmaceutically acceptable prostaglandins and their derivatives, and analogs and pharmaceutically acceptable esters and salts. Such prostaglandins include natural compounds: PGE1, PGE2, PGE3, PGFα, PGF2α, PGF3α, PGD2and PGI2(prostacyclin), as well as analogues and derivatives of these compounds, which have similar biological activity or greater, or lesser force. Analogs of the natural prostaglandins include, but are not limited to: alkyl substituents (e.g., 15-methyl or 16,16-dimethyl), which provide improved or long-term effectiveness reduction of biological metabolism or after selectivity of action; saturation (e.g., 13,14-dihydro) or desaturation (for example, 2,3-didehydro, 13,14-didehydro)that provides long-term effectiveness reduction of biological metabolism or after selectivity of action; deletions or substitutions (e.g., 11-deoxy, 9 deoxo-9-methylene), chlorine (or halogen) to oxygen (for example, Beta.-chlorine)and oxygen to carbon (e.g., 3-oxa), lower alkyl oxygen (for example, 9-methyl, hydrogen to oxygen (for example, 1-CH.sub.2 OH, 1-CH.sub.2 an Oezil), which will increase the chemical stability and/or izbiratelni is here are the steps; and modificaciones.-chain (for example, 18,19,20-trinor-17-phenyl, 17,18,19,20-tetranor-16-phenoxy), which will increase the selectivity of action and reduce the biological metabolism. Derivatives of these prostaglandins include all pharmaceutically acceptable salts and esters, which can be attached to the 1-carboxyl group, or any of the hydroxyl groups of prostaglandin appropriate alcohol or reagent organic acid, if necessary. It should be understood that the terms "analogs" and "derivatives" include compounds that are functional and physical responses such as prostaglandins on the merits. Prostaglandins, which are suitable for use in the compositions of this invention may be selected from the group comprising travoprost, latanoprost, bimatoprost, tafluprost and the like.

The present inventors accidentally discovered in relation to the teachings of the prior art that prostaglandins are not stable in plastic containers.

The present inventors found that a composition comprising a prostaglandin, can be made stable in a plastic container using a suitable grade of polyethylene resin for the container.

The present inventors have additionally discovered that adding suitable additives to the polyethylene resin used for p the produce container, which is compatible with the active, additionally influence on the stability.

The present inventors have additionally found that the dose of gamma radiation used for sterilization container of polyethylene, also affects the stability of the product prostaglandin, Packed in a plastic container.

The present inventors have additionally found that gamma radiation sterilization 15-25 kGy for low density polyethylene is optimal to maintain and improve the stability of the prostaglandin, Packed in a plastic container. Sterilization by gamma radiation above these limits leads to increased adsorption and, consequently, to analyze the effectiveness of the product prostaglandin.

The present inventors have additionally found that the stability of the compositions of prostaglandin, preferably compositions of travoprost, latanoprosta, bimatoprost, tafluprost, can be increased when these compositions are packaged in LDPE containers; preferably LDPE containers made from Purell PE 3020 D resins preferably using BFS technology.

The stability of the compositions of prostaglandin increases when performing sterilization using gamma radiation 15-25 kGy or without the use of gamma radiation. Thus, it was found that gamma radiation effect n the stability of the preferred compositions of prostaglandin, also preferably, compositions of travoprost.

The present inventors have additionally found that the adsorption of preservative or loss of prostaglandin composition can be prevented to a large extent packing compositions of prostaglandin in a plastic container, preferably in LDPE containers, also preferably in Purell PE 3020 D container and preferably with gamma radiation sterilization 15-25 KGy.

Thus, the ophthalmic composition of the present invention is preferably travoprost in the container, made of LDPE, the container having Purell PE 3020 D resin manufactured by applying the technology of blow-fill-seal (BFS), and having sufficient flexibility for distribution of drops using digital processing of the vial by the user.

In one embodiment, the invention provides a method of increasing the stability of a pharmaceutical composition comprising an active compound selected from prostaglandin-derived prostaglandin or prostaglandin analog, where the method includes the step of providing pharmaceutical composition in a container made of polyethylene.

In another embodiment, the invention provides a method of increasing the stability of a pharmaceutical composition comprising an active compound selected isoprostaglandin, derived prostaglandin or prostaglandin analog, and a preservative, and a pharmaceutically acceptable excipient, where the method includes the step of providing pharmaceutical composition in a container reusable reception, made of polyethylene, where the product prostaglandin stable at room temperature up to 25°C for more than twelve months.

In yet another embodiment, the invention provides a method of increasing the stability of a pharmaceutical composition comprising an active compound selected from prostaglandin-derived prostaglandin or prostaglandin analog, and preservative and pharmaceutically acceptable excipients, where the method includes the step of providing pharmaceutical composition in a container reusable reception, made of polyethylene, where the product prostaglandin stable without refrigeration at 2-8°C.

In yet another embodiment, the invention provides a method of increasing the stability of the prostaglandin composition comprising an active compound selected from prostaglandin-derived prostaglandin or prostaglandin analog, and preservative and pharmaceutically acceptable excipients; where the method includes the step of providing ophthalmic composition in the container reusable reception, manufactured using BFS technology from LPE container, having Purell PE 3020 D resin.

In yet another embodiment, the invention provides a method of increasing the stability of the prostaglandin composition comprising an active compound selected from travoprost, latanoprosta, bimatoprost, tafluprost, and preservative and pharmaceutically acceptable excipients, where the method includes the step of providing pharmaceutical composition in a container reusable reception, made of polyethylene, preferably LDPE, also preferably LDPE, having Purell PE 3020 D resin.

In yet another embodiment, the invention provides a method of increasing the stability of the prostaglandin composition comprising an active compound selected from travoprost, latanoprosta, bimatoprost, tafluprost, and preservative and pharmaceutically acceptable excipients, where the method includes the step of providing pharmaceutical composition in a container reusable reception, made of polyethylene, preferably LDPE, also preferably LDPE container having Purell PE 3020 D resin, where the composition is stable at 60°C and 40°C/RH is not more than 25% for more than six months or one year.

In yet another embodiment, the invention provides a method of increasing the stability of the prostaglandin composition comprising an active compound selected from travo the growth latanoprosta, bimatoprost, tafluprost, and preservative and pharmaceutically acceptable excipients, where the method includes the step of providing pharmaceutical composition in a container reusable reception, made of polyethylene, preferably LDPE, also preferably LDPE container having Purell PE 3020 D resin, where the composition is stable at room temperature up to 25°C for more than twelve months.

In yet another embodiment, the invention provides a method of increasing the stability of the prostaglandin composition comprising an active compound selected from travoprost, latanoprosta, bimatoprost, tafluprost, and preservative and pharmaceutically acceptable excipients, where the method includes the step of providing pharmaceutical composition in a container reusable reception, made of polyethylene, preferably LDPE, also preferably LDPE container having Purell PE 3020 D resin, where the composition is stable without refrigeration at 2-8°C.

In yet another embodiment, the invention provides a method of increasing the stability of the prostaglandin composition comprising an active compound selected from travoprost, latanoprosta, bimatoprost, tafluprost, and preservative and pharmaceutically acceptable excipients, where the method includes the step of providing pharmaceutical the second composition in the container reusable reception made of polyethylene, preferably LDPE, also preferably LDPE container having Purell PE 3020 D resin with gamma radiation sterilization 15-25 kGy.

In yet another embodiment, the invention provides a method of increasing the stability of the prostaglandin composition comprising an active compound selected from travoprost, latanoprosta, bimatoprost, tafluprost, and benzalconi chloride, and polyethoxysiloxane castor oil, where the method includes the step of providing pharmaceutical composition in a container, made of LDPE, with Purell PE 3020 D resin with gamma radiation sterilization 15-25 kGy.

In yet another embodiment, the invention provides a method of increasing the stability of the prostaglandin composition comprising an active compound selected from travoprost, latanoprosta, bimatoprost, tafluprost, and polyethoxysiloxane castor oil, where the method includes the step of providing pharmaceutical composition in a container made of polyethylene, preferably LDPE, also preferably LDPE container having Purell PE 3020 D resin, where the container is not subjected to sterilization by gamma radiation.

In yet another embodiment, the invention provides a method of increasing the stability of the prostaglandin composition comprising travoprost, Benz is lcony chloride and polyethoxysiloxane castor oil, where the method includes the step of providing the composition in the container reusable reception made BFS technology, using Purell PE 3020 D resin.

In yet another embodiment, the invention provides a method of increasing the stability of the prostaglandin composition comprising bimatoprost, benzalconi chloride and polyethoxysiloxane castor oil, where the method includes the step of providing the composition of bimatoprost in the reusable container receiving manufactured BFS technology, using Purell PE 3020 D resin.

In yet another embodiment, the invention provides a method of increasing the stability of the prostaglandin composition comprising latanoprost, benzalconi chloride and polyethoxysiloxane castor oil, where the method includes the step of providing the composition latanoprosta in the reusable container receiving manufactured BFS technology, using Purell PE 3020 D resin.

In yet another embodiment, the invention provides a method of increasing the stability of the prostaglandin composition comprising tafluprost, benzalconi chloride and polyethoxysiloxane castor oil, where the method includes the step of providing the composition latanoprosta in the reusable container receiving manufactured BFS technology, using Purell PE 3020 D resin.

In another embodiment, this image is eenie provides a method of increasing the stability of the composition of prostaglandin, including prostaglandin, preservative and pharmaceutically acceptable filler, where the method includes the stage at which: pack of prostaglandin composition in the container for reusable reception of low density polyethylene.

In yet another embodiment, the invention provides a method of increasing the stability of the aqueous ophthalmic composition comprising travoprost, preservative and pharmaceutically acceptable excipients, where the method includes the stage at which: pack composition travoprost in the container for reusable reception of low-density polyethylene prepared by applying the technology of blowing-filling-sealing, where the resin is low density polyethylene is a Purell PE 3020 d

In yet another embodiment, the invention provides a method of increasing the stability of the aqueous ophthalmic composition comprising latanoprost, preservative and pharmaceutically acceptable excipients, where the method includes the stage at which: pack composition latanoprosta in the container for reusable reception of low-density polyethylene prepared by applying the technology of blowing-filling-sealing, where the resin is low density polyethylene is a Purell PE 3020 d

In yet another embodiment, the invention provides a method of increasing stabilin the STI aqueous ophthalmic composition, including bimatoprost, preservative and pharmaceutically acceptable excipients, where the method includes the stage at which: pack composition bimatoprost in the container for reusable reception of low-density polyethylene prepared by applying the technology of blowing-filling-sealing, where the resin is low density polyethylene is a Purell PE 3020 d

In yet another embodiment, the invention provides a method of increasing the stability of the aqueous ophthalmic composition comprising tafluprost, preservative and pharmaceutically acceptable excipients, where the method includes a stage on which; pack composition tafluprost in the container for reusable reception of low-density polyethylene prepared by applying the technology of blowing-filling-sealing, where the resin is low density polyethylene is a Purell PE 3020 d

This invention, moreover, allows the container to increase the stability of the prostaglandin composition comprising a prostaglandin, where the container is made of polyethylene, preferably LDPE, also preferably LDPE container with Purell PE 3020 D resin. The bottle does not significantly adsorb the active connection or preservative, even when the composition is not cooled during the period of time from one to 18 months. The expression "substantially", as is using the I in this document, means less than 5 wt.%, preferably less than 3 wt.%.

Examples of suitable preservatives for ophthalmic compositions that can be entered locally many times include: benzalconi chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenethyl alcohol, disodium salt or ester of ethylenediaminetetraacetic acid, sorbic acid, Polyquad®and other means, equally well-known experts in the field of technology. Such preservatives, if present, is typically used in amounts of from about 0.001 to about 1.0 wt.%.

Composition of prostaglandin, Packed in plastic containers according to this invention, can be adapted for any route of administration. Are the preferred composition, adapted for the local introduction of the ears, nose or eyes, composition, prepared for local injection into the eye, are more preferred.

Pharmaceutically acceptable excipients according to the invention comprise a compound ingredients, such as carriers, surfactants, tonic and buffers. Known many of these compound ingredients.

As used herein, "LDPE" means low density polyethylene. Preferred compositions are preferably packaged in containers, preferably made the s BFS technology, or container, consisting of three parts, using LDPE resin selected from the group including Purell PE 1810 E, Purell PE 1840 H, Purell PE 3020 D, Purell PE 3040 D, Purell PE 3220 D, more preferably Purell PE 3020 d

Preferred compositions are preferably packaged in reusable containers for receiving, manufactured BFS technology. In BFS, the way the plastic is heated to a semi-molten state and push through the billet device using the screw and cylinder with adjustable temperature. Plastic is passed through the channel forms, which may be several for each vial or one, oval or round, which will be formed of a small bottle. The streams of air or nitrogen, sterile, if necessary, through the device during the whole time to the nearest plastic from deposition to displace resin are starobilouska.

Preferred compositions are preferably packaged in a "small amount" bottles. As used herein, the term "small volume" the bottle must mean bottle size large enough to hold the quantity of medical liquid funds sufficient for 1-3 local doses per day for 1-2 months, mostly about 20 ml or less. For example, a small volume containers include 5-, 10 - and 15-ml vials adapted for ophthalmic ka is spruce, input locally.

Examples of surfactants according to this invention are polyethoxysiloxane castor oils such as commercially available and include those that are classified as PEG-2 to PEG-200 castor oil, as well as those that are classified as PEG-5 to PEG-200 hydrogenated castor oil. Such polyethoxysiloxane castor oil include those manufactured by Rhone-Poulenc (Cranbury, N.J.) under the trademark Alkamuls®those that produces BASF (Parsippany, N.J.) under the trademark Cremophor®. It is preferable to apply polyethoxysiloxane castor oil, classified as PEG-15 - PEG-50 castor oil, and more preferable to apply PEG-30 to PEG-35 castor oil. It is most preferable to apply polyethoxysiloxane castor oil, known as Cremophor®Alkamuls EL and®EL-620; preferably Cremophor®RH-40.

Examples of suitable tools that can be used for the regulation of toychest or osmolality of the formulations include sodium chloride, potassium chloride, mannitol, dextrose, glycerin and propylene glycol. Such funds, if present, is used in an amount of from about 0.1 to about 10.0 wt.%.

Examples of suitable buffer means include acetic acid, citric acid, carbonic acid, phosphoric acid, boric acid, pharmaceutically acceptable salts, name the ones above, and tromethamine. Such buffers, if present, are used in quantities of from about 0.001 to about 1.0 wt.%.

The compositions of this invention may additionally include components for providing a delayed release and/or facilities. Such components include the high molecular weight, anionic mukokineticescoe polymers and gelling polysaccharides, such as those described in U.S. patent No. 4861760 (Mazuel et al.), U.S. patent No. 4911920 (Jani et al.) and the application of the USA of the same applicant No. 08/108,824 (Lang et al.). The contents of these patents and patent applications relating to the polymers mentioned above, are included in this description by reference.

As will be appreciated by a specialist in this prior art, the composition can be in various dosage forms suitable for delivery of the compositions. In the preferred case, local ocular delivery compositions can be, for example, aqueous or nonaqueous solutions, suspensions or emulsions. Local input ophthalmic compositions have a pH of from 3.5 to 8.0 and osmollnosti from 260 to 320 milliosmoles per kilogram (mOsm/kg).

The invention will be further illustrated in the following examples, which are illustrative, but not restrictive.

Example 1

Getting trains

The composition as shown in table 1, was prepared as follows: in the net with the UD suitable size add approximately 80% of the volume of water. This successively added and dissolved EDTA, tromethamine, boric acid, mannitol, benzalconi chloride and Cremophor®RH-40. Travoprost weighed in a glass bowl and melted using a pre-prepared solution. Then the pH of the solution was adjusted using NaOH and/or HCl, and added water to bring the volume to 100%. The resulting solution was then sterile filtered (0.2 μm filter).

Table 1
IngredientsQty /ml
Travoprost40 mcg
Benzalconi chloride0.15 mg
Cremophor RH-405.0 mg
Mannitol46,0 mg
Tromethamine1,20 mg
Boric acid3.0 mg
Disodium EDTA0.10 mg
Water for injectionsRegulation final volume
Sodium hydroxideFor pH regulation
Hydrochloric acidFor pH regulation

The resulting compositions are filled into containers made with different resins LDPE, as shown in table 2 and 3. Used or sterilized by gamma radiation, or not sterilized by gamma radiation containers and additionally studied for stability under different conditions of stability. The compositions were applied to containers of various resins LDPE, using BFS (blowing-filling-sealing) technology, and additionally studied for stability under different conditions of stability.

Table 2
No.OptionsGrade LDPE resin
Purell PE 1810 EPurell PE 1840 HPurell PE 3020 D
1Resin typeLow-density polyethyleneLow-density polyethyleneLow-density polyethylene
2DescriptionPurell PE 1810 E is a low-density polyethylene, with well is flexible and delivered in pill form Purell PE 1840 H is a low-density polyethylene, with good elasticity and delivered in pill formPurell PE 3020 D is a low density polyethylene with high stiffness, good optical and good chemical resistance. It is delivered in pill form

Table 3
No.OptionsGrade LDPE resin
Purell PE 3040 DPurell PE 3220 D
1Resin typeLow-density polyethyleneLow-density polyethylene
2DescriptionPurell PE 3040 D is a low density polyethylene with high rigidity and good chemical resistance. It is delivered in pill formPurell PE 3020 D is a low density polyethylene with high rigidity and good chemical resistance. It is delivered in pill form

The system container stabil the activity (analysis) ophthalmic solution travoprost 0,004% weight/volume studied, research on the compatibility under different stability conditions. The results are presented in table 4.

Example # 2

Another batch was prepared with the composition as shown in table 1, and the method described in example 1, this composition was filled into containers, prepared BFS technique with LDPE Purell PE 3020 D (not sterilized by gamma radiation) containers. The system container to the stability (analysis) ophthalmic solution travoprost 0,004% weight/volume studied, research on the compatibility under different conditions of stability for a long period. The results are presented in table No. 5.

1. The method of increasing the stability of the prostaglandin composition comprising a prostaglandin, a preservative and pharmaceutically acceptable excipients, where the method includes the stage at which: pack composition of prostaglandin in the container for reusable reception of low density polyethylene, where the specified container from low density polyethylene is a bottle of low-density polyethylene prepared using the technology of blowing-filling-sealing, where the resin is low density polyethylene selected from the group including Purell PE 1810 E, Purell PE 1840 H, Purell PE 3020 D, Purell PE 3040 D, Purell PE 3220 D.

2. The method according to claim 1, where the composition of the prostaglandin comprises a prostaglandin selected from the group that includes the Tr is Wprost, latanoprost, bimatoprost and tafluprost.

3. The method according to claim 1, where the composition of prostaglandin adapt to local reusable eye injection.

4. The method according to claim 1, where the container for reusable reception of the low density polyethylene is a small vial volume, adapted for local ocular delivery.

5. The method according to claim 1, where the preservative is a benzalconi chloride.

6. The method according to claim 1 where the pharmaceutically acceptable excipients comprise one or more carriers, surfactants, tonic medium or buffer.

7. The prostaglandin composition having improved stability and Packed according to the method according to claim 1 stable for more than six months or one year at 60°C and 40°C/RH is not more than 25%.

8. The composition of prostaglandin, Packed according to the method according to claim 1, where the composition is stable without refrigeration at 2-8°C.

9. The composition of prostaglandin, Packed according to the method according to claim 1, where the composition is stable at room temperature up to 25°C for more than twelve months.

10. The method of increasing the stability of the aqueous ophthalmic composition comprising travoprost, preservative and pharmaceutically acceptable excipients, where the method includes the stage at which: pack composition travoprost in the container for reusable reception of polyethylene low is lotnosti, prepared by applying the technology of blowing-filling-sealing, where the resin is low density polyethylene is a Purell PE 3020 d

11. The method of increasing the stability of the aqueous ophthalmic composition comprising latanoprost, preservative and pharmaceutically acceptable excipients, where the method includes the stage at which: pack composition latanoprosta in the container for reusable reception of low-density polyethylene prepared by applying the technology of blowing-filling-sealing, where the resin is low density polyethylene is a Purell PE 3020 d

12. The method of increasing the stability of the aqueous ophthalmic composition comprising bimatoprost, preservative and pharmaceutically acceptable excipients, where the method includes the stage at which: pack composition bimatoprost in the container for reusable reception of low-density polyethylene prepared by applying the technology of blowing-filling-sealing, where the resin is low density polyethylene is a Purell PE 3020 d

13. The method of increasing the stability of the aqueous ophthalmic composition comprising tafluprost, preservative and pharmaceutically acceptable excipients, where the method includes the stage at which: pack composition tafluprost in the container for reusable reception of low-density polyethylene prepared using those is a technology-blowing-filling-sealing, where the resin is low density polyethylene is a Purell PE 3020 d

14. The composition according to the method according to PP, 11, 12 and 13, where the composition is stable for more than six months or one year at 60°C and 40°C/RH is not more than 25%.

15. The composition according to the method according to PP, 11, 12 and 13, where the composition is stable without refrigeration at 2-8°C.

16. The composition according to the method according to PP, 11, 12 and 13, where the composition is stable at room temperature up to 25°C for more than twelve months.

17. The method according to PP, 11, 12 and 13, where the preservative is a benzalconi chloride.

18. The method according to PP, 11, 12 and 13, where the pharmaceutically acceptable excipients comprise one or more carriers, surfactants, tonic funds or buffers.



 

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1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a multidose ophthalmic composition containing prostaglandin as a therapeutic ingredient, mannitol or sorbitol 0.15-0.5 wt/vol %, propylene glycol or glycerol 0.2-1.8, borate 0.25-0.5 wt/vol %, an antimicrobial preserving agent 0.0003-0.003 wt/vol % representing a polymer quaternary ammonium compound and water. Said composition has pH 6.4-7.2 and is benzalconium chloride free. Besides, the invention refers to the use of said ophthalmic composition for preparing a drug for treating glaucoma, eye infections, allergies and inflammations.

EFFECT: preparing the ophthalmic composition which exhibits improved antimicrobial preserving activity and improved buffer properties.

16 cl, 8 tbl, 21 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely ophthalmology, and may be used for treating, stabilising and/or preventing macular degeneration. The therapy involves introduction of a therapeutically effective amount of the C5 agent in a combination with a VEGF agent in an individual in need thereof. The C5 agent is bound with C5 complement and has the sequence SEQ ID N0:4 or SEQ ID N0:67.

EFFECT: invention provides an additive or synergetic effect ensured by the combination that leads to improved visual acuity especially in the patients suffering wet age-related macular degeneration (AMD) as compared with the VEGF monotherapy.

67 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: invention relates to ophthalmology and can be applied for instillation anaesthesia in cavity eye operations on anterior segment of eye, in particular in phacoemulsification of cataract with implantation of IOL. For this purpose two hours before operation instillations of viceine or vita-iodurol in dose 2 drops into conjunctival cavity of operated eye are carried out every 15 minutes, eight times in total. One hour before operation simultaneously started is instillation of local anesthetic inocaine or alcaine in dose 2 drops every 10 minutes, five times. Interval of instillation between vitaiodineurol or viceine and local anesthetic constitutes five minutes.

EFFECT: method ensures increased anaesthesia efficiency due to increase of cornea permeability and reduction of operation and post-operation complications due to reduction of toxic action of anesthetic.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to pharmaceutical compositions for local application. Claimed compositions include sildenafil, minoxidil, testosterone, or alprostadil, euphyllin, yohimbine, or sildenafil, minoxidil, yohimbine as active agents respectively. Claimed compositions also contain hydrogenated lecithins in combination with cholesterol, emulsifying agent, preservative and demineralised water in specified weight ratios.

EFFECT: group of inventions ensures fast penetration through skin and complex therapy of erectile dysfunction taking into account impact on psychogenic and endocrine factors.

3 cl, 4 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: claimed group of inventions relates to medicine, namely to angiology, and deals with treatment of diseases of peripheral vessels. For this purpose pharmaceutical composition, containing efficient amount of 11-deoxy-prostaglandin compound, characterised by general formula III, is introduced.

EFFECT: introduction of said composition ensures enhancement of peripheral blood flow, reduction of intraocular pressure, recovery of barrier function and increase of ATP level in endothelial cells with absence of impact on arterial pressure and heart rate.

17 cl, 8 ex, 5 tbl, 22 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a multidose ophthalmic composition containing prostaglandin as a therapeutic ingredient, mannitol or sorbitol 0.15-0.5 wt/vol %, propylene glycol or glycerol 0.2-1.8, borate 0.25-0.5 wt/vol %, an antimicrobial preserving agent 0.0003-0.003 wt/vol % representing a polymer quaternary ammonium compound and water. Said composition has pH 6.4-7.2 and is benzalconium chloride free. Besides, the invention refers to the use of said ophthalmic composition for preparing a drug for treating glaucoma, eye infections, allergies and inflammations.

EFFECT: preparing the ophthalmic composition which exhibits improved antimicrobial preserving activity and improved buffer properties.

16 cl, 8 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biochemistry and concerns an agent possessing neuroprotective action representing prostamide of formula (1) which can find application in medicine in therapy of ischemic cerebral damages and neurodegenerative diseases.

EFFECT: composition shows high efficacy.

16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: stable fat emulsion contains prostaglandin as an active ingredient and phospholipids containing phosphatidylcholine and phosphatidyl glycerol in mass ratio 85:15 to 99.7:0.3. The fat emulsion under the invention and its active ingredient (prostaglandin) possess physical and chemical stability thereby increasing shelf life to approximately two years, and/or extended range of storage temperature to 10°C as compared with a commercially available fat prostaglandin emulsion.

EFFECT: fat emulsion under the invention enables satisfactory effectiveness even in the introduction of a low amount.

25 cl, 10 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is application of combination of (a) 13,14-dihydro-15-keta-16,16-dihalogen-derivative of prostaglandin, represented by formula (II) and (b) inhibitor of H+, K+-ATPase, which represents compound of general formula (II) in combination with pharmaceutically acceptable excipient for manufacturing pharmaceutical composition (demonstrating synergistic effect in treatment of gastrointestinal disorders), for treatment of gastrointestinal diseases and corresponding treatment method and synergistic pharmaceutical composition of the same purpose.

EFFECT: demonstrated is synergism of combination of 13,14-dihydro-15-keto-16,16-difluoroprostaglandin E1 in combination with omeprazole or lansoprazole in reduction of gastric ulcer dimensions.

15 cl, 1 dwg, 5 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely angiology, intensive care, cardiovascular surgery and phlebology, and may be used for integrated treatment of acute thromboembolia of pulmonary artery. That is ensured by prescribing anticoagulants, disaggregants, antibiotic therapy added by thrombolytic therapy by the oral introduction of the preparation Thrombovasim 0.02 mg/kg combined with deobliteration of pulmonary artery or pulmonary trunk by direct surgical thromboembolectomy in complete bypass with retrograde perfusion of pulmonary arteries. Treatment of acute thromboembolia is added by prescribing the preparation Vasaprostan* 60 mcg daily intravenously starting from the moment of diagnosing and up to 7 postoperative days.

EFFECT: method provides higher clinical effectiveness in the patients and preventing developing complications ensured by correction of main pathological links of developing complications of acute thromboembolia of pulmonary artery.

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is offered is using a prostaglandin compound for general formula (II) for making a pharmaceutical composition for treating inflammatory intestinal diseases, cancer, gastroesophageal reflux disease or Barrett's syndrome in a mammal subject (versions), related methods of treating (versions) and pharmaceutical compositions (versions). It has been shown that the compound of formula induces the conformational alteration in close contact which enables functional recovery of the mucosal barrier. What is shown as treating the injured mucosa with the compound: colon inflammation, colon cancer (prevented tumour growth).

EFFECT: preparing the compounds enabling the functional recovery of mucosal barrier.

25 cl, 6 dwg, 2 tbl

Eye drops // 2443416

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, in particular ophthalmology. Eye drops have a formulation as follows (g/l): timolol maleate (timolol basis) 1.0-6.0; disodium hydrogen phosphate 5.5-16.5; sodium dihydrogen phosphate 0.8-1.5; sodium chloride 2.0-6.0; ethylenediaminetetraacetatic acid disodium salt 0.1-0.5; benzalkonium chloride 0.03-0.1; polyvinylpyrrolidone 1-100, hydroxypropyl methylcellulose 1.0-5.0, water for injections - to 1 l. The viscosity values range within 5 to 20 mPa·s.

EFFECT: invention provides higher viscosity of the eye drops thereby enabling drug prolongation, as well as promotes cornea moistening and causes no irritant action on eye tissues, has long manufacturing and storage stability of the properties.

1 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention relates to applications of compound 11-deoxyprostaglandin of general formula (IV) for obtaining composition for treatment of central nervous system disorder and for obtaining composition for protection of endothelial cells of brain vessels, to pharmaceutical composition based on said compounds, to method of treating central nervous system disorder, as well as to method of treating central nervous system disorder, as well as to compounds of general formula (IV) or their pharmaceutically acceptable salts, esters or amides, on condition that compound is not 11-desoexy-13,14-dihydro-15-keto-16,16-difluor- PGE1. , where L represnts hydroxy, lower alkanoyloxy or oxo; A represents -COOH or its pharmaceutically acceptable salt, ester or amide; B represents -CH2-CH2 or -CH=CH-; Z represents , or , where R4 and R5 represent hydrogen or hydroxy. R4 and R5 cannot represent hydroxy simultaneously; X1 and X2 represent similar or different halogen atoms; R1 represents saturated or unsaturated bivalent lower or middle aliphatic hydrocarbon; R2 represents single bond or lower alkylene and R3 represents linear lower alkyl.

EFFECT: increase of treatment efficiency.

14 cl, 7 ex, 6 tbl, 20 dwg

FIELD: packaging.

SUBSTANCE: invention relates to closure devices for a container, containing food or medicinal liquid, and to its use. The closure device has an upper part, a lower part, and a side part, an opening passing through the closure device, a ledge extending from the upper part of the base of the closure device, inside which at least two ridges are located, made of rigid but flexible material. The ledge is made and located so that it is incompatible with intravenous catheters. The ledge can also include a cover. The use of the closure device provides for insertion of a needle element into the ledge, punching the membrane which seals hermetically the medical container, pushing the ridges in the ledge to center the needle inserted into the ledge, tearing of the membrane to create in the membrane of a ventilating hole and delivery the medicinal liquid to the patient.

EFFECT: closure device according to the invention provides a more reliable connection between the medical containers and devices for transfer of liquids, such as needles.

22 cl, 6 dwg

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