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WO2008136707A1 - Gel ophtalmologique et procédé de préparation - Google Patents

Gel ophtalmologique et procédé de préparation Download PDF

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Publication number
WO2008136707A1
WO2008136707A1 PCT/RU2008/000259 RU2008000259W WO2008136707A1 WO 2008136707 A1 WO2008136707 A1 WO 2008136707A1 RU 2008000259 W RU2008000259 W RU 2008000259W WO 2008136707 A1 WO2008136707 A1 WO 2008136707A1
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WO
WIPO (PCT)
Prior art keywords
gel
sodium hydroxide
xymedon
value
polyacrylic acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/RU2008/000259
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English (en)
Russian (ru)
Inventor
Lev Davidovich Rasnetsov
Iakov Yudelevich Shvartsman
Olga Konstantinovna Yashnova
Nina Borisovna Melnikova
Olga Vladimirovna Kolchik
Maria Sergeevna Gusikhina
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Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to EA200901480A priority Critical patent/EA018202B1/ru
Publication of WO2008136707A1 publication Critical patent/WO2008136707A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the invention relates to medicine, in particular to ophthalmology, and can be used for the treatment of the “eye syndrome” as an artificial lacrimal fluid, the treatment of traumatic injuries, trophic disorders and chemical burns of the conjunctiva, cornea, skin, and also during and after various operations on the cornea.
  • Known topical preparations are artificial tears, which are widely used to protect the cornea with reduced secretion of lacrimal fluid, with the syndrome of “cyx eyes”, to accelerate epithelialization of the cornea during injuries (including thermal burns of the conjunctiva and cornea), erosion and trophic ulcers of the cornea.
  • These drugs quite effective after plastic surgery on the eyelids, after keratoplasty, keratectomy, with eye irritation caused by smoke, dust, cold, wind, the sun, salt water, contact lenses; after removal of toxic substances and foreign bodies from the eye; during gonioscopy, electroretinography, electrooculography, eye ultrasound, etc.
  • Local rehydration agents are used in ophthalmology mainly in the form of eye drops (hypromellose, Lacrisin, etc.) and gels (carbomer 974P, Vidisik, etc.).
  • the main requirements for tear substitutes are the physiological value of pH 1.2-1, A, optimal viscosity, transparency and colorlessness to maintain clear vision, as well as prolonged action.
  • the most famous gel is Vidisik eye gel (Dr. Maim Pharma, Germany, 2005), designed to alleviate the symptoms of dry keratoconjunctivitis. It contains rarely cross-linked polyacrylic acid (Mm ⁇ 4,000,000) 0.2%, sorbitol (4%), which enhances thixotropic properties, purified water (95.69%) and is cationically active as a preservative and stabilizer Surfactant - cetrimide (0.01%).
  • the hydrogel also contains sodium hydroxide in an amount sufficient to achieve a pH of tear fluid pH 7.2-7.8.
  • Vidisik gel is obtained by immersing a dry polymer on a water surface (stage of wetting), after swelling and sedimentation of the polymer, the gel is mixed, auxiliary substances are introduced (stabilizer and preservative
  • tissue regeneration stimulator In the treatment of more complex ophthalmic diseases requiring the protective function of the cornea, stimulation of the processes of regeneration of the cornea, as well as an anti-inflammatory effect, such as erosion of the cornea, eye burns, keratitis of various etiologies, degenerative diseases of the cornea, as well as the prevention of corneal damage when wearing contact lenses, it is necessary Introduce a tissue regeneration stimulator into the gel.
  • tissue regeneration stimulator Currently, the following helium preparations are used to enhance reparative regeneration: animal blood dialysates (Actovegin gel 20%, solcoseryl gel 20%), corneal protector - Korneregel. The mechanism of action of most of these drugs is based on increased oxygen metabolism.
  • the active substance of Actovegin and Solcoseryl is a deproteinized hemoderivative from calf blood with low molecular weight peptides and nucleic acid derivatives. Drugs activate the metabolism in tissues, improve trophism and stimulate the regeneration process. The disadvantages of these drugs are - hypersensitivity to the drug, allergic reactions, local reactions: itching, burning, lacrimation, injection of sclera.
  • the cornegel is a hydrogel, the basis of which is a rarely cross-linked polyacrylic acid of the carbomer (carbopol) brand, excipients - a stabilizer and a preservative - are cechrimide, complexon diatrium edetate, and dexpanthenol (Panthenol) - (+) 2,4 - dioxi - N - (3-oxipropyl) is used as a medicinal substance
  • Korneregel is similar to the method of preparation of Vidisik with the addition of a drug at the final stage.
  • Korneregel gel is the relatively low viscosity of the gel, which requires frequent instillations. In some cases, due to insufficient viscosity, the preparations of this group did not form a stable lacrimal film, smoothing out corneal irregularities that occur after surgery.
  • the composition of Korneregel does not determine the thixotropic properties necessary for the treatment of a more complex complex of ophthalmic diseases.
  • the main drug substance, dexpanthenol is able to partially inactivate, which is associated with the possibility of this compound hydrolyzing, both in an acidic medium when polyacrylic acid is added to the gel at the initial stage, and in contact with sodium hydroxide in the process of bringing the gel to the desired pH. Reactions occur by analogy with pantothenic acid hydrolysis reactions.
  • Pantothenic acid is a typical hydroxy acid in its properties, which can form derivatives both in the carboxyl group (amides) and in alcohol. Chemically, this acid and pantothenic alcohol are unstable in any medium (acidic and alkaline), it is easily hydrolyzed to ⁇ -alanine and pantolactone. Therefore, the pharmacological properties of panthenol and, accordingly, Korneregel will be determined by the method of preparation of the gel, which prevents the hydrolysis of the drug substance, and the preservation of thixotropic and viscosity characteristics. Disclosure of invention
  • the problem to which the invention is directed is to create an ophthalmic gel that provides the functions of a rehydration agent, keratoprotector and reparant, showing the necessary qualities of homogeneity, uniformity, viscosity, osmolarity, thixotropy on the surface of the eyeball.
  • l- ( ⁇ -hydroxyethyl) -4,6-dimethyl-l, 2-dihydro-2-hydroxypyrimidine (xymedon) is used as a drug from the group of reporters.
  • the gel additionally contains an aqueous solution of polyethylene oxide, sodium hydroxide in an amount sufficient to obtain a gel with a pH of 6.0-7.9, contains benzalkonium chloride, disodium edetate and the aminoglycoside antibiotic gentamicin sulfate as preservatives and stabilizers. ratio of components, May. %:
  • Disodium edetate Trilon B
  • Trilon B 0.002 - 0.004
  • Gentamicin sulfate 0.02 - 0.03
  • Purified water up to 100
  • a method of preparing the proposed gel is that with vigorous stirring in a dry powder of rarely cross-linked polyacrylic acid and / or its derivatives, an aqueous 10-30% solution of polyethylene oxide taken in at least a ten-fold excess by weight relative to the powder is added, then, with stirring, add 70-90% of purified water of the total mass of the gel, after which the pH is adjusted to a value of 6.0-7.0 with sodium hydroxide solution, and then, while stirring, it is preliminarily prepared in a separate alkaline solution a thief of a stabilizer, preservative and antibiotic by mixing aqueous solutions of benzalkonium chloride, disodium edetate and gentamicin sulfate, followed by the addition of 10-20% sodium hydroxide solution, after which
  • the essence of the proposed invention lies in the fact that as a medicinal substance from the group of reparants, xymedon ⁇ 1 - ( ⁇ -hydroxyethyl) -4,6-dimethyl-1, 2-dihydro-2-hydroxypyrimidine ⁇ is used, which has anti-inflammatory and regenerative activity .
  • Xymedon is an organic base (a derivative of the pyrimidine base), which, like other amines, forms complexes with terminal carboxyl groups of polyacrylic acid (a commonly used brand of Carbopol).
  • PAK Xymedon (Xi) PAK Xymedon Complex with PAK Since 56-68% of terminal carboxyl groups in the initial carbopols (pH ⁇ 3, dynamic viscosity 0.8 Pa-s), depending on the degree of neutralization of acid groups, complex compounds of amines with carboxyl groups of polymers either precipitate from an aqueous solution, or dissolve in it. Similarly, in neutral or slightly alkaline media, soluble complexes of polyacrylic acid with lysozyme, coumarin, insulin and other natural substances are formed.
  • the formation of complex compounds of xymedon with carboxyl groups of carbopolis will depend on the sequence of input of sodium hydroxide, which regulates the degree of neutralization of carboxyl groups in the carbopol. 0.8 Pa-s.
  • the necessary qualities for homogeneity, uniformity, viscosity, osmolarity, thixotropy, the proposed gel can be achieved only with a certain method of its preparation.
  • the most optimal pH for administration of Xymedon is pH ⁇ 6-7.
  • the partial replacement of sodium ions with xymedon contributes not only to an increase in viscosity, but also to a decrease in osmolarity.
  • Lower osmoticity (osmolarity) with respect to the corneal epithelium improves the quality of ophthalmic gels, since it is known that a hypotonic solution has a better effect on the corneal epithelium compared to isotonic one (Aragopa P. et. Al. // Br. J. Orthalmol., 2002 Aug .; 86 (8), p. 879-884).
  • a slightly hypotonic solution counteracts the hyperosmolarity of the lacrimal film, typical of the "eye syndrome", and restores normal osmotic pressure.
  • PAA-Ximedon polymer-colloidal complexes leads to an increase in the viscosity of the medium without introducing an additional amount of sodium ions.
  • Table 1 shows examples of changes in viscosity with a carbopol solution at pH ⁇ 7 in the presence and absence of Xymedon.
  • Pre-wetting the dry powder of rarely cross-linked polyacrylic acid and its derivatives with a ten-fold excess (by weight) of an aqueous 10-30% solution of polyethylene oxide with stirring with the further introduction of 70-90% purified water allows to reduce the preparation time of the helium base and ensure high thixotropic properties and uniformity of the gel .
  • Phased adjustment of pH allows you to enter auxiliary components (stabilizers, preservatives, antibiotics), while maintaining the uniformity of the gel, without causing the formation of precipitation, flakes and turbidity.
  • cationic surfactants for example, benzalkonium chloride, complexone, for example disodium edetate (Trilon B) and an aminoglycoside antibiotic - for example, gentamicin sulfate:
  • xymedon in a neutral environment does not cause inactivation of the main drug substance.
  • the introduction of xymedon into a slightly acidic environment leads to the formation of pink-crimson colored products of oxidative condensation (Reznik V. S, Muslinkin AA, Shirshov AH, Spiridonova HA, Pashkurov H.G., Akamsin B.D., Gurylev E.A. Khimiko - Technological fundamentals of xymedon production // Khimiko - Pharmaceutical Journal. Volume 35, Ns 12, 2001).
  • xymedon is stable in gels.
  • compositions of the preparation of gels are presented in table 2.
  • composition N ° 4. 0.5 g of carbopol powder is placed in the reactor, 5 g of a 10-30% aqueous solution of polyethylene oxide are added with vigorous stirring, after which 70-90% of purified water of the total gel mass is added with stirring .
  • cataract surgical treatment phacoemulsification + ocular lens implantation (IOL)
  • Table 3 presents data on the state of the precorneal tear film (PSP) in patients with symptomatic dry syndrome eyes "with contact correction (wearing contact lenses) before and after the use of Vidisik preparations and the proposed drug.
  • PSP precorneal tear film
  • Traditional ophthalmic research methods were used: visometry, refraction determination, ophthalmometry, examination of the condition of the eyelids and anterior segment of the eyeball using lateral illumination, biomicroscopy of the anterior segment of the eyeball and optical media, ophthalmoscopy. To study the state of PSP, the time of its rupture was determined (test according to M.S. Norp, 1969), and the state of the lacrimal meniscus was evaluated.
  • the quantitative composition of the SRP was determined using a Schirmer test.
  • the state of the corneal epithelium was evaluated after instillation of a 1% fluorescein solution.
  • Studies have shown that the proposed drug forms a stable tear film of sufficient viscosity, smoothing out irregularities of the cornea, and has a prolonged effect.
  • the drug is not inferior to the traditionally used gel-based tear substitute Vidisik. Both drugs are effective in the treatment of postoperative dry eye transient syndrome.
  • a qualitative difference between the drug according to the invention from the drug Vidisik is the presence of xymedon in its composition.
  • the mechanism of action of xymedon is to stimulate the process of regeneration of the epithelium.
  • the proposed drug in addition to moisturizing, smoothing the surface of the cornea, accelerates the epithelization of the cornea in the postoperative period.
  • the timing of epithelization and the quality of the epithelium affect the transparency of graft engraftment.
  • Table 4 shows comparative data on the use of ophthalmic gels Vidisik, Korneregel, Actovegin and the gel of the invention after cataract surgery with a corneal incision (phacoemulsification + IOL).
  • a criterion for the clinical effectiveness of the treatment was the epithelization of the corneal incision, the disappearance of corneal edema, improved vision, etc.
  • a pronounced positive effect of the drug proposed according to the invention on the course and outcome of the postoperative process was established.
  • a decrease in edema was noted, which contributed to a shortening of the relief of the inflammatory reaction, and a decrease in pain and corneal syndrome.
  • corneal incision epithelization occurred, in the control group of patients without the use of drugs, corneal epithelization proceeded much more slowly. It should be noted that due to the stimulation of the processes of migration of epithelial cells under the influence of the proposed drug, an earlier re-epithelialization of the wound surface occurs, the gates for infection are closed, and the percentage of transparent healing of the cornea increases.
  • the preparation according to the invention was also used when performing laser operations as a contact medium.
  • Comparison drugs used Vidisik and Oligel.
  • Table 3 shows the comparative results of the use of drugs as a contact medium when performing laser operations. Studies have shown that the drug proposed in the invention has optimal viscosity and meets all the requirements for this group of drugs.
  • the drug was used in combination with soft therapeutic contact lenses.
  • therapeutic contact lenses In the presence of bullous changes in the cornea, it is advisable to use therapeutic contact lenses, while wearing them, a gradual flattening and reduction of bullous elements occurs. Then it is possible to cancel the therapeutic soft contact lens with the simultaneous administration of disinfectants in combination with the drug according to the invention.
  • the purpose of this drug led to the epithelization of defects in the epithelium and to a significant improvement in the condition of the surface of the cornea. Patients noted a decrease in pain and corneal syndromes, and in some cases the complete disappearance of painful sensations.
  • the positive effect of the drug is very valuable in case of loss of the lens by the patient and the impossibility of its quick replacement or in other circumstances when it becomes necessary to cancel the contact lens.
  • herpetic keratitis With herpetic keratitis, the drug was used only as an addition to specific treatment. However, in cases of superficial herpetic lesions, its effectiveness was quite pronounced: the completion of epithelization occurred at the end of the first week of treatment.
  • the proposed ophthalmic gel which contains xymedon, shows the necessary qualities of homogeneity, uniformity, viscosity, osmolarity, thixotropy on the surface of the eyeball and provides the functions of rehydration, keratoprotective and reparant.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Colloid Chemistry (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

L'invention concerne la médecine. Selon l'invention, un gel ophtalmologique comprend de 0,2 à 0,5 % de l'acide polyacrylique faiblement réticulé et/ou de ses dérivés, de l'eau purifiée et possède des valeurs pH comprises dans les limites du pH du liquide lacrymal. On utilise dans ce gel en tant que substance médicamenteuse faisant partie du groupe des réparateurs, à savoir le 1- (β-oxyéthyl)-4,6-diméthyl-1,2-dihydro-2-oxypyrimidine (xymedon). Le procédé de préparation du gel consiste à ajouter dans une poudre sèche de l'acide polyacrylique faiblement réticulé et/ou de ses dérivés, lors d'un mélangeage intensif, un mélange aqueux à 10-30% d'oxyde de polyéthylène dont la masse dépasse d'au moins dix fois celle de la poudre. On ajoute ensuite, tout en poursuivant le mélangeage, de l'eau purifiée constituant de 70 à 90 % du poids du gel, on corrige le pH jusqu'à 6,0-7,0 avec une solution d'hydroxyde de sodium, on ajoute pendant le mélangeage une solution alcaline de stabilisateur, de conservateur et d'antibiotique préalablement préparée dans un réacteur séparé, par le mélangeage de solutions aqueuses de benzalkonium chlorure, d'édétate de disodium, et de sulphate de gentamicine, suivi de l'ajout de 10 à 20 % d'une solution d'hydroxyde de sodium, après quoi l'on rajoute du xymedon avec une concentration massique de 1 à 10 %, après quoi on corrige le pH une nouvelle fois jusqu'à la valeur désirée de 10 à 20 % avec une solution d'hydroxyde de sodium, après quoi le gel est stérilisé.
PCT/RU2008/000259 2007-05-03 2008-04-23 Gel ophtalmologique et procédé de préparation Ceased WO2008136707A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EA200901480A EA018202B1 (ru) 2007-05-03 2008-04-23 Офтальмологический гель и способ его приготовления

Applications Claiming Priority (2)

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RU2007116779/15A RU2340327C1 (ru) 2007-05-03 2007-05-03 Офтальмологический гель и способ его приготовления
RU2007116779 2007-05-03

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WO2008136707A1 true WO2008136707A1 (fr) 2008-11-13

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EA (1) EA018202B1 (fr)
GE (1) GEP20115350B (fr)
RU (1) RU2340327C1 (fr)
UA (1) UA96193C2 (fr)
WO (1) WO2008136707A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2402316C2 (ru) * 2009-01-11 2010-10-27 Пшеничников Виталий Георгиевич Фармацевтическая антиглаукомная композиция
RU2428988C1 (ru) * 2010-07-26 2011-09-20 Государственное образовательное учреждение высшего профессионального образования "Кемеровский государственный университет" (КемГУ) Способ получения ионообменных полимерных гидрогелей для лечения химических ожогов глаз (варианты)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5441732A (en) * 1990-06-15 1995-08-15 Allergan, Inc. Reversible gelation emulsion compositions and methods of use
RU2172169C2 (ru) * 1995-03-28 2001-08-20 Др. Герхард Манн Хем.-фарм.Фабрик ГмбХ Стерильный капельножидкий офтальмологический гель-препарат и способ его производства

Family Cites Families (3)

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Publication number Priority date Publication date Assignee Title
SE9401108D0 (sv) * 1994-03-31 1994-03-31 Leiras Oy Ophthalmic composition I
IL149100A0 (en) * 1999-10-21 2002-11-10 Hoffmann La Roche Heteroalkylamino-substituted bicyclic nitrogen heterocycles as inhibitors of p38 protein kinase
RU2211037C1 (ru) * 2001-12-29 2003-08-27 Институт органической и физической химии им. А.Е.Арбузова Казанского научного центра РАН Препарат селективного действия и способ лечения остеоартрозов

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5441732A (en) * 1990-06-15 1995-08-15 Allergan, Inc. Reversible gelation emulsion compositions and methods of use
RU2172169C2 (ru) * 1995-03-28 2001-08-20 Др. Герхард Манн Хем.-фарм.Фабрик ГмбХ Стерильный капельножидкий офтальмологический гель-препарат и способ его производства

Non-Patent Citations (2)

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Title
"Registr lekarstvennykh sredstv Rossii", ENTSIKLOPEDIYA LEKARSTV OOO "RLS-2003", no. 10, pages 434 *
SPRAVOCHNIK VIDAL: "Lekarstvennye prreparaty v Rossii", ASTRAFARMSERVIS, 2006, pages B-626 *

Also Published As

Publication number Publication date
GEP20115350B (en) 2011-12-12
UA96193C2 (ru) 2011-10-10
RU2340327C1 (ru) 2008-12-10
EA018202B1 (ru) 2013-06-28
EA200901480A1 (ru) 2010-04-30

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