WO2015147665A1 - Process for manufacturing brinzolamide ophthalmic suspension and eye drops formulation - Google Patents
Process for manufacturing brinzolamide ophthalmic suspension and eye drops formulation Download PDFInfo
- Publication number
- WO2015147665A1 WO2015147665A1 PCT/PL2015/000052 PL2015000052W WO2015147665A1 WO 2015147665 A1 WO2015147665 A1 WO 2015147665A1 PL 2015000052 W PL2015000052 W PL 2015000052W WO 2015147665 A1 WO2015147665 A1 WO 2015147665A1
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- Prior art keywords
- brinzolamide
- suspension
- solution
- process according
- formulation
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Classifications
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- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
-
- 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 present invention relates to the process for manufacturing brinzolamide ophthalmic suspension and the eye drops formulation comprising brinzolamide as an active pharmaceutical ingredient.
- the eye drops are useful in controlling the elevated intraocular pressure in persons suffering from ocular hypertension or primary open angle glaucoma.
- Brinzolamide i.e. (4R)-4-ethylamino-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2- e][ l ,2]-thiazine-6 sulfonamide
- the carbonic anhydrase is a systemic enzyme which catalyzes the reversible reaction of carbon dioxide with water to form carbonic acid. Inhibition of this enzyme in ciliary processes leads to lowering the aqueous humor secretion, most probably due to the reduction of hydrocarbonic (HC0 3 ) and sodium ions' concentration.
- Brinzolamide is indicated for the topical management of primary open-angle glaucoma and ocular hypertension as either monotherapy or adjunctive therapy with topical beta-blockers or prostaglandins.
- Azopt® the medicinal product containing the active pharmaceutical ingredient brinzolamide
- sterile ophthalmic suspension According to the Physicians Desk Reference, each milliliter of 1 % Azopt® ophthalmic suspension contains 10 mg of brinzolamide, 0.01 mg of benzalkonium chloride as the preservative, as well as the inactive excipients: tonicity agent mannitol, Carbopol 974 P as the viscosity controlling agent, non-ionic polymer Tyloxapol as surfactant, a chelating agent edetate disodium, as well as sodium chloride, sterile water for the eye drops formulation and hydrochloric acid and/or sodium hydroxide to adjust pH.
- EP 941094 B l discloses the manufacturing process of the sterile ophthalmic suspension containing brinzolamide or brinzolamide - beta-blocker combination as well as thus obtained ophthalmic suspensions containing as the surfactant Tyloxapol or Triton X-100.
- the excipients used in the described formulations are consistent with the composition of the registered medicinal product Azopt®.
- Process for the manufacturing of the ophthalmic suspension includes autoclaving of the brinzolamide suspension in the presence of the surfactant and milling beads, ball milling the hot slurry until brinzolamide particles of the proper size are obtained, and aseptic adding the hot suspension to the vehicle concentrate obtained by mixing the water solution of Carbomer with the slurry of tonicity and preservative agents.
- the sterile final product is obtained by sterilizing the active substance with saturated steam and autoclaving the mixture of the excipients. Both components are combined in aseptic conditions.
- the selection of the surfactant's kind and amount, essential for the protection of the substance during milling is not arbitrary but plays a key role in this process.
- Use of surfactants other than Tyloxapol or Triton X-100 at concentrations of about 0.001-5.0% results in inaccurate milling of large brinzolamide crystals which form during cooling down following autoclaving.
- the substance is obtained in the form of quite large crystals.
- Imaging analysis in diascopic light exhibits high symmetry and sphericity of brinzolamide particles.
- the circularity parameter which can take 0-1 values (1 indicates exact roundness)
- the extension parameter is 0.266
- the average length is 37.2 ⁇
- the average width is 25.8 ⁇ .
- the medium volumetric size of brinzolamide particles D[4,3] assigned by laser diffraction method is about 63 ⁇ and the median d(0.5) is about 61 ⁇ .
- the size of 10% particles is below 30 ⁇ and the size of 90% particles - below 93 ⁇ .
- the aforementioned process is used in the brinzolamide drug technology wherein the active substance brinzolamide is dissolved and then precipitated in the form of particles with proper size, as a result of changing the pH of the medium.
- the operation of pH changing is carried out in the solution containing the main components combined in aseptic conditions.
- the sterile product is obtained by sterile filtration of both brinzolamide and the excipients' solutions, with the exception of the polymeric agent increasing the viscosity of the suspension which is sterilized separately by saturated steam in an autoclave. All other operations, i.e. homogenization of the suspension, dosing of the final drug product, closing of the containers, labeling and packing are carried out in aseptic conditions, as it is shown on the diagram in Fig. 4.
- the present invention provides the process for manufacturing of the ophthalmic suspension containing brinzolamide as an active pharmaceutical ingredient comprising the steps of:
- step (vii) Dispensing the homogenized suspension of step (vi) into the sterile containers, closing and sealing.
- the amount and type of the excipients in the formulation is selected in order to obtain ophthalmic eye drops suspension which should be characterized by the following parameters: pH within the range 6.5 - 8.5, osmolarity within the range 320 mOsm/kg H 2 0 and viscosity within the range 1.013-1.020 g/ cm 3 , which meets the physicochemical characteristics of the Azopt® drug product.
- the pH of the formulation is adjusted by the addition of the basic agent which at the same time plays the role of brinzolamide precipitating agent.
- Such agents can be selected from the hydroxides approved for use in pharmaceutical products, e.g. hydroxides of sodium, potassium, lithium, calcium or ammonium.
- Another group of the precipitating agents comprises bicarbonates, e.g. sodium, calcium or ammonium bicarbonates.
- aqueous sodium bicarbonate (NaHC0 3 ) at the concentration 0.01 - 10 M is used as the precipitating agent.
- the precipitating agent is used at the concentration from 0.1 to 5 M, more preferably 1 M.
- the proper osmolarity of the final ophthalmic suspension is achieved by the addition of polyhydroxyl alcohol, i.e. mannitol.
- mannitol polyhydroxyl alcohol
- This compound is commonly used in ophtalmic formulations as a tonicity agent.
- the amount of mannitol is found experimentally, to achieve the osmolarity of the final suspension within the range 270 - 320 mOsm kg H 2 0. It has to be taken into account that NaCl forming in the process of suspension manufacturing has its own effect on the osmolarity increase.
- the viscosity of the suspension is modified with the addition of the aqueous solution of the acrylic acid polymer approved for use in ocular preparations, such as the cross- linked acrylic acid polymers belonging to the Carbomer or Carbopol types, preferably Carbomer 974 P.
- the acrylic acid polymer approved for use in ocular preparations such as the cross- linked acrylic acid polymers belonging to the Carbomer or Carbopol types, preferably Carbomer 974 P.
- Such polymers are traditionally used in pharmacy for increasing the viscosity of solutions and for the stabilization of suspensions and emulsions.
- the viscosity increasing agent is recommended usually in the amount ranging from 0.45% to 0.5 % w/v.
- the quantity of the agent increasing the viscosity has direct influence on the distribution of particle size in the suspension.
- the preferred quantity of Carbomer 974 P in the composition of the formulation according to the invention is 4-5 mg/ml.
- concentration of the agent is 5 mg/ml or above, the size of the formed particles is too large; however, the concentration below 4 mg/ml results in a suspension that is too loose and unstable.
- the formulation further contains sodium hydroxide, added as a whole to the aqueous solution of the acrylic acid polymer in order to neutralize the acid.
- the quantity of sodium hydroxide is determined experimentally.
- the eye drops formulation additionally contains a preserving and solubilizing agent, traditionally used in ophtalmic medicines, preferably benzalkonium chloride, which is a mixture of alkylbenzyldimethylammonium chlorides with different alkyl substituents. Due to the technology used for its manufacturing, the suspension obtainable by the process of the invention do not require using of surface tension lowering agents, such as Tyloxapol.
- the eye drops formulation in the form of the suspension containing brinzolamide preferably comprises the following excipients: acrylic acid polymer, edetate disodium, benzalkonium chloride, mannitol, sodium hydroxide, hydrochloric acid, sodium bicarbonate and purified water for use in the ophthalmic formulations.
- composition of the eye drops formulation is as follows:
- the formulation of the ophthalmic eye drops containing 10 mg/ml of brinzolamide comprises, per 1 mililiter of the suspension:
- Solution I is obtained by dissolving brinzolamide in an aqueous 0.1 M hydrochloric acid in the presence of mannitol as co-solubilizer.
- Mannitol enhances solubility of brinzolamide in aqueous hydrochloric acid by forming hydrogen bonds with the hydrophilic groups of micelles to prevent their aggregation.
- the operation of dissolving is carried out at ambient temperature, thus avoiding the precipitation of brinzolamide upon cooling.
- Solution I is subjected to sterilizing filtration through a filter having the pore size 0.2 ⁇ .
- Solution II is prepared separately by dissolving the excipients, i.e. edetate disodium and benzalkonium chloride, in the solution of the precipitating agent.
- the precipitating agent i.e. edetate disodium and benzalkonium chloride
- an aqueous 1 M solution of sodium bicarbonate is used as the precipitating agent.
- the final Solution II is subjected to sterilizing filtration through a filter having the pore size 0.2 ⁇ .
- Solution III containing Carbomer 974 P and sodium hydroxide, due to its high viscosity, is subjected to autoclaving.
- Solution II is combined immediately with Solution I containing brinzolamide in hydrochloric acid, to bring about the precipitation and form a suspension.
- Solution II is added to Solution ⁇ .
- the obtained suspension is additionally stirred.
- the stirring time affects the content of brinzolamide in the final suspension, however, its influence on the distribution of particle size was not observed.
- the optimal time of stirring is 2 hrs. In case of shorter stirring time, the content of brinzolamide in the suspension is too low.
- the obtained suspension is then combined with Solution ⁇ and homogenized to form uniform particles and further limiting their size.
- the homogenization process is well known not only in the pharmaceutical industry. Besides the typical homogenization process, i.e. the homogenization of the product in the form of a liquid, cream or gel, it can be used to obtain suspensions and emulsions as well as to fragment insoluble and firm particles to a very small size.
- time and shearing force play a crucial role. The shearing force depends not only on the rotary speed of the stirrer turbine, but also on the stirrer and apparatus geometry and the volume of the homogenizer.
- the size of the obtained particles was similar to that in Azopt®.
- the extension of the homogenization duration by additional 5 min results in reducing the size of brinzolamide particles in the suspension.
- Increasing the rotary speed to 20500 rpm for 5 min. affords particles of a smaller size than required.
- the prolongation of the homogenization time has no impact on the particle size in the suspension.
- the advantageous effect can be achieved when the homogenization process is carried out with the homogenizer working on the Rotor-Stator technology, e.g. Ultra-Turrax T 25 digital, at 13500 rpm for 10 min.
- the process according to the invention allows significant simplification of the manufacturing process of brinzolamide ophthalmic suspension, by eliminating both the active substance grinding process and the necessity to add the surfactant.
- the obtained finished dosage form has proper physicochemical characteristics and is stable.
- the stability of the formulations of the invention was proved by the estimation of the active substance content in the routine stability tests.
- the product was stored for the scheduled time in strictly definite and monitored conditions of temperature and humidity (25°C/60% of relative humidity and 40°C/75% of relative humidity - accelerated test) according to the directive CPMP ICH/2736/99 "Stability Testing Guidelines: Stability testing of new drug substances and products".
- FIG. 5 An example of brinzolamide volumetric particle size distribution in the suspension is shown in Fig. 5 and a microscopic image of the formulation of the invention is presented in Fig. 6.
- the ophthalmic suspension containing 10 mg/ml of brinzolamide was prepared of the following composition: Substance/excipient g/1 ml g/1000 g
- BAC Benzalkonium chloride
- Bottles, droppers and caps were washed, dried and sterilized with radiation. Then the material was protected against secondary contamination with aluminum foil. Work surfaces were wiped with isopropyl alcohol and then sterilized with UV light. Flasks and the filtration set were washed, dried and heated with hot air in a dryer. Then the material was protected against secondary contamination with aluminum foil.
- the membrane filters made of poly(vinylidene fluoride) (PVDF) were sterilized with steam in an autoclave.
- the active ingredient was weighed and dissolved in the aqueous 0.1 M solution of hydrochloric acid with the addition of mannitol at ambient temperature while stirring with a magnetic stirrer.
- the solution was filtered through the PVDF filtration membrane having the pores size 0.2 ⁇ .
- SOLUTION II 1M aqueous sodium bicarbonate, EDTA and BAC were weighed and mixed to obtain a solution. The solution was filtered through the PVDE filtration membrane having the pores size 0.2 ⁇ . SOLUTION III
- Carbomer 974 P was weighed, added to water and homogenized. Then sodium hydroxide was added to the mixture with stirring and the whole mixture was sterilized with steam in the autoclave.
- SOLUTION II was slowly added to SOLUTION I at ambient temperature. After combining both solutions, the precipitation of brinzolamide occurred accompanied with C0 2 evolution.
- the suspension of brinzolamide (1000 mL) was homogenized for 10 min using the Ultra-Turrax T 25 digital homogenizer (from IKA) at the rotary speed of 13500 rpm.
- the suspension was dosed with the use of an automatic pipette into 5 ml bottles made of low density polyethylene. The bottles were provided with droppers and sealed with caps. Contents of the active substance in the final suspension
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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PLP.407710 | 2014-03-28 | ||
PL407710A PL407710A1 (en) | 2014-03-28 | 2014-03-28 | Method for producing the eye drops preparation in the form of a suspension containing brinzolamidum and the preparation produced by this method |
Publications (1)
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WO2015147665A1 true WO2015147665A1 (en) | 2015-10-01 |
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PCT/PL2015/000052 WO2015147665A1 (en) | 2014-03-28 | 2015-03-27 | Process for manufacturing brinzolamide ophthalmic suspension and eye drops formulation |
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WO (1) | WO2015147665A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020094930A1 (en) * | 2018-11-08 | 2020-05-14 | KITKIT ABDESLEM, Alain | Eyesight improving device |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998025620A1 (en) * | 1996-12-11 | 1998-06-18 | Alcon Laboratories, Inc. | Process for manufacturing ophthalmic suspensions |
WO2011067791A2 (en) * | 2009-12-03 | 2011-06-09 | Lupin Limited | Process for preparing pharmaceutical ophthalmic compositions |
WO2012053011A2 (en) * | 2010-10-18 | 2012-04-26 | Usv Limited | Ophthalmic compositions comprising brinzolamide |
WO2013025696A1 (en) * | 2011-08-15 | 2013-02-21 | Teva Pharmaceutical Industries Ltd. | Ophthalmic formulations and processes for their preparation |
WO2013175285A1 (en) * | 2012-05-21 | 2013-11-28 | Aurobindo Pharma Limited | Process for preparing ophthalmic suspension of brinzolamde |
-
2014
- 2014-03-28 PL PL407710A patent/PL407710A1/en unknown
-
2015
- 2015-03-27 WO PCT/PL2015/000052 patent/WO2015147665A1/en active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998025620A1 (en) * | 1996-12-11 | 1998-06-18 | Alcon Laboratories, Inc. | Process for manufacturing ophthalmic suspensions |
EP0941094B1 (en) | 1996-12-11 | 2001-12-05 | Alcon Laboratories, Inc. | Process for manufacturing ophthalmic suspensions containing brinzolamide |
WO2011067791A2 (en) * | 2009-12-03 | 2011-06-09 | Lupin Limited | Process for preparing pharmaceutical ophthalmic compositions |
WO2012053011A2 (en) * | 2010-10-18 | 2012-04-26 | Usv Limited | Ophthalmic compositions comprising brinzolamide |
WO2013025696A1 (en) * | 2011-08-15 | 2013-02-21 | Teva Pharmaceutical Industries Ltd. | Ophthalmic formulations and processes for their preparation |
WO2013175285A1 (en) * | 2012-05-21 | 2013-11-28 | Aurobindo Pharma Limited | Process for preparing ophthalmic suspension of brinzolamde |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020094930A1 (en) * | 2018-11-08 | 2020-05-14 | KITKIT ABDESLEM, Alain | Eyesight improving device |
FR3088196A1 (en) * | 2018-11-08 | 2020-05-15 | Abdeslem Alain Kitkit | DEVICE FOR IMPROVING THE VIEW OF A SOLUTION IN A BOTTLE WITH TREATMENT AND WASHING |
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PL407710A1 (en) | 2015-10-12 |
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