Bibliographic data
`
`Title:
`
`THE PROCESS FOR MANUFACTURING TOPICAL
`OPHTHALMIC PREPARATIONS WITHOUT SYSTEMIC
`EFFECTS
`
`Pub/Pat no:
`
`WO0046990A2
`
`Pub/Issue Date:
`
`2000-08-31
`
`Inventor(s):
`
`Applicant(s):
`
`KHAMAR, BAKULESH, MAFATLAL
`
`KHAMAR BAKULESH MAFATLAL[IN]
`
`Classification:
`
`ASIK9/O0AL A6GIK47/324N: ASIK4736AMN
`
`Application number;
`Priority number:
`
`WO2000IN00008-2000-02-02
`IN1999BO00090 1999-02-03;
`
`Abstract of WO0049990A2
`
`Fortreating eye diseases, various kinds of medications are used. They are used in form. of topical
`preparations or in form of systemic. preparations.to be taken orally or parenterally. Of topical
`preparations some are for topical use only e.g. framycetin, neomycin, loteprednol ebanoate, etc.
`However, large majority of topical ophthalmic drugs are for systemic use also,.e.g.; Ciprofloxacin,
`Gentamicin, Timalél, Clonidine, Dexamethasone, Betamethasone, Carbachol, ele. Some-of these
`drugs when used topically are also found to have systemic effects and if they are of serious nature
`limits the use of that drug, e.g. cardiopulmonary effects of B-blockers like timolol. Dryness of
`mouth, flush, fever, tachy cardia, ‘urinary retention, convulsion irritability with atropine.
`Hypertension with phenylephine. Increased salivation, nausea, vom iting, diarrhea, stomach
`cramps, bronchial secretions, bronchial constriction, asthma, bradycardia, paresthesia. with
`mictics, Hypotension with clonidine. Dry mouth, fatigue and drowsiness with apraclonidine and
`brimonidine.The invention relates to topical ophthalmic preperations resp. a process for
`manufacturing the same using:polymers:in such away that-they have desired topical effects but. no
`systemic effects. The polymers (e.g. polyacrylic acids, hydroxyethyl cellulose, etc.) used for this
`purpose’ have pseudo-plastic, mucoadhesive-and viscosity enhancing properties.
`
`

`

`PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`WO 00/49990
`
`31 August 2000 (31.08.00)
`
`(81) Designated States: AE, AL, AU, BA, BB, BG, BR, CA, CN,
`CR, CU, CZ, EE, GE, HU,ID,IL, IS, KP, KR, LC, LK, LR,
`LS, LT, LV, MG, MK, MN, MX, NO, PL, RO,SG,SI, SL,
`TR, TT, UA, US, UZ, VN, YU, ZA, ARIPO patent (GH,
`GM,KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,
`IE, IT, LU, MC, NL, PT, SE), OAPT patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
` (11) International Publication Number:
`
`(51) International Patent Classification 7 :
` A2
`
`AGIK
`(43) International Publication Date:
`
`
`
`
`(21) International Application Number:
`PCT/INO0/00008
`
` (22) International Filing Date: 2 February 2000 (02.02.00)
`
`
`
`
`(30) Priority Data:
`
`3 February 1999 (03.02.99)90/BOM/99 IN
`
`
`
`
`
`(71)(72) Applicant and Inventor: KHAMAR, Bakulesh, Mafatlal
`[IN/IN]; 201 "Ashadha", Vasundhara Colony, Gulbai Tekra,
`
`Ellisbridge, Ahmedabad 380 006, Gujarat (IN).
`
`Published
`Without international search report and to be republished
`
`
`
`upon receipt of that report.
`
`(54) Title!) THE PROCESS FOR MANUFACTURING TOPICAL OPHTHALMIC PREPARATIONS WITHOUT SYSTEMIC EFFECTS
`
`(57) Abstract
`
`Fortreating eye diseases, various kinds of medications are used. They are used in form oftopical preparations or in form of systemic
`preparations to be takenorally or parenterally. Of topical preparations some are for topical use only e.g. framycetin, neomycin, loteprednol
`ebanoate, etc. However, large majority of topical ophthalmic drugs are for systemic use also, ¢.g.. Ciprofloxacin, Gentamicin, Timolol,
`Clonidine, Dexamethasone, Betamethasone, Carbachol, etc. Some of these drugs when used topically are also found to have systemic
`effects and if they are of serious nature limits the use of that drug, e.g. cardiopulmonary effects of B—blockers like timolol. Dryness
`of mouth, flush, fever, tachy cardia, urinary retention, convulsionirritability with atropine. Hypertension with phenylephine.
`Increased
`salivation, nausea, vomiting, diarrhea, stomach cramps, bronchial secretions, bronchial constriction, asthma, bradycardia, paresthesia with
`miotics, Hypotension with clonidine. Dry mouth, fatigue and drowsiness with apraclonidine and brimonidine.
`
`
`
`
`

`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`Is
`IT
`JP
`KE
`KG
`KP
`
`Albania
`AL
`Armenia
`AM
`Austria
`AT
`Australia
`AU
`Azerbaijan
`AZ
`Bosnia and Herzegovina
`BA
`Barbados
`BB
`Belgium
`BE
`Burkina Faso
`BF
`Bulgaria
`BG
`Benin
`BJ
`Brazil
`BR
`Belarus
`BY
`Canada
`CA
`Central African Republic
`CF
`Congo
`CG
`Switzerland
`CH
`Cote d'Ivoire
`cl
`Cameroon
`CM
`KR
`China
`CN
`KZ
`Cuba
`cu
`Lc
`Czech Republic
`CZ
`LI
`Germany
`DE
`LK
`Denmark
`DK
`LR
`Estonia
`EE
`
`
`.
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Treland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People’s
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`sb
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`Slovenia
`si
`Slovakia
`SK
`Senegal
`SN
`Swaziland
`SZ
`Chad
`TD
`Togo
`TG
`Tajikistan
`TJ
`™ Turkmenistan
`TR
`Turkey
`TT
`Trinidad and Tobago
`UA
`Ukraine
`UG
`Uganda
`US
`United States of America
`UZ
`Uzbekistan
`VN
`Viet Nam
`YU
`Yugoslavia
`ZW
`Zimbabwe
`
`
`
`

`

`WO 00/49990
`
`PCT/IN00/00008
`
`THE PROCESS FOR MANUFACTURING TOPICAL OPHTHALMIC PREPARATIONS
`WITHOUT SYSTEMIC EFFECTS.
`
`The present invention relates to the process for manufacturing topical ophthalmic
`preparations without systemic effects, Many topical ophthalmic preparations have-
`systemic effects. These systemic effects are responsible for contraindications, side
`effects, toxicity of some of the topical ophthalmic preparations. Similarly, due to
`systemic
`effects
`certain topical
`ophthalmic preparations
`have
`not
`been
`commercialized.
`
`The present invention is directed to manufacturing topical ophthalmic preparations
`in such a way that systemic effects of that topical ophthalmic preparation do not
`manifest.
`
`Topical ophthalmic preparations can be divided into two groups. One of the group
`includes preparations in which active ingredients are for topical use only and have
`no systemic effects. These group of drugs include antibiotics like Framycetin,
`Neomycin, Fucidin, steroids like Loteprednol Ebanoate, Triamcinolone, alpha
`agonist
`like Apraclonidine, Brimonidine,
`etc.
`The other group of topical
`ophthalmic preparations have active ingredients which are generally -used for their
`effects.
`These group of preparations include antibiotics like Ciprofloxacin,
`Norfloxacin, Ofloxacin, Gentamicin, Tobramycin, steroids like Dexamethasone,
`Betamethasone, B-blockers like Timolol, Betaxolol, etc. Some of these drugs when
`used topically are also found to have systemic effects. When systemic effects are
`serious
`in nature,
`it
`results in limiting the use of a drug in the form of
`contraindication or amountof drug to be used.
`
`

`

`WO 00/49990
`
`PCT/IN00/00008
`
`No
`
`Examples of well known systemic effects of topical ophthalmic preparations
`include
`cardiopulmonary effects of B-blockers
`like Timolol, Levobunolol,
`Metipranolol, Carteolol, etc. Dryness of mouth, flush, fever, tachycardia, urinary
`retention, convulsion irritability are found with Atropine eye drops.
`Systemic
`hypertension is associated with topical mydriatic phenylephrine.
`Increased
`salivation, nausea, vomiting, diarrhoea,
`stomach cramp, bronchial secretions,
`bronchial constriction, asthma, bradycardia, parasthesia is seen with miotics.
`Systemic hypotension is main limiting factor for use of clonidine in management
`of glaucoma. Dry mouth,
`fatigue and drowsiness seen with Brimonidine and
`Apraclonidine are some of their systemic effects.
`
`The systemic side effects, manifesting with the use of topical ophthalmic
`preparations results in discontinuation of therapy or not
`initiating a therapy or
`reducing the amountof drug or drug not having wide spread acceptance.
`
`Because of this reason, attempts’ are made to reduce systemic effects of topically
`- applied drugs.
`
`It depends on
`Systemic effects are due to plasma concentration of a drug.
`absorption of the drug from conjunctiva or nasal mucosa into systemic circulation
`(serum levels of drug).
`
`The mechanisms to reduce plasma concentration of a drug includes reduction in
`drop size.
`It reduces the amount of drug available through conjunctiva as well as
`nasal mucosa.
`
`

`

`WO 00/49990
`
`PCT/INO0/00008
`
`The blockage of nasolacrimal duct temporarily or permanently also reduces drug
`reaching to nasal mucosa through nasolacrimal passages and
`thus reduces the
`amount of drug available systemically.
`Increasing the viscosity of a formulation
`also reduces the plasma concentration of a drug. Slow release of a drug through
`sustained release mechanism/device are known to reduce plasma concentration of
`topical ophthalmic preparations.
`Including vasoconstrictive agents into a topical
`ophthalmic preparation also reduces theplasma level of topically applied drugs.
`
`|
`
`The other mechanism used to reduce systemic effects include use of a prodrug as
`topical ophthalmic preparation which gets converted to active compound only at
`the site of action, e.g. Dipivetrin for epinephrine and Phenylephrine Oxazoline for
`Phenylephrine.
`
`The other mechanism known includes formulating a preparation as an ointment.
`The tear
`film formed with the use of ointment
`is
`thick, with poor
`light
`transmission and irregular anterior surface. This results in blurring of vision and
`so have not been popular.
`It also causes stickiness of lashes and lid margin. This
`limits its use to a great extent and wheneverused, its use is restricted for bed time
`
`application.
`
`None of the above described methods in isolation or in combination with each.
`
`other have been successful in eliminating systemic effects of topical ophthalmic
`preparations. Majority of efforts are centered around topical B-blockers to reduce
`their systemic effect, e.g. reduction in pulse rate. All known methods have been
`able to decrease the reduction in pulse rate, but none of them have been able to
`
`eliminate it completely.
`
`

`

`WO 00/49990
`
`PCT/IN00/00008
`
`REFERENCES:
`
`1. A Ludwig, N Unlu and M Van Ooteghem.
`Evaluatiuon of viscous ophthalmic vehicles containing carbomerby silit-
`lamp fluorophotometry in humans.
`International Journal of Pharmaceutics 1990; 61: 15-25.
`
`2. Arto Urtti, James D Pipkin, Gerald Rork, Toshiaki Sendo, Ulha Finne and
`AJ Repta.
`Contyrolled drug delivery devices for experimental ocular studies with
`timolol. 2. Ocular and systemic absorption in rabbits.
`International Journal of Pharmaceutics 1990; 61: 241-249.
`
`3. Benedetto DA, Shah DO,-Kaufman HE.
`The instilled
`fluid dynamics and surface chemistry of polymers in the
`preoculartear film.
`Invest Ophthamol 1975 Dec; 14(12): 887-902.
`
`4. Chang SC, Lee VH.
`Nasal and conjunctival contributions to the systemic absorption of topical
`timolol in the pigmented rabbit: implications in the design of strategics to
`maximise the ratio of ocular to systemic absorption.
`J Ocular Pharmacol! 1987 Summer; 3(2): 159-69.
`
`5. Chiang CH, Ho JI, Chen JL.
`Pharmacokinetics and intraocular pressure lowering effect of timolol
`preparations in rabbit eyes.
`J Ocul Pharmacol Ther 1996 Winter; 12(4): 471-80.
`
`6. Jarvinen K, Urtti A.
`Cardiac effects of different eyedrop preparations of timolol in rabbits.
`Curr Eye Res 1992 May; 11(5): 469-73.
`
`

`

`WO00/49990
`
`PCT/INO0/00008
`
`7.
`
`Johansen S, Rask-Pedersen E, Prause JU.
`A. bioavailability comparison in rabbits after a single topical ocular
`application of prednisolone acetate formulated as a high-viscocity gel and
`aS a aqueous suspension.
`Acta Ophthalmol Scand 1996 June; 74(3): 253-8
`
`Johansen S, Rask-Pedersen E, Prause JU.
`An ocular bioavailability comparison in rabbits of prednisolone acetate
`after repeated topical applications formulated as a high-viscocity gel and as
`an aqueous suspension.
`Acta Ophthalmol Scand 1996 June; 74(3): 259-64.
`
`Kumar V, Schoenwald RD, Barcellos WA, Chien DS, Folk JC, Weingeist
`TA.
`viscous
`vs
`Agueous
`cardiovascular effects.
`Arch Ophthalmol! 1986 Aug; 104(8): 1189-91.
`
`phenylephrine.
`
`I.
`
`Systemic
`
`absorption
`
`and
`
`10.
`
`Kumar S, Himmelstein KJ.
`Modification of
`in situ gelling behaviour of carbopol
`hydroxypropyl methy!cellulose.
`J Pharm Sci 1995 Mar; 84(3): 344-8.
`
`solutions by’
`
`11.
`
`Kyyronen K, Urtti A.
`Improved ocular: systemfc absorption ratio of timolol by viscous vehicle
`and phenylephrine.
`Invest Ophthalmol Vis Sci 1990 Sep; 31(9): 1827-33.
`
`12.
`
`Marco F Saetonne, Patrizia Chetoni, Maria Tilde Torracca, Susi Burgalassi
`and Boris Giannaccini.
`Evaluation of muco-adhesive properties and in vivo activity of ophthalmic
`vehicles based on hyaluronic acid.
`International Journal of Pharmaceutics 1989; 59: 203-212.
`
`

`

`WO 00/49990
`
`PCT/IN00/00008
`
`13.
`
`Romanelli L, Valeri P, Morrone LA, Pimpinella G, Graziani G, Tita B.
`Ocular absorption and distribution of benzadac after topical administration
`to rabbits with different vehicles.
`Life Sci 1994; 54(13): 877-85.
`
`14.
`
`Sieradzki E.
`Bioavailability of drugs applied to the eye externally [Article in Polish].
`‘Klin Oczna 1991 jan; 93(1): 34-6.
`
`15.
`
`Urtti A.
`Delivery of antiglaucoma drugs: ocular vs systemic absorption.
`J Ocular Pharmacol 1994 Spring; 10(1): 349-57.
`
`. Urtti A, Salminen L.
`Minimizing systemic absorption of topically administered ophthalmic
`drugs.
`Surv Ophthalmol 1993 May-June; 37(60: 435-56.
`
`. ven der Ohe N, Stark M, mayer H, Brewitt H.
`How can the bioavailability of timolol be enhanced? A pharmacokinetic
`pilot study of novel hydsrogels.
`Graefes Arch Clin Exp Ophthalmol 1996 July; 234(7): 452-6.
`
`. Wilson CG, Olejnik O, Hardy JG.
`Precorneal drainage of polyvinyl alcoho! solutions in the rabbit assessed by
`gamma scintigraphy.
`J Pharm Pharmacol 1983 July; 35(7): 451-54.
`
`

`

`WO 00/49990
`
`PCT/IN00/00008
`
`The objective of present invention is to provide topical ophthalmic preparations
`
`without systemic effects without reducing the concentration of active ingredient.
`
`The further objective of present
`
`invention is
`
`to provide topical ophthalmic
`
`preparations which does not cause significant visual disturbances to limit its use
`
`during waking hours.
`
`to provide topical ophthalmic
`invention is
`The further objective of present
`preparations which are equally effective after longer period of storage.
`
`invention is to provide topical ophthalmic
`present
`of
`The further objective
`preparations which do not require special storage conditions.
`
`Accordingly there is provided a process of manufacturing topical ophthalmic
`
`preparations without systemic side effects which comprises of the followingsteps.
`
`lL Liquid formulation of a selected drug is prepared which contains excipients
`buffers and preservatives in distilled water. The pl of this solution is
`
`adjusted to provide stable formulation for topical ophthalmicuse.
`
`2.
`
`- In a separate vessel polymer.is dissolved into a solvent preferably water and
`
`stirred well till gel is formed.
`
`3.
`
`Solution containing selected drug as formulated in step 1
`
`is gradually added
`
`to the gel as formed in step 2.
`
`

`

`WO 00/49990
`
`PCT/INO00/00008
`
`4.
`
`5.
`
`Volume is made up by addingdistilled water/solvent as required.
`
`pH is checked and adjusted as necessary to provide stable formulation for
`topical instillation into eye.
`
`The drug described above can be any of the existing ophthalmic preparations or
`any other drug which cannot be used as a topical preparation in a desired
`concentration for instillation into eye. The drugs which are most frequently used
`and are known to have systemic effects
`include fB-blockers
`like Timolol,
`
`Levobunolol, Metipranalol, etc.
`
`Similarly,- mydriatics like phenylephrine, atropine, cyclopentolate,
`
`tropicamide
`
`have systemic effects and their use is restricted byit.
`
`Clonidine is an example of a drug which lowers J.0.P. significantly but cannot be
`
`used as 0.1% or 0.2% concentration due to its systemic hypotensive effect.
`The polymer to be used for preparing topical formulation as per present invention
`should form a gel when solubilized. For the purpose of present invention it
`is
`desirable to select a polymer with mucoadhesive properties. To avoid discomfort
`
`and visual disturbances associated with use of viscous solutions, it is desirable that
`
`*
`
`polymerselected demonstrates pseudoplastic behaviour in a formulation.
`
`

`

`WO00/49990
`
`PCT/IN00/00008
`
`Polymer to be used for the purpose of present invention having above properties
`are known and includes polyacrylic acid, polyacrylic esters, polycarbophile,
`polyvinyl Acetate, Acrypol, Xantham gum, Guar gum, hydroxy ethyl cellulose,
`polyvinyl alcohol, PVP, carbomers, hydrogels prepared by combination of various
`polymers etc. Names of above polymer exemplifies the process and are not
`restricted to for the purpose of invention.
`
`For the purpose of avoiding systemic effects of a formulation prepared as per
`present
`invention,
`it
`is necessary to have viscosity above
`100,000 cps (one
`hundred thousand cps), preferably above 400,000 (four hundred thousandcps).
`
`The final volume adjustment and amount of polymer to be used has to be designed
`considering these requirements. The amount of polymer in a final formulation to
`get desired viscosity is variable but is well known.
`It varies with polymer to
`polymerand also with molecular weight of some polymer.
`
`Pharmaceutical preparations so manufactured can be sterilized by known methods
`of sterilizing, including autoclaving.
`If sterilization process is likely to result in
`unstabilization of drug,
`it can be prepared as a sterile product throughout the
`
`process.
`
`

`

`WO 00/49990
`
`PCT/IN00/00008
`
`10
`
`Examples of formulations
`
`I.
`
`Timolol
`
`A.. Timolol 0.5%
`Timolol Maleate
`Benzylconium chloride
`Polyacrylic Acid
`(Carbopol 940)
`Sodium hydroxide to adjust pH 6.5 to 7.5
`Water for injection QS to make 100 ml.
`
`0.72 gm. equivalent to 0.5 gm of Timolol
`0.0107 gm
`1.5 gm to 2.5 gm
`
`B.
`
`Timolol 0.25%
`Timolol Maleate
`Benzylconium chloride
`Polyacrylic Acid
`(Carbopol 940)
`Sodium hydroxide to adjust pH 6.5 to 7.5
`Water for injection QS to make 100 ml
`
`0.36 gm equivalent to 0.5 gm of Timolol
`0.0107 gm
`1.5 gm to 2.5 gm
`
`Timolol
`I.
`A.. Timolol 0.5%
`0.72 gm. equivalent to 0.5 gm of Timolol
`Timolol Maleate
`0.0107 gm
`Benzylconium chloride
`1.5 gm to 2.5 gm
`Carbopol ETD 2001
`Sodium hydroxide to adjust pH 6.5 to 7.5
`Water for injection
`Q.S. to make 100 ml.
`
`B.
`
` Timolol 0.25%
`0.36 gm equivalent to 0.5 gm of Timolol
`Timolol Maleate
`— 0.0107 gm
`Benzylconium chloride
`1.5 gm to 2.5 gm
`Carbopol ETD 2001
`Sodium hydroxide to adjust pH_ 6.5 to 7.5
`Waterfor injection
`Q.S. to make 100 ml
`
`I.
`
`Timolol
`
`A.. Timolol 0.5%
`0.72 gm. equivalent to 0.5 gm of Timolol
`Timolol Maleate
`0.0107 gm
`Benzylconium chloride
`1.5 gm to 2.5 gm
`Carbopol 981
`Sodium hydroxide to adjust pH 6.5 to 7.5
`Water for injection
`Q.S. to make 100 ml.
`
`

`

`WO 00/49990
`
`PCT/IN06/00008
`
`Timolol 0.25%
`0.36 gm equivalent to 0.5 gm of Timolol
`Timolol Maleate
`0.0107 gm
`Benzylconium chloride
`1.5 gm to 2.5 gm
`Carbopol 981
`Sodium hydroxide to adjust pH_ 6.5 to 7.5
`Waterfor injection
`Q.S. to make 100 ml
`
`IV.
`
`Timolol
`
`Timolol 0.5%
`0.72 gm. equivalent to 0.5 gm of Timolol!
`Timolol Maleate .
`0.0107 gm
`Benzylconium chloride
`1.5 gm to 2.5 gm
`Polycarbophil
`Sodium hydroxide to adjust pH_ 6.5 to 7.5
`Waterfor injection
`Q.S. to make 100 ml.
`
`Timolol 0.25%
`0.36 gm equivalent to 0.5 gm of Timolo!
`Timolol Maleate
`0.0107 gm
`Benzylconium chloride
`1.5 gm to 2.5 gm
`Polycarbophil
`Sodium hydroxide to adjust pH_ 6.5 to 7.5
`Water for injection
`Q.S. to make 100 ml
`
`Clonidine
`
`Clonidine 0.1%
`Clonidine hydrochloride
`Benzylconium chloride
`Polyacrylic Acid
`(Carbopol 940)
`Sodium hydroxide to adjust pH 6.5 to 7.5
`Waterfor injection QS to make 100 ml
`
`0.1 gm
`0.0107 gm
`1.5 gm to 2.5 gm
`
`Clonidine 0.2%
`Clonidine hydrochloride
`Benzylconium chloride
`Polyacrylic Acid
`(Carbopol 940)
`Sodium hydroxide to adjust pH_ 6.5 to 7.5
`Water for injection QS to make 100 ml
`
`0.2 gm
`0.0107 gm
`1.5 gm to 2.5 gm
`
`

`

`WO 00/49990
`
`PCT/INO0/60008
`
`12
`
`VIL
`
`Clonidine
`
`A. Clonidine 0.1%
`Clonidine hydrochloride . 0.1 gm
`Benzylconium chloride
`0.0107 gm
`Carbopol ETD 2001
`1.5 gmto 2.5 gm
`Sodium hydroxide to adjust pH_ 6.5 to 7.5
`Water for injection
`Q.S. to make 100 ml
`
`Clonidine 0.2%
`0.2 gm
`Clonidine hydrochloride
`0.0107 gm
`Benzylconium chloride
`1.5 gm to 2.5 gm
`Carbopol ETD 2001
`Sodium hydroxide to adjust pH_ 6.5 to 7.5
`Waterfor injection
`Q.S. to make 100 ml
`
`VII.
`
`Clonidine
`
`Clonidine 0.1%
`0.1 gm
`Clonidine hydrochloride
`0.0107 gm
`Benzylconium chloride
`1.5 gm to 2.5 gm
`Carbopol 981
`Sodium hydroxide to adjust pH 6.5 to 7.5
`Water for injection
`Q.S. to make 100 ml
`
`Clonidine 0.2%
`|
`0.2 gm_
`Clonidine hydrochloride
`0.0107 gm
`Benzylconium chloride
`1.5 gm to 2.5 gm
`Carbopol 981
`Sodium hydroxide to adjust pH_ 6.5 to 7.5
`Waterfor injection
`Q.8S. to make 100 ml
`
`

`

`WO 00/49990
`
`PCT/INO00/00008
`
`VIII. Clonidine
`
`A. Clonidine 0.1%
`0.1 gm
`Clonidine hydrochloride
`0.0107 gm
`Benzylconium chloride
`1.5 gm to 2.5 gm
`Polycarbophil
`Sodium hydroxide to adjust pH_ 6.5 to 7.5
`Waterfor injection
`Q.8. to make 100 ml
`
`Clonidine 0.2%
`0.2 gm
`Clonidine hydrochloride
`0.0107 gm
`Benzylconium chloride
`1.5 gm to 2.5 gm
`Polycarbophil
`Sodium hydroxide to adjust pH_ 6.5 to 7.5
`Waterfor injection
`Q.S. to make 100 ml
`
`IX.
`
`Betaxolol
`
`Betaxolol 0.5%
`0.56 gm. equivalent to 0.5 gm of Betaxolol
`Betaxolol hydrochloride
`0.01 gm
`Benzylconium chloride
`Dibasic sodium phosphate 0.05 gm
`Sodium phosphate monobasic 0.025 gm
`Disodium EDTA
`0.05 gm
`Sodium chloride
`0.3 gm
`Propylene glycol
`2.5 pm
`Carbopol ETD 2001
`2.0 gm
`Water for injection
`Q.S. to make 100 ml.
`
`

`

`WO 00/49990
`
`PCT/INO00/00008
`
`Betaxolol
`
`Betaxolol 0.5%
`0.56 gm. equivalent to 0.5 gm of Betaxolol
`Betaxolol hydrochloride
`0.01 gm
`Benzylconium chloride
`Dibasic sodium phosphate 0.05 gm
`Sodium phosphate monobasic 0.025 gm
`Disodium EDTA
`0.05 gm
`Sodium chloride
`0.3 gm
`Propylene glycol
`2.5 gm
`Polyacrylic acid
`2.0 gm
`(Carbopol 940)
`Waiterfor injection
`
`Q.S. to make 100 ml
`
`XI
`
`Betaxolol
`
`Betaxolol 0.5%
`0.56 gm. equivalent to 0.5 gm of Betaxolol
`Betaxolol hydrochloride
`0.01 gm
`Benzylconium chloride
`Dibasic sodium phosphate 0.05 gm
`Sodium phosphate monobasic 0.025 gm
`Disodium EDTA
`0.05 gm
`Sodium chloride
`0.3 gm
`Propylene glycol
`2.5 gm
`Carbopol 981
`2.0 gm
`Water for injection
`Q.S. to make 100 ml.
`
`Betaxolol
`
`Betaxolol 0.5%
`0.56 gm. equivalent to 0.5 gm of Betaxolol
`Betaxolol hydrochloride
`0.01 gm
`Benzylconium chloride
`Dibasic sodium phosphate 0.05 gm
`Sodium phosphate monobasic 0.025 gm
`Disodium EDTA
`0.05 gm
`Sodium chloride
`0.3 gm
`Propylene glycol
`2.5 gm
`Polycarbophil
`2.0 gm
`Water for injection
`Q.S. to make 100 ml.
`
`

`

`WO 00/49990
`
`PCT/IN00/00008
`
`Pharmaceutical composition so manufactured is evaluated for
`
`stability and
`
`efficacy.
`
`The Pharmaceutical composition so manufactured is evaluated at different test
`
`conditions of temperature and humidity (as per ICH guidelines, 40°C/75% RH,
`
`25°C/60% RH) for time interval extending upto 12 months.
`
`The samples of formulations so prepared were used for study.
`
`The topical ophthalmic preparation of Clonidine 0.1% and 0.2% so prepared were
`
`evaluated in vivo studies.
`
`Healthy normal volunteers (10) had instillation of drug in their eyes.
`
`IO.P. and
`
`B.P. were measured every 2 hours. Control group (10) received placebo.
`
`Drop in I.0.P. was seen only in eyes receiving Clonidine.
`
`It was found to be in
`
`the range of 30%of initial 1.O.P. The effect on I.O.P. was found to last 8 ~ 10
`
`hours.
`
`Effect on blood pressure in both groups i.e. Clonidine and placebo was identical
`
`for systolic as well as diastolic blood pressure and it was insignificant. Peak
`
`reduction in systolic B.P. was 4.4 mm of Hg was for placebo, 4.11 mm of Hg for
`
`—
`
`0.1% Clonidine and 3.93 mm. of Hg for 0.2% Clonidine.
`Peak reduction in
`diastolic B.P. was 4.23 mm of Hg for placebo, 4.49 mm of Hg. for Clonidine 0.1%
`and 2.89 mm of Hg for Clonidine 0.2%.
`
`

`

`WO 00/49990
`
`PCT/IN00/00008
`
`Clonidine eye drops even when used at 0.05 % to 0.06 % concentration are
`
`associated with reduction in systemic B.P.
`
`The topical ophthalmic preparation of Timolol Maleate 0.5% made according to
`
`present invention was evaluated for systemic effects and compared with Timolol
`
`eye drops and Timoptic XE.
`
`In healthy normal volunteers (10 in each group) various formulations of Timolol
`and placebo drug wereinstilled in both eyes. LO.P. and resting pulse rate were
`measured every 2 hours. The peak reduction in mean I.0.P. was 25% with
`Timolol drops, 27% with Timoptic XE and 40% with Timolol made as per present
`
`invention. The change in resting pulse rate was identical in placebo and Timolol
`
`as per present
`
`invention.
`
`It was 13.2% with Timolol drops and 13.33% with
`
`Timoptic XE.
`
`Thus, both the preparations of Clonidine as well as Timolol made according to
`
`present invention were found to have no systemic effect. The efforts were made to
`
`find out plasma concentration of drugs but none ofthe drugs achieved detectable
`
`plasma concentrations.
`
`Thus, present invention provides process for manufacturing of topical ophthalmic
`
`preparations without systemic effects.
`
`The above examples of formulations are provided as a proof of working of this
`
`invention and should not be restricted to this only. Any drug useful after
`
`instillation into eye can be formulated according to present
`
`invention without
`
`systemic effect.
`
`

`

`WO 00/49990
`
`ITeclaim:
`
`PCT/IN00/00008
`
`l.
`
`formulation of topical ophthalmic
`The process of manufacturing of
`preparations without systemic effect comprising the followingsteps.
`i.
`Making a gel using polymers with or without physiologically
`acceptable excipients buffers and preservatives
`Adding liquid formulation of a drug into a prepared gel of step (i)
`while stirring slowly.
`
`il.
`
`iii.
`
`Adjusting the pH and volumebeforefinal packing
`
`2.
`
`A process as claimed in claim | wherein Polymer can be any polymer
`having pseudoplastic behaviour.
`
`3.
`
`A process as claimed in claim 1 & 2 wherein polymer should have
`
`mucoadhesive property.
`
`4.
`
`A process as claimed in claim 1
`
`to 3. wherein polymer can be but not
`
`to Carbopol 940 (Polyacrylic acid), Carbopol ETD 2001,
`restricting
`981,
`Polycarbophil,
`Polyvinyl Alcohol, Hydroxyethyl.
`Carbopol
` Polyacrylic esters, Acrypol, Xantham gum, Guar gum, poly-
`Cellulose,
`vinyl ester, Carbomer etc. .
`
`|
`
`5.
`
`Polymer as claimed in claim 1
`
`to 4 can be used alone or in combination
`
`with other polymers.
`
`

`

`WO 00/49990
`
`PCT/IN00/00008
`
`to 5 wherein viscosity of final:
`The process as claimed in claim 1
`formulation is more than 100,000 cps (One hundred thousand cps).
`
`to 6 physiologically acceptable buffers
`‘The process as claimed in claim 1
`excipients and preservatives are used.
`
`The process as claimed in claim 1 to 7 wherein liquid formulation of a drug _
`can be in the form of aqueous solution, suspension or emulsion.
`
`The process as claimed in claim 1
`
`to 8 wherein volume of formulation is
`
`adjusted to get desired concentration of a drug into final formulation.
`
`10.
`
`A process as claimed in claim 1 to 9 and substantially described in example
`in accompanyingspecification.
`
`