Note: Descriptions are shown in the official language in which they were submitted.
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THE PROCESS FOR MANUFACTURING TOPICAL OPHTHALMIC PREPARATIONS
' WITHOUT SYSTEMIC EFFECTS.
' The 'present invention relates to the process for manu#~acturing 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, ~i-bIockers like Timolol, Betaxolol, etc. Some of these drugs
when
used topically are also found to have systemic effects. When systemic effects
are
serious m nature, it results in limiting the use of a drug in the form of
contraindication or amount of drug to be used.
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Examples of well known systemic effects of topical ophthalmic preparations
include cardiopulmonary effects of (3-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 amount of drug or drug not having wide spread acceptance.
Because of this reason, attempts' are made to reduce systemic effects of
topically
applied drugs.
Systemic effects are due to plasma concentration of a drug. 1t depends on
absorption of the drug fram 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.
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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 the plasma 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. 1t also causes stickiness of lashes and lid margin.
This
limits its use to a great extent and whenever used, its use is restricted for
bed time
V
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 (3-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.
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REFERENCES:
1. A Ludwig, N Unlu and M Van Ooteghem.
Evaluatiuon of viscous ophthalmic vehicles containing carbomer by slit-
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
preocular tear 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 strategies 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.
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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
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.
9. Kumar V, Schoenwald RD, Barcellos WA, Chien DS, Folk JC, Weingeist
TA.
Aqueous vs viscous phenylephrine. I. Systemic absorption and
cardiovascular effects.
Arch Ophthalmol 1986 Aug; 104(8): 1189-91.
10. Kumar S, Himmelstein KJ.
Modification of in situ gelling behaviour of carbopol solutions by'
hydroxypropyl methyl cellulose.
J Pharm Sci 1995 Mar; 84(3): 344-8.
11. Kyyronen K, Urtti A.
Improved ocular: systemcc 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.
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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( I ): 34-6.
15. Urtti A.
Delivery of antiglaucoma drugs: ocular vs systemic absorption.
J Ocular Pharmacol 1994 Spring; 10(1): 349-57.
16. Urtti A, Salminen L.
Minimizing systemic absorption of topically administered ophthalmic
drugs.
Surv Ophthalmol 1993 May-June; 37(60: 435-56.
17. 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.
18. Wilson CG, Olejnik O, Hardy JG.
Precorneal drainage of polyvinyl alcohol solutions in the rabbit assessed by
gamma scintigraphy.
J Pharm Pharmacol 1983 July; 35(7): 451-54.
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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.
The further objective of present invention is to provide topical ophthalmic
preparations which are equally effective after longer period of storage.
The further objective of present invention is to provide topical ophthalmic
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 following
steps.
1. Liquid formulation of a selected drug is prepared which contains excipients
buffers and preservatives in distilled water. The pH of this solution is
adjusted to provide stable formulation for topical ophthalmic use.
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.
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4. Volume is made up by adding distilled water/solvent as required.
5. 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 (3-blockers like Timolol,
Levobunolol, Metipranalol, etc.
Similarly, mydriatics like phenylephrine, atropine, cyclopentolate,
tropicamide
have systemic effects and their use is restricted by it.
Clonidine is an example of a drug which lowers LO.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 '
polymer selected demonstrates pseudoplastic behaviour in a formulation.
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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 thousand cps).
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
polymer and 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.
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Examples of formulations
I. Timolol
A.. Timolo10.5%
Timolol Maleate 0.72 gm. equivalent to 0.5 gm of Timolol
Benzylconium chloride 0.0107 gm
Polyacrylic Acid 1.5 gm to 2.5 gm
(Carbopol 940)
Sodium hydroxide to adjust pH 6.5 to 7.5
Water for injection QS to make 100 ml.
B. Timolo10.25%
Timolol Maleate 0.36 gm equivalent to 0.5 gm of Timolol
Benzylconium chloride 0.0107 gm
Polyacrylic Acid 1.5 gm to 2.5 gm
(Carbopol 940)
Sodium hydroxide to adjust pH 6.5 to 7.5
Water for injection QS to make 100 ml
II. Timolol
A.. Timolo10.5%
Timolol Maleate 0.72 gm. equivalent to 0.5 gm of Timolol
Benzylconium chloride O.OI07 gm
Carbopol ETD 2001 1.5 gm to 2.5 gm
Sodium hydroxide to adjust pH 6.5 to 7.5
Water for injection Q.S. to make 100 ml.
B. Timolo10.25%
Timolol Maleate 0.36 gm equivalent to 0.5 gm
of Timolol
Benzylconium chloride 0.0107 gm
Carbopol ETD 2001 1.5 gm to 2.5 gm
Sodium hydroxide to
adjust pH 6.5 to 7.5
Water for injection Q.S. to make 100 ml
III. Timolol
A.. Timolo10.5%
Timolol Maleate 0.72 gm. equivalent to 0.5 gm of Timolol
Benzylconium chloride 0.0107 gm
Carbopol 981 1.5 gm to 2.5 gm
Sodium hydroxide to adjust pH 6.5 to 7.5
Water for injection Q.S. to make 100 ml.
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B. Timolol0.25%
Timolol Maleate 0.36 gm equivalent to 0.5 gm of Timolol
Benzylconium chloride 0.0107 gm
Carbopol 981 1.5 gm to 2.5 gm
Sodium hydroxide to adjust pH 6.5 to 7.5
Water for injection Q.S. to make 100 ml
IV. Timolol
A.. Timolo10.5%
Timolol Maleate 0.72 gm. equivalent to 0.5 gm of Timolol
Benzylconium chloride 0.0107 grn
Polycarbophil 1.5 gm to 2.5 gm
- Sodium hydroxide to adjust pI-I b.5 to 7.5
Water for injection Q.S. to make 100 ml.
B. Timolo10.25%
Timoloi Maleate 0.36 gm equivalent to 0.5 gm of Timolol
Benzylconium chloride 0.0107 gm
Polycarbophil 1.5 gm to 2.5 gm
Sodium hydroxide to adjust pH 6.5 to 7.5
Water for injection Q.S. to make 100 ml
V. Clonidine
A. Clonidine 0. I
Clonidine hydrochloride 0.1 gm
Benzylconium chloride 0.0107 gm
Polyacrylic Acid 1.5 gm to 2.5 gm
(Carbopol 940)
Sodium hydroxide to adjust pH 6.5 to 7:5
Water for injection QS to make 100 ml
B. Clonidine 0.2%
Clonidine hydrochloride 0.2 gm
Benzylconium chloride 0.0107 gm
Polyacrylic Acid I .5 gm to 2.5 gm
(Carbopol 940)
' Sodium hydroxide to adjust pH 6.5 to 7.5
Water for injection QS to make 100 ml
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VI. Clonidine
A. Clonidine 0.1
Clonidine hydrochloride. 0.1 gm
Benzylconium chloride0.0107 gm
Carbopol ETD 2001 1.5 gm to 2.5
~ gm
Sodium hydroxide to
adjust pH b.5 to
7.5
~
Water for injection Q.S. to make
100 m!
B. Clonidine 0.2%
Clonidine hydrochloride 0.2 gm
Benzylconium chloride 0.0107 gm
CarbopoI ETD 2001 1.5 gm to 2.5 gm
Sodium hydroxide to adjust pH 6.5 to 7.5
Water for injection Q.S. to make 100 ml
VII. Clonidine
A. Clonidine 0.1
Clonidine hydrochloride 0.1 gm
Benzylconium chloride 0.0107 gm
Carbopol 981 1.5 gm to 2.5 gm
Sodium hydroxide to adjust pH 6.5 to 7.5
Water for injection Q.S. to make 100 ml
B. Clonidine 0.2%
Clonidine hydrochloride 0.2 gm
Benzylconium chloride 0.0107 gm
Carbopol 981 1.5 gm to 2.5 gm
Sodium hydroxide to adjust pH 6.5 to 7.5
Water for injection Q.S. to make 100 ml
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VIII. ~lonidine
A. Clonidine 0.1
Clonidine hydrochloride 0.1 gm
Benzylconium chloride 0.0107 gm
' Polycarbophil 1.5 gm to 2.5 gm
Sodium hydroxide to adjust pH 6.5 to 7.5
Water for injection Q.S. to make 100 ml
B. Clonidine 0.2%
Clonidine hydrochloride 0.2 gm
Benzylconium chloride 0.0107 gm
_ Polycarbophil 1.5 gm to 2.5 gm
Sodium hydroxide to adjust pH 6.5 to 7.5
Water for injection Q.S. to make 100 ml
IX. Betaxolol
Betaxolol 0.5%
Betaxolol hydrochloride0.56 gm. equivalent to 0.5 gm
of Betaxolol
Benzylconium chloride0.01 gm
Dibasic sodium phosphate0.05 gm
Sodium phosphate
monobasic 0.025
gm
Disodium EDTA 0.05 gm
Sodium chloride 0.3 gm
Propylene glycol 2.5 gm
Carbopol ETD 2001 2.0 gm
Water for injection Q.S. to make 100 ml.
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X. Betaxolol
Betaxolol 0.5%
Betaxolol hydrochloride0.56 gm. equivalent to 0.5 gm
of Betaxolol
Benzylconium chloride0.01 gm
Dibasic sodium phosphate0.05 gm
Sodium phosphate sic 0.02 gm
monoba
Disodium EDTA 0.05 gm
Sodium chloride 0.3 gm
Propylene glycol 2.5 gm
Polyacrylic acid 2.0 gm
(Carbopol 940)
Water for injectionQ.S. to make 100 ml
X.I Betaxolol
Betaxolol 0.5%
Betaxolol hydrochloride0.56 gm. equivalent to 0.5 gm
of Betaxolol
Benzylconium chloride0.01 gm
Dibasic sodium phosphate0.05 gm
Sodium phosphate sic 0.025 gm
monoba
Disodium EDTA 0.05 gm
Sodium chloride 0.3 gm
Propylene glycol 2.5 gm
Carbopol 981 2.0 gm
Water for injectionQ.S. to make 100 ml.
XLI. Betaxolol
Betaxolol 0.5%
Betaxolol hydrochloride0.56 gm. equivalent to 0.5 gm
of Betaxolol
Benzylconium chloride0.01 gm
Dibasic sodium phosphate0.05 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 injectionQ.S. to make 100 ml.
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t 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. LO.P.
and
B.P. were measured every 2 hours. Control group (10) received placebo.
Drop in LO.P. was seen only in eyes receiving Clonidine. It was found to be in
the range of 30% of initial LO.P. The effect on LO.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 mrim of Hg. for Clonidine
0.1
and 2.89 mm of Hg for Clonidine 0.2%.
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Clonidir~e 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 were instilled in both eyes. LO.P. and resting pulse rate
were
measured every 2 hours. The peak reduction in mean LO.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 of the 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.
