DESC:Field of Invention
The present invention relates to an ophthalmic pharmaceutical composition comprising Loteprednol or its pharmaceutically acceptable salts and derivatives. More specifically, the present invention relates to stable ophthalmic suspension of Loteprednol etabonate and provides method of preparing the same. 5
Background of Invention
Loteprednol etabonate is suitable for seasonal allergic conjunctivitis and also for the treatment of steroid sensitive inflammation of the eyelid and bulbar conjunctiva, cornea and anterior part of the eyeball, such as allergic conjunctivitis, erythematous keratitis, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, and selectively 10 infectious conjunctivitis.
Dry eye, also known generically as keratoconjunctivitis sicca (KCS), is a common ophthalmological disorder affecting millions of Americans each year. The condition is particularly widespread among post-menopausal women due to hormonal changes following the cessation of fertility. Dry eye may afflict an individual with varying 15 severity. In mild cases, a patient may experience burning, a feeling of dryness, and persistent irritation such as is often caused by small bodies lodging between the eye lid and the eye surface. In severe cases, vision may be substantially impaired. Other diseases, such as Sjogren's disease manifest dry eye complications.
3
Topical corticosteroids are useful in a variety of ophthalmic conditions and are generally indicated for treatment of steroid-responsive inflammatory conditions of the palpebral and bulbar conjunctiva, cornea and anterior segment of the eye. Although corticosteroids are widely used as a topical agent for post-operative ocular inflammation, most possess a safety risk profile that limits their more general utility. 5 A common risk associated with corticosteroid therapy is an elevation of intraocular pressure (IOP). In addition, chronic use of topical corticosteroids may result in the development of cataracts. The older corticosteroids such as dexamethasone and prednisolone acetate have effective anti-inflammatory efficacy however they significantly increase IOP. Loteprednol etabonate is a compound designed as a site-10 active corticosteroid that will undergo a predictable transformation to an inactive metabolite. The relatively rapid metabolism of Loteprednol etabonate to an inactive metabolite improves the safety profile of this corticosteroid and have lesser adverse effects. Thus loteprednol etabonate is an efficacious and safe corticosteroid for the treatment of postoperative inflammation which have less impact on IOP as compared 15 to existing topical corticosteroids.
U. S. patent application. Publication No. 20030008853 discloses 22,29-epoxy-3,4,6,7,29-pentahydroxy-, (3ƒ¿,4ƒÀ,5ƒ¿,6ƒ¿,7-ƒÀ,14ƒÀ,22S)-stigmastan-15-one as useful for treating dry eye disorders and other disorders requiring the wetting of the eye. This publication further notes that corticosteroids, such as prednisolone, dexamethasone, 20 fluoromethalone, hydrocortisone, loteprednol, triamcinolone, etc., cannot be used for
4
prolonged therapy in dry eye patients without causing side effects. This publication further notes that steroid-related complications including increased intraocular pressure and cataract formation have been observed in dry eye patients treated with corticosteroids after several months of therapy. Therefore, it was surprisingly discovered that a topical ophthalmic formulation containing Loteprednol etabonate, 5 when used for four weeks, was efficacious and well tolerated in the management of patients with KCS with inflammation. Moreover, a differential treatment effect, which was in some cases significant, was seen in subsets of patients who presented a moderate to severe inflammatory component corresponding with more severe KCS.
US20230364012A1 disclosed stable ophthalmic composition comprising loteprednol 10 or its pharmaceutically acceptable salt thereof, one or more suspending agents, and optionally one or more excipients wherein the composition is free of non-ionic cellulosic derivatives and comprises poloxamer 407 as surfactant.
Loteprednol etabonate (INVELTYS) is USFDA approved 1% ophthalmic suspension which is a prescription eye drop medication indicated for the treatment of inflammation 15 and pain after ocular surgery. The suspension contains glycerin, sodium citrate dihydrate, Poloxamer 407, sodium chloride, edetate disodium dihydrate, citric acid, and water for injection with benzalkonium chloride as preservative which is covered in US patent 11596599 B2 and11872318 B2.
5
The patent covers use of poloxamer as a surface altering agent which helps in solubilizing poorly water soluble drug. Since loteprednol etabonate is poorly soluble in water, a solubilizing agent or surfactant is required.
Poloxamer is a block copolymer which is well known for its thermoreversible property. Poloxamer 407 and P188 at a certain concentration have reverse temperature-sensitive 5 properties, the concentrated aqueous solution of these poloxamers forms a reverse temperature-sensitive gel. These hydrogels maintain a fluid state at low temperatures, but at body temperature (or room temperature), they become a semisolid gel, and when the temperature decreases, they return to their original fluid state. Therefore, to maintain the fluid state of Poloxamer, an extra excipient needs to be added in the 10 composition which added extra cost to the composition.
The earlier known attempts to provide ophthalmic compositions of Loteprednol etabonate were all based on the use of Poloxamer as surfactant or encapsulating agent. WO2015066444 uses poloxamer to encapsulate loteprednol and form a nanosuspesntion. WO2016123079 also uses poloxamer as surfactant in combination 15 with suspending agents selected from carbomer and non-ionic cellulosic derivative. And US20230364012 uses poloxamer in combination with a single suspending agent selected from cabomers, by removing non-ionic cellulosic compound disclosed in WO2016123079. Further the prior art includes additional steps of milling the coarse aqueous suspension in form of coarse or micronized crystals to produce a 20 nanosuspension.
6
Problems associated with the use of Poloxamer: Poloxamers can pose stability issues when used in suspension formulations, as they may not sufficiently prevent the settling of the suspended particles. This could affect the consistency and efficacy of the ophthalmic composition. There is a possibility that poloxamers could cause irritation to the ocular surface, especially in higher concentrations. This can limit their usability 5 in sensitive formulations designed for prolonged contact with the eye. Poloxamers exhibit thermal gelling properties, which might complicate the formulation process. The temperature-dependent sol-gel transition can affect the stability and delivery of the active ingredient in the ocular environment.
Therefore, there is still a need in the art for a formulation that overcome the issue 10 associated with formulation of loteprednol. The present invention aims to provide a simple and cost effective ophthalmic composition of Loteprednol etabonate without using Poloxamer. Objective of Invention.
The main object of the present invention is to develop simpler and cost effective 15 composition and process of manufacturing ophthalmic pharmaceutical formulation comprising therapeutically effective amount of Loteprednol or pharmaceutically acceptable salts thereof Another objective of the invention is to provide ophthalmic composition comprising 1% Loteprednol etabonate without using Poloxamer. 20
7
Yet another object of the present invention is to provide a process which is simpler and cost effective. Summary of the Invention The present invention relates to a pharmaceutical formulation for topical administration comprising a therapeutically effective amount of Loteprednol or its pharmaceutically 5 acceptable salts thereof used for the treatment of post-operative inflammation and pain following ocular surgery. In another embodiment the present invention provides ophthalmic formulation comprising: a. an aqueous suspension of micronized loteprednol etabonate from about 0.1 to 10 5.0% (w/v), b. viscosity enhancer and one or more pharmaceutically acceptable excipients wherein the said pharmaceutically acceptable excipient is not Poloxomer and the said, ophthalmic composition is non-irritating to the eye. Yet another embodiment the present invention provides a process which is simpler 15 and cost effective. Detailed Description While this invention is susceptible of embodiments in many different forms, and will herein be described in detail, preferred embodiments of the invention are disclosed with the understanding that the present disclosure is to be considered as exemplifications of 20
8
the principles of the invention and are not intended to limit the broad aspects of the invention to the embodiments illustrated.
Definitions
For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions 5 should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have their meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
The present disclosure is not to be limited in scope by the specific embodiments 10 described herein, which are intended for the purposes of exemplification only. Functionally equivalent products and processes are clearly within the scope of the disclosure, as described herein.
gOphthalmic suspensionh in the present invention refers to ophthalmic liquid formulation comprising solid particles suspended in a vehicle. 15
The term "pharmaceutically acceptable" is meant a carrier comprised of a material that is not biologically or otherwise undesirable.
As used herein, the term "vehicle" means any solvent or carrier in a pharmaceutical product that has no pharmacological role.
9
The present invention provides a simpler and cost effective ophthalmic pharmaceutical composition comprising effective amount of Loteprednol or its pharmaceutically acceptable salts. In an embodiment the present invention provides ophthalmic composition comprising Loteprednol or its pharmaceutically acceptable salts. 5 In an embodiment the invention provides an ophthalmic pharmaceutical composition comprising Loteprednol or its pharmaceutically acceptable salts or derivative thereof. In another embodiment the present invention provides an ophthalmic pharmaceutical composition comprising Loteprednol or its pharmaceutically acceptable salts and pharmaceutically acceptable excipients. 10 In an embodiment Loteprednol or pharmaceutically acceptable salts is present in the concentration of 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.3%, 0.31%, 0.32%, 0.33%,0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.4%, 0.41%, 0.42%, 15 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.5%,0.51%,0.52%,0.53%.0.54%,0.55%,0.56%,0.57%,0.58%,0.59%,0.60%,0.61%,0.62%,0.63%,0.64%,0.65%,0.66%,0.67%,0.68%,0.69%,0.70%,0.71%,0.72%,0.73%,0.74%,0.75%,0.76%,0.77%,0.78%,0.79%,0.80%,0.81%,0.82%,0.83%,0.84%,0.85%,0.86%,0.87%,0.88%,0.89%,0.90%,0.91%,0.92%,0.93%,0.94%,0.95%,0.96%,0.97%,0.20 98%,0.99%,1.0% by weight of the composition
10
In a preferable embodiment Loteprednol is present in the amount of 0.2%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.3% w/v In a most preferred embodiment Loteprednol is present in the amount of 0.93%, 0.94%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99%, 1.0% w/v. In an embodiment the pharmaceutically acceptable salt is selected from Etabonate 5 wherein loteprednol has particle size D90 less is less than 100 microns, preferably D90 less than 50 microns more preferably D90 < 20 microns. The ophthalmic formulations of the present disclosure may be formulated in various dosage forms suitable for topical ophthalmic delivery, including solutions, suspensions, emulsions, and gels. The compositions are suitably aqueous. 10 In an embodiment of the invention comprised pharmaceutically acceptable excipients selected from tonicity agents, Humectant, chelating agents, preservatives, Viscosity Enhancer, stabilizers, buffering agents, antioxidants, thickeners, surfactants, solubilizers, suspending agents, cooling agents, dispersants, oily bases, emulsion bases, and water based vehicles. 15 In a preferred embodiment the pharmaceutically acceptable excipients are selected from Humectant, preservatives, Viscosity Enhancer, Buffering Agent, Surfactant. Examples of buffering agents that can be used in the present invention are those conventionally used in ophthalmic compositions.
11
Examples of preservative that can be used in the present invention are Quaternary ammonium compounds such as benzalkonium chloride (BKC) and benzethonium chloride; Organic mercurials such asphenylmercuric acetate, phenylmercuric nitrate and thimerosal; Parabens such as methyl and propyl paraben; ethyl paraoxybenzoate or butyl paraoxybenzoate; Acids and their pharmaceutically acceptable salts such as 5 sorbic acid, potassium sorbate, boric acid, borax, salicylic acid ; Substituted alcohols and phenols such as chlorobutanol, benzyl alcohol; phenyl ethanol; Amides such as acetamide; and the like, and combinations thereof. Preferably the ophthalmic compositions of the present invention comprise 'quaternary ammonium compound' as a preservative, particularly benzalkonium chloride. 10 In an embodiment preservative is present in amount ranging from 0.005 to 1% more preferably 0.05% more preferably 0.02%. In an another embodiment the present provides ophthalmic suspension which is free from benzalkonium chloride. Examples of Humectant that can be used in the present invention are selected from 15 glycerine, Urea, hyaluronic acid, salicylic acid, alpha hydroxy acids (AHAs), such as glycolic acid and lactic acid, propylene glycol, honey, sorbitol, particularly glycerine. In an embodiment the humectant is present in an amount ranging from 0.5 to 5% more preferably 1 to 1% more preferably 1.8%
12
Examples of surfactant that can be used in the present invention are selected from group consisting of polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (2) cetylether , polyoxyetylene (10) cetylether, polyoxyethylene (20) cetylether, Tyloxapol. In a preferred embodiment preferred surfactant used in present invention is Tyloxapol. 5 In a preferred embodiment surfactant is present in an amount ranging from 0.05 to 2% more preferably 0.05 to 1% more preferably 0.05 to 0.1%. Examples of Buffering Agent that can be used in the present invention are selected from citrate, phosphate, Tris-HCl (Tris), and borate buffer, particularly combination of Citric Acid Monohydrate, Sodium Citrate. 10 In an embodiment buffering agent is present in an amount ranging from 0.05 to 5% more preferably 0.05 to 2% more preferably 0.1 to 0.5%. In further embodiment, the pH of the formulation is about 2 and 10 more preferably 3 to 7 more preferably 5 to 6.
Examples of viscosity enhancer which can be used in present invention include 15 hydroxypropylcellulose or other water-soluble cellulose derivatives, polymethylmethacrylate or other polyacrylic acid derivatives, chitosan, hyaluronic acid, polyvinylpyrrolidone (povidone) or combinations thereof. In a preferred embodiment viscosity enhancer is polyvinylpyrrolidone (povidone).
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In an embodiment viscosity enhancer is present in an amount ranging from 0.1 to 2% more preferably 0.5 to 1% more preferably 0.8%. In another embodiment the ophthalmic composition of the present invention comprises a further one or more active agent. In a preferred embodiment the active agent is selected from but not limited to corticosteroid Prednisolone, betamethasone, 5 dexamethasone, hydrocortisone. In an embodiment the present invention provides an ophthalmic composition comprising: a. loteprednol or pharmaceutically acceptable salts thereof from about 0.1 to 5.0% (w/v), 10 b. one or more pharmaceutically acceptable excipients wherein the said pharmaceutically acceptable excipient is not Poloxomer. In an embodiment the present invention provides ophthalmic suspension comprises: a. loteprednol or pharmaceutically acceptable salts thereof from about 0.1 to 5.0% (w/v) and; 15
b. viscosity enhancer is present in an amount ranging from 0.1 to 2% and; c. humectant is present in an amount ranging from 0.5 to 5% and; d. surfactant is present in an amount ranging from 0.05 to 2% and; e. buffering agent is present in an amount ranging from 0.05 to 5%
14
In an another embodiment the present invention provides ophthalmic suspension comprising: i. micronized 1% w/v loteprednol Etabonate and; ii. 0.8% Povidone (PVPK-30) as viscosity enhancer and; iii. 1.8% Glycerin as humectant and; 5 iv. 0.1% Tyloxapol as surfactant and; v. 0.1% citric acid monohydrate and 0.5% sodium citrate as buffering agent and vi. 0.1% Disodium Edetate as chelating agent and;
The invention discloses ophthalmologically suitable pharmaceutical compositions comprising an effective amount of a Loteprednol Etabonate for treatment of post-10 operative inflammation and pain following ocular surgery and for dry eyes. In an another embodiment the present invention provides a cost effective manufacturing process comprising: Phase A: Preparation of aqueous suspending phase i. Add and dissolve povidone in water for injection with continuous stirring to 15 obtain clear solution. ii. Sterilize the solution obtained in step 1 and aseptically transfer the solution in to pre-sterilized holding tank. Phase B: Preparation of bulk solution:
15
i. Add and dissolve Disodium Edetate in water for injection with continuous stirring to obtain clear solution. ii. Add and dissolve citric acid monohydrate into above step with continuous stirring. To this solution add sodium citrate with continuous stirring. iii. To this solution add and dissolve Benzalkonium Chloride Solution and stir the 5 bulk solution. In this solution add and dissolve Tyloxapol to the bulk solution. iv. Aseptically filter the solution into pre-sterilized holding tank Phase C (Mixing Phase): i. Aseptically transfer Phase-B solution into Phase-A solution under LAF with continuous stirring. 10 ii. Aseptically add & dispersed Loteprednol Etabonate (Micronized & Sterile) into above solution and stir the bulk solution. iii. Volume makeup with sterile water for injection and homogenise the solution to obtain stable ophthalmic solution. EXAMPLES 15
The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention. 20
16
Example-1: 1% ophthalmic suspension Table 1: Composition details of 1% loteprednol etabonate ophthalmic suspension S.NO Composition % Rationale 1
Loteprednol Etabonate
1.0%
API 2
Benzalkonium Chloride Solution
0.02%
Preservative 3
Povidone (PVPK-30)
0.8%
Viscosity Enhancer 4
Glycerin
1.8%
Humectant 5
Tyloxapol
0.1%
Surfactant 6
Citric Acid Monohydrate
0.1%
Buffering Agent 7
Sodium Citrate
0.5%
Buffering Agent 8
Disodium Edetate
0.1%
Chelating agent 9
water
1.0%
Vehicle
Example 2: MANUFACTURING PROCESS:
PHASE A: 5
Step-01 Collect 220 Ltr. Water for Injections IP (80‹C-85‹C) in compounding vessel and purging 0.2ƒÊ filtered nitrogen gas throughout manufacturing process.
Step-02 Add & dissolve Povidone (PVPK-30) IP (80‹C-85‹C) into step-01 & continuous stirring at 300 RPM for 20 minutes. Check the clarity of the solution.
17
Step-03 Sterilize Step-02 solution at 121.4oC for 45 minutes by passing steam in jacketed manufacturing vessel or by autoclave at 121.4oC for 45 min.
Step-04 Aseptically transfer the sterilized step-03 solution in to pre-sterilized holding tank through Sterilized cone filtration (#40).
PHASE B: 5
Step-01 Collect 250 Ltr. Water for Injections IP (80‹C-85‹C) in compounding vessel and purging 0.2ƒÊ filtered nitrogen gas throughout manufacturing process. Cool down the solution till (50‹C-60‹C).
Step-02 Add & dissolve Disodium Edetate IP (50‹C-60‹C) into step-01 & continuous stirring at 300 RPM for 10 minutes. Check the clarity of the solution. 10
Step-03 Add & dissolve Glycerin IP (45‹C-50‹C) into step-02 & continuous stirring at 300 RPM for 10 minutes each ingredient. Check the clarity of the solution.
Step-04 Add & dissolve Citric Acid Monohydrate IP (40‹C-45‹C) into step-03 & continuous stirring at 300 RPM for 05 minutes each ingredient. Check the clarity of the solution. 15
Step-05 Add & dissolve Sodium Citrate IP (35‹C-40‹C) into step-04 & continuous stirring at 300 RPM for 05 minutes each ingredient. Check the clarity of the solution.
Step-06 Add & dissolve Benzalkonium Chloride Solution IP (30‹C-35‹C) into step-05 & stir the bulk solution at 300 RPM for 05 minutes. Check the clarity of the solution.
18
Step-07 Add & dissolve Tyloxapol USP (25‹C-35‹C) into step-06 & stir the bulk solution at 300 RPM for 10 minutes. Check the clarity of the solution.
Step-08 Aseptically filter the step-07 solution through 1.0ƒÊ+0.2ƒÊ cartridge filter and aseptically transfer into pre-sterilized holding tank in sterile area.
PHASE C (Mixing Phase): 5
Step-01 Aseptically transfer Phase-B solution into Phase-A (step-04) solution under LAF with continuous stirring. Stir the solution for 15 min at 250 RPM.
Step-02 Aseptically add & dispersed Loteprednol Etabonate (Micronized & Sterile) (25‹C) into step-01 & stir the bulk solution at 300 RPM for 10 minutes.
Step-03 Make up the 95% volume by using Sterile (by 0.2ƒÊ filter) Water for Injections 10 (25‹C-30‹C).
Step-04 Homogenize at 2200-2800 RPM for 3 hours.
19
Step-05 Check pH of the bulk solution of step-04 between (pH limit-4.50 to 5.50).
Step-06 Make up the final volume upto 500 liter. by using Sterile (by 0.2ƒÊ filter) Water for Injections (25‹C-30‹C) & stir at 250 RPM for 10 minutes.
Step-07 Again homogenize step-06 suspension at 2200-2800 RPM for 1 hour.
pH Limit of Bulk Solution : 4.50 . 5.50 5
pH Limit of Finished Product : 3.50 . 6.50
Example 3: Stability Study:
The loteprednol etabonate ophthalmic suspension prepared from example 2 was subjected under stability study at temperature 30‹C } 2‹C / 35% RH } 5% RH
Test
Acceptance criteria
Initial Testing
After 3 month
After 6 month
After 9 month
After 12 month
After 18 month
After 24 month
description
White colour suspension filled in opaque white
White colour suspension filled in opaque
White colour suspension filled in opaque
White colour suspension filled in opaque
White colour suspension filled in opaque
White colour suspension filled in opaque
White colour suspension filled in opaque
White colour suspension filled in opaque
20
colour LDPE bottle
white colour LDPE bottle
white colour LDPE bottle
white colour LDPE bottle
white colour LDPE bottle
white colour LDPE bottle
white colour LDPE bottle
white colour LDPE bottle
pH
Between 5.00 and 6.00
5.30
5.39
5.37
5.24
5.39
5.48
5.34
Osmolality
Between 250 and 350 mOsmol/kg
327 mOsmol/kg
NA
NA
NA
NA
NA
309 mOsmol/kg
Particle size (by Malven mastersizer 2000)
Median diameter D90: not more than 20.0 microns
NA
NA
NA
NA
NA
NA
D90: 4.785 microns
Related substance
Known impurities
Cortienic acid at RRT about 0.32
Not more than 1.0%
Not detected
0.18%
0.06%
0.11%
0.010%
0.02%
0.04%
Cortienic acid Etabonate or dechloromethyl Loteprednol at RRT about 0.52
Not more than 1.0 %
0.12%
0.063%
0.50%
0.51%
0.58%
0.68%
0.73%
21
11-keto loteprednol at RRT about 0.93
Not more than 0.5%
0.07%
0.003%
0.03%
0.02%
0.04%
0.02%
0.05%
Single maximum impurity
Not more than 0.5%
0.11%
0.07%
0.15%
0.07%
0.07%
0.60%
0.67%
Total impurities (excluding known impurities)
Not more than 1.5%
0.30%
0.17%
0.31%
0.23%
0.19%
0.99%
1.12%
sterility
No microbial growth should be observed
No microbial growth observed
NA
NA
NA
No microbial growth observed
NA
No microbial growth observed
Preservative content- Each ml contains
Benzalkonium chloride solution 0.0200% v/v
NLT 80.00% and NMT 120.00% of label claimed
93.00%
NA
NA
NA
NA
NA
93.50%
Assay- Each ml contains:
Loteprednol Etabonate 10.00 mg
NLT 90.00% and NMT 110.00% of label claimed
99.00%
101.70%.
98.30%
97.50%
98.80%
96.80%
96.40%
22
Water loss test
Not more than 5.00%
NA
0.43%
0.74%
0.93%
1.29%
1.32%
1.52%
23
Temperature 25‹C } 2‹C/40 % RH } 5% RH
Test
Acceptance criteria
Initial Testing
After 3 month
After 6 month
After 9 month
After 12 month
After 18 month
After 24 month
description
White colour suspension filled in opaque white colour LDPE bottle
White colour suspension filled in opaque white colour LDPE bottle
White colour suspension filled in opaque white colour LDPE bottle
White colour suspension filled in opaque white colour LDPE bottle
White colour suspension filled in opaque white colour LDPE bottle
White colour suspension filled in opaque white colour LDPE bottle
White colour suspension filled in opaque white colour LDPE bottle
White colour suspension filled in opaque white colour LDPE bottle
pH
Between 5.00 and 6.00
5.30
5.38
5.26
5.45
5.39
5.47
5.40
Osmolality
Between 250 and 350 mOsmol/kg
327 mOsmol/kg
NA
NA
NA
NA
NA
310 mOsmol/kg
Particle size (by Malven mastersizer 2000)
Median diameter D90: not more than 20.0 microns
NA
NA
NA
NA
NA
NA
D90: 5.070 microns
Related substance
24
Known impurities
Cortienic acid at RRT about 0.32
Not more than 1.0%
Not detected
0.18%
0.03%
0.05 %
0.004 %
0.01%
0.04%
Cortienic acid Etabonate or dechloromethyl Loteprednol at RRT about 0.52
Not more than 1.0 %
0.12%
0.60%
0.32%
0.36%
0.47%
0.53%
0.63%
11-keto loteprednol at RRT about 0.93
Not more than 0.5%
0.07%
0.003%
0.03%
0.02%
0.05%
0.02%
0.05%
Single maximum impurity
Not more than 0.5%
0.11 %
0.06 %
0.11 %
0.07 %
0.12 %
0.22 %
0.27 %
Total impurities (excluding known impurities)
Not more than 1.5%
0.30 %
0.14 %
0.23 %
0.24 %
0.32 %
0.52 %
0.62 %
sterility
No microbial growth should be observed
No microbial growth observed
NA
NA
NA
No microbial growth observed
NA
No microbial growth observed
Preservative content- Each ml contains ,CLAIMS:An ophthalmic suspension comprising:
a. loteprednol or pharmaceutically acceptable salts thereof from about 0.1 to 5.0% (w/v),
b. one or more pharmaceutically acceptable excipients wherein the said 5 pharmaceutically acceptable excipient is not Poloxomer.
2. An ophthalmic suspension as claimed in claim 1 wherein one or more pharmaceutically acceptable excipients are selected from humectant, preservatives, viscosity enhancer, buffering agent, surfactant.
3. An ophthalmic suspension as claimed in claim 2 comprises: 10
a. loteprednol or pharmaceutically acceptable salts thereof from about 0.1 to 5.0% (w/v) and;
b. viscosity enhancer is present in an amount ranging from 0.1 to 2% and;
c. humectant is present in an amount ranging from 0.5 to 5% and;
d. surfactant is present in an amount ranging from 0.05 to 2% and; 15
e. buffering agent is present in an amount ranging from 0.05 to 5%
4. An ophthalmic suspension as claimed in claim 3 further comprises preservative wherein preservative is present in an amount ranging from 0.005 to 1%.
5. An ophthalmic suspension as claimed in claim 4 comprises 0.02% Benzalkonium chloride as preservative. 20
27
6. An ophthalmic suspension as claimed in claim 5 is free from Benzalkonium chloride.
7. An ophthalmic suspension as claimed in claim 3 further comprises:
i. micronized 1% w/v loteprednol Etabonate and;
ii. 0.8% Povidone (PVPK-30) as viscosity enhancer and; 5
iii. 1.8% Glycerin as humectant and;
iv. 0.1% Tyloxapol as surfactant and;
v. 0.1% citric acid monohydrate and 0.5% sodium citrate as buffering agent and
vi. 0.1% Disodium Edetate as chelating agent and; 10
8. An ophthalmic suspension as claimed in claim 1 wherein the pH of ophthalmic suspension is about 5 to 6.
9. An ophthalmic suspension as claimed in claim 7 wherein loteprednol has particle size D90 less is less than 100 microns, preferably D90 less than 50 microns more preferably D90 < 20 microns. 15
10. A process of preparing ophthalmic suspension comprises:
Phase A: Preparation of aqueous suspending phase:
i. Add and dissolve povidone in water for injection with continuous stirring to obtain clear solution.
ii. Sterilize the solution obtained in step 1 and aseptically transfer the 20 solution in to pre-sterilized holding tank.
28
Phase B: Preparation of bulk solution:
i. Add and dissolve Disodium Edetate in water for injection with continuous stirring to obtain clear solution.
ii. Add and dissolve citric acid monohydrate into above step with continuous stirring. To this solution add sodium citrate with continuous stirring. 5
iii. To this solution add and dissolve Benzalkonium Chloride Solution and stir the bulk solution. In this solution add and dissolve Tyloxapol to the bulk solution.
iv. Aseptically filter the solution into pre-sterilized holding tank
Phase C (Mixing Phase):
i. Aseptically transfer Phase-B solution into Phase-A solution under LAF with 10 continuous stirring.
ii. Aseptically add & dispersed Loteprednol Etabonate (Micronized & Sterile) into above solution and stir the bulk solution.
iii. Volume makeup with sterile water for injection and homogenise the solution to obtain stable ophthalmic solution. 15