DESC:FIELD OF INVENTION:
The present invention related to an ophthalmic composition comprising Brinzolamide and Brimonidine tartrate more particularly benzalkonium chloride (BAK) free aqueous ophthalmic composition.
BACKGROUND:
Primary open angle Glaucoma (POAG) is usually a chronic, slowly progressive disease. The philosophy of glaucoma management is to preserve the visual function and quality of life (QOL) of the individual with minimum effects on QOL in terms of side effects, treatment regime, follow-up schedules as well as socioeconomic 10 burden. The current treatment generally involves lowering intraocular pressure (IOP) via topical or oral or, laser treatment and incisional surgery. Still topical therapy is being preferred as a first-line treatment in most forms of glaucoma.
Topical glaucoma monotherapy uses glaucoma drugs with different mechanism include prostaglandin analogues, beta-blockers, alpha-2 adrenergic agonists, 15 carbonic anhydrase inhibitors and parasympathomimetics however monotherapy may provide insufficient IOP reduction in some patients, thereby necessitating the use of multiple IOP-lowering medications. Multidrug regimens may be complex, may increase the risk of preservative-related ocular symptoms, and may potentially
3
reduce overall drug exposure as a consequences of drug washout during closely timed sequential administrations; these difficulties may reduce overall drug efficacy and decrease patient persistence and adherence with multidrug treatment regimens. Furthermore, because there is no immediate negative consequence of non-adherence, patients are less motivated to be overly concerned with 5 compliance. Patients are instructed to wait 5 minutes between multiple applications of glaucoma drugs. If the intervals are shorter due to impatience, the concern is that newly instilled drug will washout the previously administered drug. Therefore, there is still need in an art which provide fixed dose combinations of one or more glaucoma drugs in a single formulation to address the above mentioned prior arts. 10
The present invention provides a fixed dose combinations of two Anti-glaucoma agents which acting differently but provide synergistic drug activity over monotherapy and concurrent multi regimen drugs. In a present invention carbonic anhydrase inhibitor is combined with alpha-2 adrenergic receptor agonist to provide a safe and stable ophthalmic formulation for effective management of primary open 15 angle Glaucoma wherein carbonic anhydrase inhibitor is selected from Brinzolamide or acceptable salts thereof and alpha-2 adrenergic receptor agonist is Brimonidine or acceptable salts thereof.
4
US Patent no. 6242442 discloses use of brinzolamide in combination with brimonidine to treat ocular diseases which have their etiology in compromised blood flow.
US Patent no. 20210177753 A1 discloses an aqueous ophthalmic composition comprising 1% Brinzolamide and 0.2% Brimonidine tartarate for the decrease of 5 intraocular pressure in patients with ocular hypertension or open angle glaucoma.
US Patent no. 20210369728 discloses topical formulation comprising Brinzolamide and Brimonidine tartrate use for the reduction of elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension.
The above cited prior art formulation comprised benzalkonium chloride (BAK) as 10 preservative, BAK is used approximately 70% of topical ophthalmic eye drops. BAK has been proposed to enhance drug penetration into the cornea and subsequently the anterior chamber by disrupting the hydrophobic barrier of the corneal epithelium, breaking cell-cell junctions, and thus resulting in greater tissue and aqueous drug concentration and thereby improving efficacy, however use of BAK for 15 long time is not safe. There has been a growing evidence of preservative toxicity associated with benzalkonium chloride (BAK) that is correlated with duration of use and multiple doses. The disruption to the corneal barrier may contribute to the ocular surface toxicity of BAK. The cytotoxic effects of BAK on ocular tissue cells (particularly conjunctival and corneal epithelium) has been well studied and 20
5
documented. The threshold concentration at which toxicity from BAK occurs has been estimated to be 0.005%- much lower than many of its commercially used concentrations. Animal studies have shown dose-dependent corneal epithelial damage and conjunctival inflammation changes, findings which have been validated in human subjects. BAK has been shown in patients to result in decreased goblet cell 5 density which normally produce mucins and participate in tear film stability. Since preservatives are used in multi-dose ophthalmic products to prevent the growth of bacteria, fungi and other microbes prolonged use of BAK may cause toxicity and damages the cells of ocular damages. Therefore, there is need in art to develop an ophthalmic composition with preservative which are safe and efficient with low 10 toxicity.
SIMBRINZA™ is USFA approved ophthalmic suspension used for the treatment of Open-Angle Glaucoma or Ocular Hypertension which is a fixed dose combination of 10 mg/mL brinzolamide and 2 mg/mL brimonidine tartrate. Simbrinza uses a ionic buffer system and benzalkonium chloride as preservative to protect the composition 15 against microbial contamination. Even though the marketed product is preserved with ionic buffer solution it still needs additional preservative i.e. benzalkonium chloride (BAK). Therefore there is still need in the art for a novel ophthalmic composition which can be preserved without BAK or any other preservative that is known to have toxic effects. 20
6
To avoid toxicity associated with benzalkonium chloride (BAK) or other preservatives, the inventors of present invention have developed an ophthalmic formulation that doesn’t require the use of BAK or any other preservative known to have toxic effects. SUMMARY OF THE INVENTION: 5
The present invention provides an ophthalmic composition comprising effective amounts of carbonic anhydrase inhibitor(s) and alpha-2-adrenergic agonist(s) without benzalkonium chloride as preservative. In aspects the invention provides fixed dose combinations of Brimonidine and Brinzolamide or pharmaceutical acceptable salts thereof for effective management of elevated intraocular pressure 10 (IOP) wherein the ophthalmic composition comprises a synergistic combination comprising EDTA, propylene glycol, mannitol, borate and zinc or salt thereof to preserve the composition against microbial growth.
BRIEF DESCRIPTION OF THE DRAWINGS:
FIGURE 1: Graphical representation of change in left eye mean IOP from Baseline to 15 each visit.
FIGURE 2: Graphical representation demonstrating non-inferiority change in mean of left eye mean IOP from Baseline to each visit.
7
FIGURE 3: Graphical representation of change in right eye mean IOP from Baseline to each visit.
FIGURE 4: Graphical representation demonstrating non-inferiority change in mean of left eye mean IOP from Baseline to each visit.
FIGURE 5: Graphical representation of change in 0-hour time point left eye IOP from 5 Baseline to each visit.
FIGURE 6: Graphical representation of change in 0-hour time point right eye IOP from Baseline to each visit.
FIGURE 7: Graphical representation of change in 2-hour time point left eye IOP from Baseline to each visit. 10
FIGURE 8: Graphical representation of change in 2-hour time point left eye IOP from Baseline to each visit.
FIGURE 9: Graphical representation showing percentage with target IOP = 21 mmHg at week 12/End of the study. DETAILED DESCRIPTION: 15 While the making and using of various embodiments of the present invention are discussed in detail below, it should be appreciated that the present invention provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely
8
illustrative of specific ways to make and use the invention and do not delimit the scope of the invention. To facilitate the understanding of this invention, several terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present invention. Terms such as "a", "an" and "the" are not intended to refer to only a 5 singular entity but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not delimit the invention, except as outlined in the claims.
The present invention provides a stable ophthalmic composition suitable for topical 10 administration to the eye comprising effective amounts of carbonic anhydrase inhibitor(s) and alpha-2-adrenergic agonist(s) wherein the composition is free of benzalkonium chloride (BAK).
In an embodiment carbonic anhydrase inhibitor(s) decreases aqueous production by inhibiting carbonic anhydrase and are selected from Dozolamide, Brinzolamide, 15 Acetazolamide, Methazolamide or pharmaceutical acceptable salts thereof wherein carbonic anhydrase is selected from Brinzolamide or pharmaceutical acceptable salts thereof.
In an another embodiment alpha-2-adrenergic agonist(s) decreases aqueous humor secretion and increasing uveoscleral outflow and are selected from Apraclonidine, 20
9
Brimonidine, Clonidine, Tizanidine or pharmaceutical acceptable salts thereof wherein alpha-2-adrenergic agonist(s) is selected from Brimonidine or pharmaceutical acceptable salts thereof more preferably Brimonidine Tartrate.
In a preferred embodiment the present invention provides an ophthalmic composition comprising fixed dose combination of Brinzolamide and Brimonidine 5 Tartrate wherein ophthalmic composition is applied topically to the eye.
In an another embodiment the present invention provides benzalkonium chloride (BAK) free ophthalmic composition wherein the composition is preserved by buffered system comprising one or more anti-microbial agents.
In an another embodiment the present invention provides an aqueous ophthalmic 10 composition comprising fixed dose combination of Brinzolamide and Brimonidine Tartrate wherein ophthalmic composition are formulated as a sterile aqueous solution, emulsions or suspensions, in-situ gel.
In an another embodiment of the present invention an ophthalmic composition is a sterile aqueous solution for topical administration into eyes. 15
In an another embodiment the present invention provides a multi-dose aqueous suspension comprising one or more preservatives in order to prevent the growth of bacteria, fungi and other microbes wherein the composition of present invention is BAK free and provide an improved preservation over the prior art composition. The
10
inventors of the present invention have surprisingly found that the use EDTA can provide synergistic effect in preservation of ophthalmic suspension against the microbial growth. EDTA may act to reduce DNA degradation during tissue storage by sequestering divalent cations that are required by nucleases naturally occurring in animal tissues. The use of EDTA as preservative has also been reported by Martina 5 Cristaldi et.al, wherein the authors concluded that EDTA at 0.1% in combination with NIG showed to have antimicrobial effects. The study also reported that EDTA 0.1% alone or combination shows no toxicity and even resulted in eye cell growth promotion after 48 hours of treatment. [Cristaldi M et al., Cutan Ocul Toxicol. 2018 Mar;37(1):71-76]. The inventors of the present invention have found that the use 10 Ethylenediaminetetraacetic acid (EDTA) in combination with a buffered solution composed of mannitol, zinc or salt thereof and borate was found to be more stable, safe and efficacious than BAK preservative.
In a preferred embodiment, the present invention provides an ophthalmic aqueous suspension comprising Brinzolamide and Brimonidine Tartrate and a synergistic 15 combination of EDTA with Propylene glycol mannitol, zinc chloride and borate for effective management of intraocular pressure related with glaucoma.
In an another embodiment, Brinzolamide present in effective amount of 5-15 mg/ml more preferably 10mg/ml corresponding to 1.0% w/v of total volume of composition. In further embodiment Brinzolamide is present in micronized form. 20
11
In an another embodiment, Brimonidine tartrate present in an effective amount of 0.5 mg/ml more preferably 2 mg/ml corresponding to 0.2% w/v of Brimonidine Tartrate.
In an embodiment the ophthalmic suspension further comprises one or more excipients selected from viscosity agent, surfactant and pH modifiers. 5
In an another embodiment viscosity agent are selected from group consisting of hydroxypropyl methylcellulose and guar gum; hydroxypropyl methylcellulose and a carboxyvinyl polymer; a carboxyvinyl polymer and guar gum; hydroxypropyl methylcellulose and hydroxyethylcellulose; hyaluronic acid and hydroxypropyl methylcellulose; hyaluronic acid and a carboxyvinyl polymer; and hyaluronic acid 10 and guar gum.
In a preferred embodiment viscosity agent is Carboxyvinyl polymers also known as “carbomers” or carboxypolymethylene. The concentration of carbomer in the composition of the present invention generally range from 0.01-0.5%, more preferably 0.2% w/v. 15
In an another embodiment the ophthalmic formulation further comprises surfactant selected from poloxamers, polyalkylene glycolether, polyoxyethylene fatty acid esters, e.g. polyoxyethylene sorbitan, mono- or polyesters and/or polyoxyethylene
12
fatty ethers, e.g. derived from lauryl, alkyl aryl polyether alcohol, cetyl, stearyl and oleyl alcohols.
In a preferred embodiment surfactant is alkyl aryl polyether alcohol preferably tyloxapol presents in amount range from 0.05 to 0.5% more preferably 0.1%.
In an another embodiment the ophthalmic suspension further comprises pH 5 modifiers selected from group consisting of but are not limited to dibasic sodium phosphate, monobasic sodium phosphate, hydrochloric acid, sodium hydroxide, sodium hydrogen carbonate. Sodium hydroxide or hydrochloric acid are the pH modifiers of choice in the present invention.
In an embodiment the present invention provides an ophthalmic suspension 10 comprising: 1.0% w/v Brinzolamide and; 0.2% w/v Brimonidine Tartrate and; 0.004% zinc chloride and; 0.5% mannitol and; 0.5% Propylene glycol and 1.2% boric acid, 0.2% Carbomer, 0.1% Tyloxapol, 0.1% hydrochloric acid and 0.3% sodium hydroxide.
In an embodiment the present invention provides method of preparing stable and sterile ophthalmic formulation wherein the method comprising the steps of: 15
a. Preparation of sterile carbomer solution to form a sterilized solution A;
b. Mixing Disodium Edetate, Boric acid, Mannitol, zinc chloride, Tyloxapol and Propylene glycol in water for injection to obtain a clear solution B;
13
c. Adding and dissolving Brimonidine Tartrate to solution B to obtain a clear solution C;
d. Adding solution C to sterilized solution A through filtration assembly to obtain a solution D;
e. Adding and mixing Brinzolamide to solution D to obtain a clear ophthalmic 5 suspension of Brinzolamide and Brimonidine tartrate;
f. Adjusting the pH to 6.0 to 7.5 with 10% w/v sterile sodium hydroxide solution or 10% v/v sterile Hydrochloric acid solution.
In a preferred embodiment the present invention provides BAK free ophthalmic aqueous suspension comprising 10
i. Brinzolamide present in an amount 10mg/ml
ii. Brimonidine Tartrate present in an amount 2 mg/ml
iii. EDTA in combination with a buffered solution composed of Propylene glycol, mannitol, zinc chloride and borate
14
Examples:
The scope of the present invention is illustrated by the following examples which is not meant to restrict the scope of the invention in any manner whatsoever.
EXAMPLE-1: Formula for Brinzolamide & Brimonidine Tartrate Ophthalmic Suspension 5
The Brinzolamide & Brimonidine Tartrate fixed dose combination is presented in table-1 is a sterile, preserved ophthalmic suspension. The formulation is preserved with EDTA in combination with a buffered solution composed of mannitol, zinc chloride propylene glycol and borate.
Table-1 10
S. No
COMPOSITION
mg /ml
%w/v
1.
Brinzolamide (Sterile & Micronized)
10.000
1.0%
2.
Brimonidine Tartrate
2.000
0.2%
3.
Zinc Chloride
0.04
0.004%
4.
Carbomer 974 P
2.000
0.2%
5.
Mannitol
5.000
0.5%
6.
Tyloxapol
1.000
0.1%
7.
Propylene Glycol
5.000
0.5%
8.
Boric Acid
12.000
1.2%
9.
Disodium Edetate
1.000
0.1%
15
10.
Hydrochloric Acid
0.001 ml/ml
0.1%
11.
Sodium Hydroxide (Pellets)
3.000
0.3%
12.
Water for Injections
q.s.
qs
The Brinzolamide & Brimonidine Tartrate ophthalmic suspension was prepared as mentioned here.
In example 1, carbomer (974P USNF) was dissolved in water for injections with continuous stirring for 30 minutes or till a lumps free solution was obtained. The 5 carbomer solution was sterilized at 121.6°C for 45 minutes by passing steam in jacketed manufacturing vessel or by autoclave at 121.6°C for 30 min. After sterilization, the sterilized solution was aspectically transferred into presterilized holding tank through sterilized cone filteration. After sterilization, Disodium Edetate, boric acid, mannitol, zinc chloride, Tyloxapol and Propylene Glycol was 10 dissolved in water for injection with continuous stirring at 300 RPM to obtain a clear solution.
To the clear solution Brimonidine Tartrate was added and stirred to obtain a clear solution, to this solution carbomer solution was added and Brinzolamide was mixed and homogenized at 2200-2800 RPM for 1 hour. The suspension obtained after 15 homogenization was checked for pH and if required the pH was adjusted between
16
6.0 to 7.5 by using 10%w/v sterile sodium hydroxide solution or with 10%v/v sterile hydrochloric acid solution.
17
Example-2 Stability Study: The Brinzolamide & Brimonidine Tartrate Ophthalmic Suspension of Example 1 was tested after being stored at 30°C ± 2°C & RH 35%±5% The formulation was tested for change in appearance, pH, osmolality, particle size by microscopy, 5 impurities, assay and water loss. Table-2: Test Acceptance criteria Initial testing After 3 months After 6 months After 9 months After 12 months After 24 months Description White colour suspension filled in opaque white colour LDPE vial White colour suspension filled in opaque white colour LDPE vial White colour suspension filled in opaque white colour LDPE vial White colour suspension filled in opaque white colour LDPE vial White colour suspension filled in opaque white colour LDPE vial White colour suspension filled in opaque white colour LDPE vial White colour suspension filled in opaque white colour LDPE vial pH Between 5.70 and 8.50 6.99 6.96 7.37 7.12 7.08 7.02 Osmolality Between 250 and 350 mOsmol/kg 319 mOsmol/kg NA NA NA NA 327 mOsmol/kg Particle size (by Malvern) Median diameter D90: not more than 20.0 microns D(0.90)= 1.192µM NA NA NA NA D(0.90)= 0.734 µM Particle size by Microscopy Particle size greater than 25 µm Not more than 20 1 NA NA NA NA NIL
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Particle size greater than 50 µm Not more than 10 NIL NA NA NA NA NIL Particle size greater than 100 µm Should be NIL NIL NA NA NA NA NIL Related Substance Single Maximum impurity Not more than 0.50% 0.16% 0.175% 0.170% 0.175% 0.182% 0.165% Total impurities Not more than 2.00% 0.21% 0.251% 0.264% 0.293% 0.255% 0.241% Debromobrimonidine impurity of Brimonidine Tartrate Not more than 0.50% 0.01% 0.007% 0.014% 0.039% 0.065% 0.132% Impurity A of Brinzolamide Not more than 1.50% 0.12% 0.132% 0.145% 0.165% 0.298% 0.319% Sterility No microbial growth observed No microbial growth observed NA NA NA NO microbial growth observed NO microbial growth observed Assay: Each ml contains Brinzolamide IP 10.00 mg NLT 90.00% and NMT 110.00% of label claimed. 99.50% 101.80% 98.80% 102.50% 100.10% 99.00% Brimonidine Tartrate IP 1.00 mg NLT 90.00% and NMT 110.00% of label claimed. 100.00% 97.00% 97.00% 99.00% 98.00% 99.00% Water Loss Not more than 5.00% NA 0.12% 0.43% 0.71% 0.98% 2.18%
As observed from the Table 2, the formulation was found to be stable even after 24 months
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Example-3: Toxicity study
The aim of this example is to elicit the Eye Irritation/Corrosion Test of Brinzolamide & Brimonidine Tartrate Ophthalmic Suspension for 28 days in rats.
Dose administration: 5
The suspension was administered into the conjunctival sac of the right eye of 36 rats at the dose levels of 0.1, 0.2 & 0.3 ml/eye/animal. The left eyes were considered as control. The control eyes were administered with normal saline (0.9% NaCl) solution.
Examination of Eyes Prior to Test:
Both eyes of each rat provisionally selected for testing, examined within 24 h before testing starts by the 10 same procedure to be used during the test examination, Animals have no eye irritation, ocular defects and pre-existing corneal injury.
Clinical Examination and Scoring:
The eyes were examined ophthalmascopically with a “Fujitron Hand-held slit lamp” prior to the administration and 0, 7, 14, 21, 28 days after the administration. The eyes reactions were observed and 15 registered.
It was found that there was no evidence of irritation at 28 days, hence the study was not extended further.
Parameters
Group I
Group II
Group III
Cornea opacity
0 (No Opacity)
0 (No Opacity)
0 (No Opacity)
20
IRIS opacity
0 (Normal)
0 (Normal)
0 (Normal)
Conjunctival redness
0 (Normal)
0 (Normal)
0 (Normal)
Chemosis
0 (Normal)
0 (Normal)
0 (Normal)
21
Results:
Under the toxicity test condition, multiple instillations of 0.1 ml Brinzolamide and Brimonidine Tartrate ophthalmic suspension per animal into the conjunctival sac of the right eye of six rats did not cause any changes. The cornea, irises and conjunctivae were not affected by multiple instillations of the present invention’s formulation. There was no systemic intolerance reaction. 5
Individuals results are summarized in the following tables:
Table-3- Examinations of the Rats (male) treated Eye
Animal No. 1/2/3/4/5/6
Right eye: 0.1 ml Brinzolamide & Brimonidine Tartrate Ophthalmic Suspension
Time after administration
Cornea Opacity
IRIS opacity
Conjunctival redness
Chemosis
Before dosing
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
7 days
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
14
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
21
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
28
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
Animal No. 7/8/9/10/11/12 10
Right eye: 0.2 ml Brinzolamide & Brimonidine Tartrate Ophthalmic Suspension
22
Table-4 Examinations of the Rats (male) treated Eye
Time after administration
Cornea Opacity
IRIS opacity
Conjunctival redness
Chemosis
Before dosing
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
7 days
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
14
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
21
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
28
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
Animal No. 13/14/15/16/17/18
Right eye: 0.3 ml Brinzolamide & Brimonidine Tartrate Ophthalmic Suspension
Table 5- Examinations of the Rats (male) treated Eye
Time after administration
Cornea Opacity
IRIS opacity
Conjunctival redness
Chemosis
Before dosing
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
7 days
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
14
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
21
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
28
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
0/0/0/0/0/0
Redness-refers to palpebral and bulbarconjunctivae; excluding cornea and iris. 5
23
Chemosis (Swelling)-refers to lids and/or nictitating membrane
Example-4 Clinical study of Brinzolamide 1% w/v plus Brimonidine 0.1% w/v IP Ophthalmic Suspension
The objective of the study was: 5
PRIMARY OBJECTIVE:
To evaluate efficacy of FDC of Brinzolamide 1% w/v plus Brimonidine 0.1% w/v IP Ophthalmic Suspension versus Brinzolamide Ophthalmic Suspension 1% w/v(preserved with BKC) plus Brimonidine Tartrate Ophthalmic solution 0.1% w/v (preserved with OxyChloro complex) in patients with open-angle glaucoma or ocular hypertension. 10
SECONDARY OBJECTIVE:
To evaluate safety of FDC of Brinzolamide 1% w/v plus Brimonidine 0.1% w/v IP Ophthalmic Suspension versus Brinzolamide Ophthalmic Suspension 1% w/v plus Brimonidine Tartrate Ophthalmic solution 0.1% w/v in patients with open-angle glaucoma or ocular hypertension.
EFFICACY OUTCOMES: 15
PRIMARY ENDPOINT:
Change in mean IOP from baseline. [Time Frame: Baseline, week 4, week 8 and week 12].
SECONDARY ENDPOINT:
24
a. Mean Change in 0-hour time point IOP from baseline. [Time Frame: Baseline, week 4, week 8 and week 12].
b. Mean Change in 2-hour time point IOP from baseline. [Time Frame: Baseline, week 4, week 8 and week 12].
c. Percentage of patients with target IOP (= 21mmHg). [Time Frame: 12 weeks] 5
d. Change in the mean value of Morisky medication adherence scale between two groups. [Time Frame: 12 weeks]
DOSAGES:
Test drug: one drop of FDC of Brinzolamide 1% w/v plus Brimonidine 0.1% w/v IP Ophthalmic Suspension (Preserved by Iconic Solvent) twice daily 10
Comparator drug: one drop of Brinzolamide suspension 1% w/v and Brinzolamide Tartrate Ophthalmic solution 0.1% w/v individually twice daily.
METHODOLOGY:
Randomization: Patients were randomized into 2 masked treatment groups (FDC AND Brinzolamide suspension 1% w/v and Brinzolamide Tartrate Ophthalmic solution 0.1% w/v. 15
Visit Schedule: Screening, base line (Day 1), Week 4, Week 8, Week 12
No. of patients: 219 planned to enroll, 216 enrolled (FDC: 108; combination: 108); 213 Completed
SUMMARY OF PRIMARY EFFICACAY CRITERIA:
25
Change in mean of Left Eye IOP from baseline to each visit (See for Example Figures 1 &2):
? 9.38 Unit reduction (improvement) in FDC of Brinzolamide and Brimonidine (Test Arm).
? 9.11 unit reduction (improvement) in Brinzolamide and Brimonidine (Comparator Arm)
Change in mean of Right Eye IOP from baseline to each visit (See for Example Figures 3 & 4):
? 9.35 Unit reduction (improvement) in FDC of Brinzolamide and Brimonidine (Test Arm). 5
? 9.19 Unit reduction (improvement) in Brinzolamide and Brimonidine (Comparator Arm)
Table 6- Change in mean of Left Eye IOP from baseline to each visit.
Visits
FDC Brinzolamide and Brimonidine (Test)
N=105
Brinzolamide and Brimonidine (Control)
N=104
Mean Difference Between Treatment Group
(Control – Test)
95 % Confidence Interval (Control - Test)
P-Value*
Mean (S.D.)
Mean Difference from Baseline
Mean (S.D.)
Mean Difference From Baseline
Baseline
27.84(2.31)
-
27.68(2.33)
-
-
-
-
Week 4
21.89(2.51)
-5.95
21.62(2.06)
-6.05
-0.106
(-0.80, 0.59)
<0.001
Week 8
19.92(1.98)
-7.92
19.95(1.70)
-7.73
0.1956
(-0.51, 0.90)
<0.001
Week 12
18.46(1.85)
-9.38
18.57(1.95)
-9.11
0.2734
(-0.44, 0.99)
<0.001
Analysis is performed on per protocol population * P value is determined by using unpaired t-test with non-inferiority hypothesis (non-inferiority margin is 1.5).
10
26
Table 7- Change in mean of right Eye IOP from baseline to each visit.
Visits
FDC Brinzolamide and Brimonidine (Test)
N=105
Brinzolamide and Brimonidine (Control)
N=104
Mean Difference Between Treatment Group
(Control – Test)
95 % Confidence Interval (Control - Test)
P-Value*
Mean (S.D.)
Mean Difference from Baseline
Mean (S.D.)
Mean Difference From Baseline
Baseline
27.83(2.51)
-
27.70(2.23)
-
27.70(2.23)
-
-
Week 4
22.05(2.59)
-5.78
21.81(2.20)
-5.89
21.81(2.20)
-5.89
<0.001
Week 8
19.90(2.12)
-7.93
19.93(1.76)
-7.77
19.93(1.76)
-7.77
<0.001
Week 12
18.48(1.93)
-9.35
18.51(2.14)
-9.19
18.51(2.14)
-9.19
<0.001
Analysis is performed on per protocol population * P value is determined by using unpaired t-test with non-inferiority hypothesis (non-inferiority margin is 1.5).
SUMMARY OF SECONDARY EFFICACAY CRITERIA
Table 8- Mean change in 0-hour time point Left Eye IOP from baseline to each visit. 5
Visits
FDC Brinzolamide and Brimonidine (Test)
Brinzolamide and Brimonidine (Control)
P-Value
Mean (S.D.)
Mean Difference from Baseline
Mean (S.D.)
Mean Difference from Baseline
Baseline
28.13(2.59)
-
27.94(2.57)
-
-
Week 4
22.31(2.65)
-5.82
22.00(2.37)
-5.94
0.771
27
Week 8
20.38(2.27)
-7.75
20.46(2.17)
-7.48
0.542
Week 12
18.91(2.19)
-9.22
19.08(2.26)
-8.86
0.409
Conclusion:
• The mean difference in IOP reduction at 0-hour time point from baseline to week 4, 8, 12 was similar for patients in the FDC of Brinzolamide plus Brimonidine Ophthalmic Suspension and Brinzolamide Ophthalmic Suspension plus Brimonidine Tartrate Ophthalmic Solution groups. (See for example figure 5) 5
• These mean differences were found to be statistically not significant (p>0.05). i.e., similar efficacy at each visit in mean reduction of left eye IOP at 0-hour time point.
Table 9- Mean change in 0-hour time point right Eye IOP from baseline to each visit.
Visits
FDC Brinzolamide and Brimonidine (Test)
Brinzolamide and Brimonidine (Control)
P-Value
Mean (S.D.)
Mean Difference from Baseline
Mean (S.D.)
Mean Difference from Baseline
Baseline
28.06(2.82)
-
27.98(2.52)
-
-
Week 4
22.44(2.71)
-5.61
22.19(2.33)
-5.79
0.688
Week 8
20.39(2.36)
-7.67
20.47(1.96)
-7.51
0.730
Week 12
18.97(2.24)
-9.09
19.02(2.33)
-8.96
0.777
Conclusion:
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• The mean difference in IOP reduction at 0-hour time point from baseline to week 4, 8, 12 was similar for patients in the FDC of Brinzolamide plus Brimonidine Ophthalmic Suspension and Brinzolamide Ophthalmic Suspension plus Brimonidine Tartrate Ophthalmic Solution groups. (See for example figure 6)
• These mean differences were found to be statistically not significant (p>0.05). i.e., similar 5 efficacy at each visit in mean reduction of right eye IOP at 0-hour time point.
Table 10- Mean change in 2-hour time point Left Eye IOP from baseline to each visit.
Visits
FDC Brinzolamide and Brimonidine (Test)
Brinzolamide and Brimonidine (Control)
P-Value
Mean (S.D.)
Mean Difference from Baseline
Mean (S.D.)
Mean Difference from Baseline
Baseline
27.56(2.27)
-
27.41(2.38)
-
-
Week 4
21.48(2.65)
-6.08
21.25(2.24)
-6.17
0.802
Week 8
19.46(2.07)
-8.10
19.44(1.74)
-7.97
0.719
Week 12
18.01(1.83)
-9.55
18.06(1.93)
-9.35
0.583
Conclusion:
• The mean difference in IOP reduction at 2-hour time point from baseline to week 4, 8, 12 was similar for patients in the FDC of Brinzolamide plus Brimonidine Ophthalmic Suspension 10 and Brinzolamide Ophthalmic Suspension plus Brimonidine Tartrate Ophthalmic Solution groups. (See for example figure 7)
• These mean differences were found to be statistically not significant (p>0.05). i.e., similar efficacy at each visit in mean reduction of left eye IOP at 2-hour time point.
Table 11- Mean change in 2-hour time point right Eye IOP from baseline to each visit. 15
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Visits
FDC Brinzolamide and Brimonidine (Test)
Brinzolamide and Brimonidine (Control)
P-Value
Mean (S.D.)
Mean Difference from Baseline
Mean (S.D.)
Mean Difference from Baseline
Baseline
27.60(2.45)
-
27.43(2.30)
-
-
Week 4
21.65(2.75)
-5.94
21.43(2.44)
-5.99
0.903
Week 8
19.41(2.19)
-8.19
19.39(1.88)
-8.03
0.684
Week 12
17.98(1.91)
-9.61
18.00(2.23)
-9.43
0.626
Conclusion:
• The mean difference in IOP reduction at 2-hour timepoint from baseline to week 4, 8, 12 was similar for patients in the FDC of Brinzolamide plus Brimonidine Ophthalmic Suspension and Brinzolamide Ophthalmic Suspension plus Brimonidine Tartrate Ophthalmic Solution groups. (See for example figure 8) 5
• These mean differences were found to be statistically not significant (p>0.05). i.e., similar efficacy at each visit in mean reduction of right eye IOP at 2-hour time point.
Table 12- Percentage of patients with target IOP = 21 mmHg at week 12/End of the study
Target IOP
FDC Brinzolamide and Brimonidine (Test)
Brinzolamide and Brimonidine (Control)
P-Value
Left Eye Target IOP
Target IOP = 21mmHg
94 (89.52)
97 (93.27)
0.335
Right Eye Target IOP
Target IOP = 21mmHg
94 (89.52)
95 (91.35)
0.654
• The percentage of patients achieved left eye target IOP = 21 mmHg at end of study visit/week 12 was similar for patients in the Test vs Comparator groups (89.52% versus 10 93.27%) & Right Eye (89.52% versus 91.35%)
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• The observed results demonstrated that both the treatment groups have statistically insignificant difference in both eyes target IOP (p>0.05) i.e., similar percentage of patients achieved target IOP (= 21 mmHg). (See for example figure 9)
Mean change in Morisky medication adherence scale between two groups
In both treatment groups, all the patients reported Morisky medication adherence score as 4 5 which means all the patients were highly adhered to study medication.
0 = Low adherence,
1 to 2 = Medium adherence
3 to 4 = High adherence
10
Efficacy Conclusion:
• The change in mean IOP for left and right eye at each visit has shown that upper bound of 95% CI (Control-Test) was within the non-inferiority margin 1.5 mmHg which demonstrated that Test Group Vs Control Group.
• In both treatment groups, the reduction in mean IOP over 5 mmHg in both left and right 15 eyes were observed as early week 4 and continued to the end of study visit (over 9 mmHg).
• Test Group & Control Group has shown similar efficacy in reduction of mean IOP at 0-hour and 2-hour time points with respect to each visit, percentage of patients achieved target IOP (= 21 mmHg) and adherence to study medication. 20
31
• Overall, the results of efficacy analysis demonstrated that FDC of Brinzolamide plus Brimonidine Ophthalmic Suspension (Test) has similar efficacy compared to Brinzolamide Ophthalmic Suspension plus Brimonidine Tartrate Ophthalmic Solution (Control) for reducing elevated IOP in patients with open-angle glaucoma or ocular hypertension. 5
ADVERSE EVENTS:
Summary-
• 218 patients (108 in each group) were considered for safety analysis
• 11/108 (10.19 %) patients experienced 12 adverse events in FDC of Brinzolamide plus Brimonidine Ophthalmic Suspension 10
• 11/108 (10.19 %) patients experienced 11 adverse events in Brinzolamide Ophthalmic Suspension plus Brimonidine Tartrate Ophthalmic Solution group
• experienced 11 adverse events in Brinzolamide Ophthalmic Suspension plus Brimonidine Tartrate Ophthalmic Solution group
Table 13-Overall Summary of Adverse Events – Treated Population 15
Event
FDC of Brinzolamide plus Brimonidine Ophthalmic Suspension (Test) N=108
Brinzolamide Ophthalmic Suspension plus Brimonidine Tartrate Ophthalmic Solution (Control) N=108
Overall
N=216
n (%), E
n (%), E
Adverse Event
11(10.19), 12
11(10.19), 11
22 (10.19), 23
Related Adverse
8(7.41), 9
9(8.33), 9
17 (7.87), 18
32
Event
Serious Adverse Event
0(0), 0
0(0), 0
0(0), 0
Related Serious Adverse Event
0(0), 0
0(0), 0
0(0), 0
Adverse Event Leading to Early Termination
0(0), 0
0(0), 0
0(0), 0
Safety Conclusion:
• A total of 23 adverse events reported in 22 patients, among these 12 and 11 adverse 5 events reported in FDC of Brinzolamide plus Brimonidine Ophthalmic Suspension and Brinzolamide Ophthalmic Suspension plus Brimonidine Tartrate Ophthalmic Solution groups respectively. All the reported adverse events were mild in severity.
• In both treatment groups, compared from baseline to all visits there were no clinically relevant changes in vital signs like body temperature, blood pressure (SBP, 10 DBP), pulse rate and respiratory rates.
• Compared from baseline to end of study abnormal mean laboratory values did not reveal any relevant untoward effects and were not considered clinically significant.
• There were no incidences of serious TEAEs including death. No drug-related SAE was reported in both treatment groups. 15
Over all Conclusion:
The FDC of Brinzolamide 1% w/v plus Brimonidine 0.1% w/v Ophthalmic Suspension (preserved by Ionic Solvent) have similar efficacy and safety with good tolerability as compared to concomitant administration for the treatment of patients with open angle glaucoma or ocular hypertension with Brizolamide 1% (preserved by BKC) and Brimonidine 0.1% (preserved by OxyChloro Complex). ,CLAIMS:1. An ophthalmic composition comprising combinations of carbonic anhydrase inhibitor(s) and alpha-2-adrenergic agonist(s) wherein said composition is free of benzalkonium chloride.
2. An ophthalmic composition as claimed in claim 1 comprises carbonic anhydrase inhibitor(s) is Brinzolamide or pharmaceutical acceptable salts thereof and alpha-2-adrenergic agonist(s) is Brimonidine or pharmaceutical acceptable salts thereof.
3. An ophthalmic composition as claimed in claim 2 comprises 0.5-2% w/v Brinzolamide more preferably 1.0% w/v.
4. An ophthalmic composition as claimed in claim 2 comprises 0.05%-0.5% w/v Brimonidine 10 Tartrate more preferably 0.2% w/v.
5. An ophthalmic composition as claimed in claim 1 is preserved by synergistic combinations of EDTA with Propylene glycol mannitol, zinc chloride and borate.
6. An ophthalmic composition as claimed in any previous claims is an ophthalmic suspension comprising an effective combination of: 15
1. 1.0% w/v brinzolamide and;
2. 0.2% w/v Brimonidine Tartrate and;
3. 0.004% zinc chloride and;
4. 0.5% mannitol and;
5. 0.5% Propylene glycol and 20
35
6. 1.2% boric acid.
7. An ophthalmic suspension as claimed in claim 6 further comprises 0.2% Carbomer as viscosity agent, 0.1% Tyloxapol as surfactant, 0.1% hydrochloric acid and 0.3% sodium hydroxide as pH modifier.
8. An ophthalmic suspension as claimed in previous claims is used topically for 5 effective management of intraocular pressure related with glaucoma.
9. A method for producing an ophthalmic suspension comprising following steps:
a) Preparation of sterile carbomer solution to form a sterilized solution A;
b) Mixing Disodium Edetate, Boric acid, Mannitol, zinc chloride, Tyloxapol and Propylene glycol in water for injection to obtain a clear solution B; 10
c) Adding and dissolving Brimonidine Tartrate to solution B to obtain a clear solution C;
d) Adding solution C to sterilized solution A through filtration assembly to obtain a solution D;
e) Adding and mixing Brinzolamide to solution D to obtain a clear ophthalmic 15 suspension of Brinzolamide and Brimonidine tartrate;
f) Adjusting the pH to 6.0 to 7.5 with 10% w/v sterile sodium hydroxide solution or 10% v/v sterile Hydrochloric acid solution.
10. An ophthalmic suspension comprising 1.0% w/v Brinzolamide and 0.2%w/v Brimonidine Tartrate wherein said ophthalmic suspension is free of benzalkonium chloride.