DESC:
TECHNICAL FIELD OF THE INVENTION:
The present invention relates to topical compositions of Pregabalin. More particularly the present invention relates to Stable Pregabalin composition comprising 8% w/w of Pregabalin and a process of preparation thereof.

BACKGROUND AND PRIOR ART:
Lifestyle changes, stress, food habits can affect the general health of an individual and would involve direct affect to the body systems. One such important system which can be affected is the Nervous system. Nervous system damages can lead to changes in the way of perception associated with almost all the sensory organs and thus affect the touch, temperature, movement and pressure associated functions. The pain signals to the nerves are disrupted or damaged due to injury or disease. Nervous system can be impaired due to various diseases such as diabetes, cancer, shingles, neurological conditions, stroke, HIV, autoimmune diseases, blood vessel disease and the like. Types of Neuropathies which affects the Nervous system may be Peripheral, Autonomic, Focal, Proximal, diabetic, compression mononeuropathy, phantom limb syndrome, trigeminal neuralgia, postherapeutic neuralgia, thoracic or lumbar radiculopathy. Symptoms of Neuropathic pain include severe pain, numbness, changes in the perception of the sense organs etc.
Diabetic neuropathy is a common complication of both type 1 and type 2 diabetes, which affects over 90% of the diabetic patients.
The first line of treatment for Neuropathic pain involves administration of Anticonvulsants and antidepressant and further therapies such as physical, relaxation, massage therapy or Acupuncture. However, such therapies may aggravate the conditions in some cases and hence would demand a multidisciplinary approach.
First line of treatment includes antiseizure medications, Antidepressants. Second line treatments include Capsaicin and Lidocaine patches, Tramadol and third line treatment which include opioids. Pregabalin an antiepileptic drug is one such drug candidate which is used for Neuropathic pain. The dosage forms currently available are in the form of liquids or solid dosage forms such as tablets, capsules etc.
Prior art literature also discloses various compositions of Pregabalin.
WO2014168228 provides a pregabalin-containing composition through topical administration. The pregabalin is preferably present in a water-dissolved form. The pregabalin content in this Gel is 0.2-3 wt% with respect to total composition weight. Pregabalin is preferably present in a water-dissolved form.
WO2022157527 relates to Topical formulation containing pregabalin for long-term analgesic activity. It claims a Topical pharmaceutical composition comprising pregabalin and phospholipid obtainable by a process in which a mixture comprising the phospholipid and solvent is homogenized with a high shear mixing equipment and wherein the pregabalin and the phospholipid are in dispersed form in the composition.
WO2022157524 relates to a topical pharmaceutical composition comprising pregabalin and a reduced micellar phospholipid as an active ingredient.
US20110065627 relates in general to the field of transdermal and dermal drug delivery by using formulations of said compositions including chemical penetrants molecules, polar solvents, cream base, antioxidants and therapeutic pharmaceutical or cosmetic active agents for treating various diseases, pains, skin conditions and other neurological and non-neurological maladies. The compositions disclosed comprise 0.01% to 15% of pregabalin or gabapentin in a cream base containing the penetrant group cetylated fatty esters.
WO2017172603 provides topical formulations comprising pregabalin, water, DMSO, a keto acid, and and/or a fatty alcohol.
WO2016061328 The composition comprises pregabalin and/or gabapentin in a base containing water. Pregabalin and/or gabapentin preferably exists in the form dissolved in water.
Further Non patent literature Topical pregabalin and diclofenac for the treatment of neuropathic orofacial pain in rats", Plaza-Villegas et al., ", B.Achrai et.al., The Journal of Physical Chemistry B, 2011; Vol.115: 825-835discloses a skin composition using PLO (Pluronic Thin Organogel) and anhydrous gel as a base, and further discloses that topical application of a composition comprising 10% pregabalin is most effective for pain relief.
Marketed preparations include gels comprising Diclofenac, Capsaicin based Rubefacients, Menthol, methyl salicylate and Pregabalin.
Prior art discloses various dosage forms and various compositions wherein Pregabalin is present along with other actives such as Phospholipids, herbals actives and other actives. There still exists a lacuna in the available dosage forms their compositions and bioavailability.
Pregabalin has been considered as a drug of choice in Neuropathic pain. Oral dosage forms such as Tablets, Capsules, solution are currently available. After oral dosing administered in the fasted state, pregabalin absorption is rapid and extensive.
Pregabalin is sparingly soluble in water. Cmax is attained within 1.5 hours after single or multiple doses, and steady state is attained within 24 to 48 hours with repeated administration. Food decreases the rate of pregabalin absorption and as a result lowers the Cmax by an estimated 25 -30% and increases the Tmax to approximately 3 hours. The elimination half-life of Pregabalin is 6.3 hours.
However, available literature (Pregabalin; latest safety and clinical implications for the management of Neuropathic pain Ther.Adv.DrugSaf.2014 Feb;5(1);38-56.doi:10.1177/2042098613505614) discloses that the oral clearance of PGB is likely to decrease with increasing age; therefore, dose reductions should be considered for older patients. Pregabalin may possibly be associated with significant respiratory depression postoperatively [Eipe and Penning, 2011].
Further if sufficient pain relief is not obtained from the available regimen or it becomes intolerable to the patient it is either administered along with other drugs or discontinued.
Bearing in mind the lacuna of the available dosing regimens, dosage forms of Pregabalin, their drug effect and the time interval at which the drug is available to relieve the symptoms specifically in Neuropathic pain which requires rapid effect and bioavailability and efficacy the inventors have paved a way for Pregabalin for Neuropathic pain by providing Pregabalin alone in the form of a topical composition particularly a Gel.

OBJECTIVE OF THE INVENTION:
The objective of the present invention is to provide Pregabalin 8%w/win the form of a stable topical composition.
Accordingly, the objective of the present invention is to provide Pregabalin along with the pharmaceutically acceptable excipients in the form of Gel with minimum complexity and good product quality.
Yet another objective of the present inventions is to provide a process for preparing Pregabalin Gel 8%w/w stable topical composition.
Yet further objective of the present invention is to provide Pregabalin 8%w/w in the form of a stable topical composition for Neuropathic Pain.
Another objective of the present invention is to provide Pregabalin 8%w/w in the form of a stable topical composition for Diabetic Neuropathic Pain.

SUMMARY OF THE INVENTION:
In accordance with the above objective, in an aspect, the present invention providesa topical composition of Pregabalin wherein the content of Pregabalin on w/w basis in the Gel is 8%.
In another aspect, the present invention provides a stable topical composition of Pregabalin Gel 8% w/w for Neuropathic pain.
In another aspect, the present invention provides a stable topical composition of Pregabalin 8%w/w for Diabetic Neuropathic pain.
In another aspect the present invention provides a stable topical composition comprising Pregabalin 8%w/w wherein Carbomer (Carbomer Homopolymer Type C) is used as a Gelling agent.
In a further aspect the present invention provides a process for preparation of a stable composition of Pregabalin Gel comprising Pregabalin8%w/w.
In yet another aspect the present invention provides a process for preparation of a stable composition of Pregabalin Gel comprising Pregabalin 8%w/w wherein Pregabalin is added in Emulsion phase at a temperature of 40 -50?.
In a further aspect the present invention provides a stable topical composition of Pregabalin Gel 8%w/w wherein the Pregabalin Lactum impurity in the final product is NMT 0.5%.

DESCRIPTION OF THE FIGURES:
Figure 1 depicts manufacturing Flow chart

DETAILED DESCRIPTION OF THE INVENTION:
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which the invention belongs. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.
“Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

Throughout the description and claims of this specification, the word “comprise” and variations of the word, such as “comprising” and “comprises,” means “including but not limited to,” and is not intended to exclude, for example, other additives, components, integers or steps.

The inventors based on their excipient compatibility and research studies have arrived at a stable composition of Pregabalin Gel wherein Carbomer (Carbomer Homopolymer Type C) is used as a gelling agent. The dispersion of Pregabalin in Emulsion phase at a temperature of 40? -50? and the use of Carbomer (Carbomer Homopolymer Type C) as a gelling agent imparts excellent stability to the product.
The final product is in the form of a Gel and exhibits better stability. The final product is more selective for a specific site and is convenient and easy to apply. The Gel avoids the first pass metabolism and gastrointestinal incompatibility. Thus, the Pregabalin Gel 8% w/w in the form of Gel score over the existing dosage form of Pregabalin.
Disclosed are components that can be used to perform the disclosed methods and systems. These and other components are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these components are disclosed that while specific reference of each various individual and collective combinations and permutation of these may not be explicitly disclosed, each is specifically contemplated and described herein, for all methods and systems. This applies to all aspects of this application including, but not limited to, steps in disclosed methods. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods.
Pregabalin

IUPAC Name of Pregabalin is(3S)-3-(aminomethyl)-5-methylhexanoic acid with Molecular formula C8H17NO2and Molecular Weight 159.23. (CAS No: 148553-50-8).
As used herein, term “Pregabalin” (along with its synonyms (3S)-3-(aminomethyl)-5-methylhexanoic acid) is denoted in broad sense to include not only Pregabalin per se but also its pharmaceutically acceptable derivatives. Suitable pharmaceutically acceptable derivatives include pharmaceutically acceptable salts pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable anhydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable tautomers, pharmaceutically acceptable complexes etc.

The present invention relates to a stable pharmaceutical topical composition comprising Pregabalin or its pharmaceutically acceptable derivatives along with one or more pharmaceutically acceptable excipients.
In an embodiment the present invention includes Pregabalin in an amount of 8% w/w of the total composition.
Preferably, Pregabalin may be provided in the form of a pharmaceutical composition such as, but not limited to, semi -solid dosage form as Gel.
Further various physicochemical properties of Pregabalin such as solubility, better absorption, bioavailability, increased shelf life, etc. could be improved by micronization and nanosizing techniques which may achieve one or more of the benefits aimed hereinabove, and may also assist in dose reduction. For instance, Pregabalin may be present in the form of nanoparticles which have an average particle size of not more than50,000 nm (i.e., NMT 50µm). The particle size is in the range of 10 to 50µm.
Accordingly in an embodiment the average particle size of Pregabalin is not more than 50 µm.
Suitable pharmaceutically acceptable excipients may be used for formulating the dosage forms according to the present invention such as, but not limited to, gelling agents , emulsifying agents , vehicles , emollient bases , cosolvent , chelating agents , antioxidants , preservatives Surface stabilizers or surfactants, viscosity modifying agents, polymers including extended release polymers, stabilizers, opacifiers, anti-microbial agents, antifoaming agents, buffering agents, coloring agents ,texture enhancers, surface stabilizers, channeling agents, or combinations thereof.
Accordingly in an embodiment the topical composition of Pregabalin of the present invention comprises Pregabalin along with gelling agents, emulsifying agents, vehicles, emollient bases, cosolvent, chelating agents, antioxidants, neutralizing agents and preservatives.
Accordingly, in another embodiment, the present invention provides a topical gel composition of Pregabalin which comprises;
a) Pregabalin in an amount of 8 %;
b) Gelling agent in an amount of 0.1 to 0.5%;
c) Emulsifying agent in an amount of 1 to 10%;
d) Emollient base in an amount of 5 to 15 %;
e) Chelating agent in an amount of 0.05 to 1 %;
f) Antioxidant in an amount of 0.01 to 0.05%;
g) Preservatives in an amount 0.01 to 0.3%;
h) Neutralizing agent in an amount 0.005 to 0.01% and
i) Vehicles and cosolvent in an amount of 5 to 50%
Gelling agents used in the topical gel composition of the present invention are present in an amount of 0.1 to 2.0% more preferably 0.1 to 0.5% and selected from the group consisting of Carbomer (Carbomer Homopolymer Type C), Xanthan Gum, Veegum, Hydroxypropyl Cellulose, Hydroxymethyl cellulose, Hydroxyethyl cellulose, Carboxymethyl Cellulose and the like.
In an embodiment the Gelling agent used is Carbomer (Carbomer Homopolymer Type C) in an amount of 0.2%w/w of the total composition.
After dispersion in Water, Carbomer (Carbomer Homopolymer Type C) begins to hydrate and partially uncoil. Maximum thickening can be achieved by converting the acidic Carbomer (Carbomer Homopolymer Type C) to neutral pH. Neutral pH is easily achieved by neutralizing the Carbomer range with recommended neutralizers to adjust the pH of Carbomer range solution.
Neutralizing agent used in the topical gel compositions are selected from the group consisting of Sodium hydroxide (NaOH), Potassium hydroxide (KOH), Triethanolamine (TEA), Ammonia (28%) and other alkali.
It is a high molecular weight polymer. It does not absorb by body tissues and is totally safe for human oral and Topical consumption.
Emulsifying agent used in the topical gel composition of the present invention are present in an amount of 1.0 to 20 %, more preferably 1 to 10% and selected from the group consisting of Cetostearyl Alcohol, Cetomacrogol 1000, Cetyl Alcohol, Polysorbate 80, polysorbate 60, Sorbitan monooleate and the like.
In an embodiment the Emulsifying agent used is Cetostearyl alcohol in an amount of 8%w/w of the total composition.
Cetostearyl alcohol increases the viscosity and stabilizes the gel. Cetostearyl alcohol also acts as an emulsifier in both Water-in-oil and oil-in-Water emulsions. Cetostearyl alcohol stabilizes the emulsion and also act as a co-emulsifier, thus decreasing the total amount of surfactant required to form a stable emulsion.
In yet another embodiment Cetomacrogol 1000 is used as emulsifying agent in an amount of 2% w/w of the total composition.
Emollient base used in the topical gel composition of the present invention are present in an amount of 3.0 to 20.0 % more preferably 5 to 15% and selected from the group consisting of White Soft paraffin, Light liquid paraffin, Hard paraffin and the like.
In a further embodiment White soft paraffin is used as oleaginous base in an amount of 12% w/w of the total composition.
Chelating agent used in the topical gel composition of the present invention are present in an amount of 0.01 to 2%, more preferably 0.05 to 1% and selected from the group consisting of Disodium EDTA, Calcium Disodium EDTA and the like.
In another embodiment Disodium Edetate is used as Chelating agent in an amount of 0.1% w/w of the total composition.
Antioxidant used in the topical gel composition of the present invention are present in an amount of 0.01 to 0.2 % more preferably 0.01 to 0.05% and selected from the group consisting of Butylated Hydroxytoluene, Butylated Hydroxy Anisole, Vitamin C, Vitamin E and the like.
In an embodiment Butylated Hydroxytoluene is used as Antioxidant in an amount of 0.02% w/wof the total composition.
Preservatives used in the topical gel composition of the present invention are present in an amount of 0.01 to 3.0 % more preferably 0.01 to 3% and selected from the group consisting of Benzyl Alcohol, Methyl paraben, Propyl Paraben and the like.
In an embodiment Methylparaben is used as “preservative” in an amount of 0.2% w/w of the total composition.
In another Propylparaben is used as “preservative embodiment in an amount of 0.02% w/w of the total composition.
Vehicles and cosolvent used in the topical gel composition of the present invention are present in an amount of 2 to 80% more preferably 5 to 50% and selected from the group consisting of Propylene Glycol, purified water, Glycerine and the like.
In a further embodiment Light mineral oil is used as oleaginous vehicle in an amount of 6% w/w of the total composition.
In yet another embodiment Propylene glycol is used as Cosolvent in an amount of 19.0% w/w of the total composition.
In a further embodiment Purified water is used to make up the volume of the Gel composition of the present invention.
The topical composition of the present invention increases rate of absorption, improves penetration, increase bioavailability due to its localized and targeted action.

In another embodiment the present invention relates to a process for preparing the topical Gel composition, which process comprises the following stages:
Stage 1: - Preparation of Carbomer phase
Stage 2: Preparation of Water phase
Stage 3: Preparation of Water Phase and Soak Mixture
Stage 4: Preparation of Oil phase
Stage 5: Preparation of Drug phase and
Stage 6: Mixing phase

In yet another embodiment Pregabalin is dispersed in the co solvent to form the drug phase. This drug phase is then added into the Emulsion phase at a temperature of 40 – 50? under stirring. The weight is then made up.
The product of Pregabalin Gel 8% w/w was subjected to stability studies three stability batches were incubated at accelerated stability at 40°C ± 2°C / 75% RH ± 5%RH and Real time stability at 30°C ± 2°C / 75% RH ± 5% RH to assess the stability of the optimized formula.
In a further embodiment the Pregabalin Lactum Impurity of Pregabalin Gel 8% w/w is NMT 0.5 %.
In an embodiment the Pregabalin Gel 8% w/w is used for treating Neuropathic pain.
In yet another embodiment the pregabalin Gel 8%w/wis administered /applied for relieving Neuropathic Pain.
In another embodiment the Pregabalin Gel 8% w/w is used for treating Diabetic Neuropathic pain.
In a further embodiment the Pregabalin Gel 8%w/w is administered /applied for relieving Diabetic Neuropathic Pain.

The Pregabalin Gel 8 % w/w was also subjected to Preclinical Study- Acute and Sub-Acute Dermal Toxicity Study and Clinical Study.
The 8% Pregabalin Gel was also subjected to a phase III randomized, double blinded, double dummy, parallel group, placebo controlled, two arm, multicenter clinical study to evaluate the safety and efficacy of Pregabalin Gel 8 % w/w in comparison with Pregabalin Capsule as a standard of care in patients with diabetic neuropathic pain.
In an embodiment the Pregabalin Gel 8% w/w exhibits lesser somnolence as compared to oral Pregabalin and can be used as an alternative method for Diabetic Neuropathic Pain.
EXAMPLES
The following examples are set forth below to illustrate the composition, process and results according to the disclosed subject matter and embodiments. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative compositions, process and results. These examples are not intended to exclude equivalents and variations of the present invention, which are apparent to one skilled in the art.
Example 1:
Drug Excipients Compatibility study:
Based on compatibility study data, excipients were selected for development activities. Drug and excipients are weighed and mixed in a ratio of 1:1. Sample filled in clear transparent glass vials in closed condition. Vials were charged at 40°C/75 % RH for4 weeks. Initialand4-week samples were observed for any physical changes and level of related impurities.
Observation: No significant changes were observed in physical description and any individual unknown degradant during the compatibility study. Pregabalin was found to be compatible with selected excipients.
Conclusion: Based on compatibility study data, proposed excipients were selected for final formulation development. Pregabalin was found compatible with selected excipients.

Example 2:
Product Development Studies
The product development studies were designed based on the Excipient compatibility. Table 1 below gives product development batch details
Product development batches were designed considering the excipients which were found to be compatible through the Excipient Compatibility studies.

Product development batch details
Product Development Trials:
Objective was to develop a product that is stable and scalable for commercialization. The product development was initiated using laboratory scale equipment’s.

Experiment -1/2/3
Trial batches of Pregabalin Gel 8 % w/w with different concentration of emulsifying agents Cetostearyl Alcohol and White Soft Paraffin.
Trial -1 contains 4 % of Cetostearyl Alcohol, 6% White soft paraffin & Carbomer 0.5%
Trial -2 contains 8% of Cetostearyl Alcohol, 12% White soft paraffin & Carbomer0.5%
Trial- 3 contains 12% of Cetostearyl Alcohol, 16% White soft paraffin & Carbomer 0.5%

Table 1
Sr. No. Material Trial-1 Trial-2 Trial-3
1 Pregabalin IP
(2% overages) 8.16 8.16 8.16
2 Carbomer Homopolymer Type C (Acrypol 980 IP) 0.50 0.50 0.50
3 Cetostearyl Alcohol IP 4.00 8.00 12.00
4 White soft paraffin IP 6.00 12.00 16.00
5 Cetomacrogol 1000 BP 2.00 2.00 2.00
6 Light liquid paraffin IP 6.00 6.00 6.00
7 Propylene Glycol IP 19.00 19.00 19.00
8 Disodium EDTA IP 0.10 0.10 0.10
9 Butylated Hydroxytoluene IP 0.02 0.02 0.02
10 Methylparaben IP 0.20 0.20 0.20
11 Propylparaben IP 0.02 0.02 0.02
11 Triethanolamine IP Qs Qs Qs
12 Purified Water IP 54.00
Qs to 100 g 44.00
Qs to 100 g 36.00
Qs to 100 g

Batch Manufacturing process:
Stage 1: - Preparation of Carbomer phase
Step- I: Soak Preparation
Took batch quantity of Purified Water in a suitable S.S. container and heated to 75°C. Added Disodium EDTA to above heated Purified Water and mixed under stirring until clear solution obtained. Acrypol 980 was weighed and added in above mixture under continuous stirring and hydrated till uniform dispersion obtained (stirring for 30 min). Kept aside overnight for soak.
Step-II: Neutralization process
Prepared 50% Triethanolamine solution (1:1 ratio of Purified Water and Triethanolamine). Checked initial pH of soak and neutralized to obtain a pH of 5.3 (range- 5.0-5.5).
Stage 2: Preparation of Water phase
In suitable S.S. vessel weighed and added Part quantity of Purified Water added Methylparaben in Purified Water, heated up to 80-85 °C with continuous stirring, until clear solution obtained.
Stage 3: Preparation of Water Phase and Soak Mixture
Added Carbomer phase of stage-1 into Water phase of stage-2. This mixture was heated up to 75-80°C.
Stage 4: Preparation of Oil phase
Batch quantity of Cetostearyl Alcohol, Cetomacrogol 1000, Light liquid paraffin, White soft paraffin, Propyl Paraben and Butylated Hydroxytoluene was charged into wax melting tank. Heated this mixture up to 80°C under continuous stirring (stirring for 20 mins).
Stage 5: Preparation of Drug phase
Weighed and added Propylene glycol in S.S. vessel followed by addition of Pregabalin slowly in vortex in continuous stirring and mixing till uniform dispersion is formed. (White slurry form).
Stage 6: Mixing phase
Added Water and Soak Mixture of stage 3 into main bulk tank under continuous stirring and maintained the temperature at 75-85°C. Added oil phase (temp 75-85°C) into main bulk tank under continuous stirring followed by adding the drug phase into main bulk tank under continuous stirring (stirring for 30 mins) at a temperature of 75-85°C. The weight was made up to 100 gm with Purified Water and stirring was continued till white homogeneous gel was formed.

Batch Observations and Results:
Table 2
Sr. No Test Trial-1 Trial-2 Trial-3
Initial Initial Initial
1 Appearance White colored thick gel White colored thick gel White colored very thick gel
2 pH 6.07 6.05 6.09
3 Pregabalin Assay 101.58% 102.14% 101.17%
4
Related Substances
i) Pregabalin Lactum Impurity 0.043% 0.061% 0.047%

Observation:

From above 3 trials, it was observed that Gel had thick consistency.
Trial -2 composition was considered for further optimization of formulation by reducing the gelling agent concentration.

Further trials were planned with 8 % of Cetostearyl Alcohol and 12% White soft paraffin and different concentration of Carbomer (Acrypol 980) 0.1%/ 0.2%/ 0.3%.

Experiment -4/5/6

Trial batches of Pregabalin Gel 8 % w/w with different concentration of Carbomer (Acrypol 980) for optimization of consistency of Gel.

Table 3
Sr. No. Material Trial-4 Trial-5 Trial-6
1 Pregabalin IP
(2% overages) 8.16 8.16 8.16
2 Carbomer Homopolymer Type C (Acrypol 980 IP) 0.10 0.20 0.30
3 Cetostearyl Alcohol IP 8.00 8.00 8.00
4 White soft paraffin IP 12.00 12.00 12.00
5 Cetomacrogol 1000 BP 2.00 2.00 2.00
6 Light liquid paraffin IP 6.00 6.00 6.00
7 Propylene Glycol IP 19.00 19.00 19.00
8 Disodium EDTA IP 0.10 0.10 0.10
9 Butylated Hydroxytoluene IP 0.02 0.02 0.02
10 Methylparaben IP 0.20 0.20 0.20
11 Propylparaben IP 0.02 0.02 0.02
11 Triethanolamine IP Qs Qs Qs
12 Purified Water IP 44.40
Qs to 100 g 44.30
Qs to 100 g 44.20
Qs to 100 g

Batch Manufacturing process:
Stage 1: - Preparation of Carbomer phase
Step- I: Soak Preparation
20.0 gm of Purified Water in a suitable S.S. container and heat to 75°C. Added Disodium EDTA to heated Purified Water and mixed under stirring until clear solution obtained. Weighed and added Carbomer Homopolymer Type C (Acrypol 980) in above mixture under continuous stirring and hydrated till uniform dispersion was obtained (stirring for 30 min). Kept aside overnight for soak.
Step-II: Neutralization process
Prepared 50% Triethanolamine solution (1:1 ratio of Purified Water and Triethanolamine). Checked the initial pH of soak and neutralized to obtain a pH of 5.3 (range- 5.0-5.5).
Stage 2: Preparation of Water phase
In suitable S.S. vessel weighed and added24.0 gm of Purified Water add Methylparaben in above Purified Water, heated up to 80-85 °C with continuous stirring, until clear solution was obtained.
Stage 3: Preparation of Water Phase and Soak Mixture
Added Carbomer phase of stage-1 into the water phase of stage-2 and heated the mixture up to 75-80°C.
Stage 4: Preparation of Oil phase
Batch quantity of Cetostearyl Alcohol, Cetomacrogol 1000, Light liquid paraffin, White soft paraffin, Propyl Paraben and Butylated Hydroxytoluene was charged in a wax melting tank. Heated this mixture up to 80°C under continuous stirring (stirring for 20 mins).
Stage 5: Preparation of Drug phase
Weighed and added Propylene glycol in S.S. vessel followed by addition of Pregabalin slowly in vortex stirring continuously and mixing till uniform dispersion was formed. (White slurry form).
Stage 6: Mixing phase
Added the Water and Soak Mixture of stage 3 into main bulk tank under continuous stirring and maintain the temperature 75-85°C. Added oil phase (temperature 75-85°C) into main bulk tank under continuous stirring followed by addition of drug phase into main bulk tank under continuous stirring (stirring for 30 mins) at a temperature of 75-85°C. Then weight was made up to 100 gm with Purified Water and stirred till white homogeneous gel was formed.
Batch Observations and Results:
Table 4
Sr. No Test Trial-4 Trial-5 Trial-6
Initial Initial Initial
1 Appearance White slightly thin gel White smooth gel White slightly thick gel
2 pH 6.50 6.35 6.10
3 Pregabalin Assay 101.19% 100.97% 100.68%
4 Related Substances
i) Pregabalin Lactum Impurity ND ND 0.041%

Trials were taken with different concentration of carbomer (Acrypol 980).
Trial -4 contains 8 % of Cetostearyl Alcohol, 12% White soft paraffin & Carbomer 0.1%
Trial -5 contains 8 % of Cetostearyl Alcohol, 12% White soft paraffin & Carbomer 0.2%
Trial- 6 contains 8 % of Cetostearyl Alcohol, 12% White soft paraffin & Carbomer 0.3%.

Observation:

From above 3 trials, it was observed that trial No-5 Gel had a smooth consistency.

Trial -5 composition i.e carbomer (Acrypol 0.2%) was taken for further optimization of formulation.

Experiment -5A
Scale up batches of Pregabalin Gel 8 % w/w of batch size 5 kg, as per Trial 5.
Table 5
Sr. No. Material Batch No.: SU/PG/001
5000 gm (5kg)
1 Pregabalin IP
(2 % Overages) 408.0 gm
2 Carbomer Homopolymer Type C (Acrypol -980 IP)
10.0 gm
3 Cetostearyl alcohol IP 400.0 gm
4 White soft paraffin IP 600.0 gm
5 Cetomacrogol -1000 BP 100.0 gm
6 Light liquid paraffin IP 300.0 gm
7 Propylene glycol IP 950.0 gm
8 Disodium EDTA IP 5.0 gm
9 Butylated Hydroxytoluene IP 1.0 gm
10 Methyl paraben IP 10.0 gm
11 Propyl Paraben IP 1.0 gm
12 Triethanolamine IP Q. S
13 Purified water IP Q.S to 5000 gm
(2215.0 gm)

Manufacturing process for 5.0 kg Batch:

Stage 1: - Preparation of Carbomer phase
Step-I: Soak Preparation
Took a batch quantity of 0.866 kg of Purified Water in a suitable S.S. container and heated to 75°C. Added 0.005 kg Disodium EDTA to above heated Purified Water and mixed under stirring until clear solution obtained. Added the weighed quantity 0.010 kg of Carbomer Homopolymer Type C (Acrypol 980) in above mixture under continuous stirring and hydrated till uniform dispersion obtained (stirring for 30 min). The dispersion was kept aside overnight for soaking.
Step-II: Neutralization process
Prepared 50% Triethanolamine solution (1:1 ratio of Purified Water and Triethanolamine). (Purified Water -8.0 gm and Triethanolamine -8.0 gm) and checked initial pH of soak. Added 50% diluted Triethanolamine to soak till pH of 5.3 is obtained. Checked the bulk pH (5.0- 5.5) preferably 5.3.

Stage 2: Preparation of Water phase
In suitable S.S. vessel added the weighed quantity 1.0 kg Purified Water. Added 0.01 kg Methylparaben in above Purified Water and heated up to 75-80°C with continuous stirring, until clear solution was obtained.
Stage 3: Preparation of Water Phase and Soak Mixture
Added Carbomer phase (stage 1) into Water phase (stage 2) and heated this mixture up to 75-80°C.
Stage 4: Preparation of Oil phase
Charged the following batch quantity of materials in wax melting tank as per sequence given below:
i. Cetostearyl Alcohol: - 0.400 kg
ii. Cetomacrogol 1000: - 0.100 kg
iii. Light liquid paraffin: -0.300 kg
iv. White soft paraffin: -0.600 kg
v. Propyl Paraben: -0.001 kg
vi. Butylated Hydroxytoluene: -0.001 kg
Heated this mixture up to 80°C under continuous stirring (stirring for 20 mins).

Stage 5: Preparation of Drug phase
Added 0.933 kg Propylene glycol in S.S. vessel followed by addition of 0.408 kg Pregabalin slowly in vortex under continuous stirring. Mixing was continued till a uniform dispersion was formed. (White slurry form).

Stage 6: Mixing phase
Added stage 3 into main bulk tank under continuous stirring by maintaining the temperature between 75-85°C.
Added the oil phase (temp 75-85°C) into main bulk tank under continuous stirring followed by addition of drug phase into main bulk tank under continuous stirring (stirring for 30 mins) at a temperature of 75-85°C.
Rinsed the drug phase S.S. vessel with 328.0 gm of Purified Water and 17.00 gm of Propylene glycol and added the rinsing to main tank under continuous stirring.
The weight was made up to 5.0 kg with Purified Water and stirred continuously for 5 min. (Note extra quantity of Purified Water required.)
Continued stirring till white smooth homogeneous gel was formed.

Table 6
Sr. No. Test B.No-SU/PG/001
Initial
1 Appearance White Smooth gel
2 pH 6.07
3 Pregabalin Assay 101.55 %
4
Related Substances
Pregabalin Lactum Impurity (Limit NMT 0.5%) 0.66 %

Further trials were taken with 8 % of Cetostearyl Alcohol and 12% White soft paraffin and Carbomer (Acrypol 980) 0.2%, by modifying the manufacturing process i.e addition of drug phase of Pregabalin in Propylene glycol (in slurry form) into the emulsion phase at different lower temperatures/ temperature ranges of emulsion viz. 50°C, 45°C and 40 °C instead of 75°C -85°C to control the impurity level.

Experiment -7/8/9
Trial batches of Pregabalin Gel 8 % w/w for addition of drug phase at different temperature (50°C/ 45°C/ below 40°C) of Emulsion Phase while manufacturing the batch to control the impurities.

Table 7
Sr. No. Material Trial-7
50? Trial-8
45? Trial-9
40?
1 Pregabalin IP
(2% overages) 8.16 8.16 8.16
2 Carbomer Homopolymer Type C (Acrypol 980 IP) 0.20 0.20 0.20
3 Cetostearyl Alcohol IP 8.00 8.00 8.00
4 White soft paraffin IP 12.00 12.00 12.00
5 Cetomacrogol 1000 BP 2.00 2.00 2.00
6 Light liquid paraffin IP 6.00 6.00 6.00
7 Propylene Glycol IP 19.00 19.00 19.00
8 Disodium EDTA IP 0.10 0.10 0.10
9 Butylated Hydroxytoluene IP 0.02 0.02 0.02
10 Methylparaben IP 0.20 0.20 0.20
11 Propylparaben IP 0.02 0.02 0.02
11 Triethanolamine IP Qs Qs Qs
12 Purified Water IP 44.30
Qs to 100 g 44.30
Qs to 100 g 44.30
Qs to 100 g
Batch Manufacturing process:

Stage 1: - Preparation of Carbomer phase
Step- I: Soak Preparation
20 .0 gm of Purified Water was taken in a suitable S.S. container and heated to 75°C. Added Disodium EDTA to heated Purified Water and mixed under stirring until a clear solution was obtained. Weighed and added Acrypol 980 in above mixture under continuous stirring and hydrated till uniform dispersion was obtained (stirring for 30 min). Kept aside overnight for soak.
Step-II: Neutralization process
Prepared 50% Triethanolamine solution (1:1 ratio of Purified Water and Triethanolamine). Checked initial pH of soak and neutralized to obtain pH of 5.3 (range- 5.0-5.5).

Stage 2: Preparation of Water phase
In suitable S.S. vessel weighed and added20 .0 gm of Purified Water. Added Methylparaben in Purified Water and heat up to 80-85 °C with continuous stirring, until clear solution was obtained.
Stage 3: Preparation of Water Phase and Soak Mixture
Added Carbomer phase of stage-1 into Water phase of stage-2. Heated this mixture up to 75-80°C.
Stage 4: Preparation of Oil phase
Batch quantity of Cetostearyl Alcohol, Cetomacrogol 1000, Light liquid paraffin, White soft paraffin, Propyl Paraben and Butylated Hydroxytoluene were charged in a wax melting tank. Heat this mixture up to 80°C under continuous stirring (stirring for 20 mins).
Stage 5: Preparation of Drug phase
Weighed and added Propylene glycol in S.S. vessel followed by addition of Pregabalin slowly in vortex with continuous stirring and mixing to obtain a uniform dispersion. (White slurry form).
Stage 6: Mixing phase
Added the Water Soak Mixture of stage 3 into main bulk tank under continuous stirring and maintained the temperature at 75-85°C. Added oil phase (temperature 75-85°C) into main bulk tank under continuous stirring followed by addition of drug phase into main bulk tank under continuous stirring (stirring for 30 mins) at respective temperature of emulsion phase 50°C/ 45°C /and 40°C. The weight was made up to 100 gm with Purified Water and stirred continuously till white homogeneous gel was formed.
Batch observations and Results:
Table 8
Sr. No Test Trial-7 Trial-8 Trial-9
Initial Initial Initial
1 Appearance White smooth gel White smooth gel White smooth gel
2 pH 6.16 6.25 6.13
3 Pregabalin Assay 100.18% 100.79% 99.29%
4
Related Substances
i) Pregabalin Lactum Impurity ND ND ND

The above trials were taken by modifying the manufacturing process i.e addition of drug phase at different temperature of emulsion phase.

Trial -7 contains 8 % of Cetostearyl Alcohol, 12% White soft paraffin &Carbomer 0.2%, where drug phase was added in emulsion phase when temperature of emulsion phase reached to 50°C.
Trial -8 contains 8 % of Cetostearyl Alcohol, 12% White soft paraffin & Carbomer 0.2%, where drug phase added in emulsion phase when temperature of emulsion phase reached to 45°C.
Trial- 9 contains 8 % of Cetostearyl Alcohol, 12% White soft paraffin & Carbomer 0.2%, where drug phase added in emulsion phase when temperature of emulsion phase reached to 40°C.
From above 3 trials, it was observed that Gel had smooth consistency.
Trials were kept for stability.
Observation:

Pregabalin Lactum impurity of Trial -7, 8 and 9 was Nil. (Not Detected)

It concludes that the temperature of the emulsion phase has an impact on the related substances of Pregabalin gel.

Trial -9 composition and manufacturing process were optimized for manufacturing of stability batches of Pregabalin gel 8% at CGMP area.

Table 9
Scale up & Stability
Batch No. ?
1
2
3
Sr. No. Material gm/100 gm gm/100 gm gm/100 gm
1 Pregabalin (with 2% overages) 8.16 (micronized) 8.16 (micronized) 8.16 (micronized)
2 Carbomer Homopolymer Type C (Acrypol 980) 0.20 0.20 0.20
3 Cetostearyl Alcohol 8.00 8.00 8.00
4 Cetomacrogol 1000 2.00 2.00 2.00
5 Light liquid paraffin 6.00 6.00 6.00
6 White soft paraffin 12.00 12.00 12.00
7 Propylene Glycol 19.00 19.00 19.00
8 Disodium EDTA 0.10 0.10 0.10
9 Butylated Hydroxytoluene 0.02 0.02 0.02
10 Methylparaben 0.20 0.20 0.20
11 Propylparaben 0.02 0.02 0.02
12 Triethanolamine Qs Qs Qs
13 Purified Water 44.00
Qs to 100 g 44.00
Qs to 100 g 44.00
Qs to 100 g

Example 3:

Manufacturing process for 5.0 kg Batch:
Stage 1: - Preparation of Carbomer phase
Step-I: Soak Preparation
Took a batch quantity of 0.866 kg of Purified Water in a suitable S.S. container and heated to 75°C. Added 0.005 kg Disodium EDTA to above heated Purified Water and mixed under stirring until clear solution obtained. Added the weighed quantity 0.010 kg of Carbomer (Carbomer Homopolymer Type C) (Acrypol 980) in above mixture under continuous stirring and hydrated till uniform dispersion obtained (stirring for 30 min). The dispersion was kept aside overnight for soaking.
Step-II: Neutralization process
Prepared 50% Triethanolamine solution (1:1 ratio of Purified Water and Triethanolamine). (Purified Water -8.0 gm and Triethanolamine -8.0 gm) and checked initial pH of soak. Added 50% diluted Triethanolamine to soak till pH of 5.3 is obtained. Checked the bulk pH (5.0- 5.5) preferably 5.3.

Stage 2: Preparation of Water phase
In suitable S.S. vessel added the weighed quantity 1.0 kg Purified Water. Added 0.01 kg Methylparaben in above Purified Water and heated up to 75-80°C with continuous stirring, until clear solution was obtained.
Stage 3: Preparation of Water Phase and Soak Mixture
Added Carbomer phase (stage 1) into Water phase (stage 2) and heated this mixture up to 75-80°C.
Stage 4: Preparation of Oil phase
Charged the following batch quantity of materials in wax melting tank as per sequence given below:
i. Cetostearyl Alcohol: - 0.400 kg
ii. Cetomacrogol 1000: - 0.100 kg
iii. Light liquid paraffin: -0.300 kg
iv. White soft paraffin: -0.600 kg
v. Propyl Paraben: -0.001 kg
vi. Butylated Hydroxytoluene: -0.001 kg
Heated this mixture up to 80°C under continuous stirring (stirring for 20 mins).

Stage 5: Preparation of Drug phase
Added 0.933 kg Propylene glycol in S.S. vessel followed by addition of 0.408 kg Pregabalin slowly in vortex under continuous stirring. Mixing was continued till a uniform dispersion was formed. (White slurry form).

Stage 6: Mixing phase
Added stage 3 into main bulk tank under continuous stirring by maintaining the temperature between 75-85°C.
Added the oil phase (temp 75-85°C) into main bulk tank under continuous stirring.
When temperature of emulsion phase reached to 45 °C, added the drug phase into main bulk tank under continuous stirring and mixing. (Approximately 30 Minutes).
Rinsed the drug phase S.S. vessel with 328.0 gm of Purified Water and 17.00 gm of Propylene glycol and added the rinsing to main tank under continuous stirring.
The weight was made up to 5.0 kg with Purified Water and stirred continuously for 5 min. (Note extra quantity of Purified Water required.)
Continued stirring till white smooth homogeneous gel was formed.

Example 4:
Stability Study:
The optimized formula of Pregabalin gel 8% w/w was subjected to stability studies. According to the stability protocol, three stability batches were incubated at accelerated stability at 40°C ± 2°C / 75% RH ± 5%RH and Real time stability at 30°C ± 2°C / 75% RH ± 5% RH to assess the stability of the optimized formula. Stability batches were taken using the same manufacturing process and specification of the respective reproducible batch.
Table 10
B.No. Specification Scale up & stability batch- 1
Initial (40°C / 75% RH) (30°C / 75% RH)
Test 3 Months 6 Months 6 Months 12 Months 24 Months
Description White to off white homogeneous gel White homogeneous gel White homogeneous gel White homogeneous gel White homogeneous gel White homogeneous gel White homogeneous gel
pH 5.0 to 7.5 6.12 6.27 6.32 6.36 6.45 6.50
Assay (By HPLC)
1. Pregabalin 90 - 110% of Label claim 102.00 102.70 102.34 102.68 99.12 99.93
2. Methyl Paraben 90 - 110% of Label claim 99.80 100.80 100.50 100.00 99.00 98.69
3. Propyl Paraben 90 - 110% of Label claim 100.00 99.20 98.90 98.20 98.30 97.21
Related Substances
1. Pregabalin Lactum Impurity NMT 0.5% Not Detected 0.14% 0.22% 0.038% 0.14% 0.28%
2. Any other individual Impurity NMT 1.0 % Not Detected Not Detected Not Detected Not Detected Not Detected Not Detected
3. Total Impurities other than Lactum Impurity NMT 2.5% NIL NIL NIL NIL NIL NIL
Microbial Limit Test
1. Total Viable Aerobic Count NMT 100 cfu/gm 45 cfu/gm 30 cfu/gm 35 cfu/gm 45 cfu/gm 35 cfu/gm
55 cfu/gm
2. Total combined yeast and mould count NMT 10 cfu/gm NIL NIL NIL NIL NIL
NIL
3. Pathogen
a.E.coli Should be absent/gm Absent Absent Absent Absent Absent
Absent
b. Salmonellae Should be absent/10gm Absent Absent Absent Absent Absent
Absent
c. Pseudomonas aeruginosa Should be absent/gm Absent Absent Absent Absent Absent
Absent
d. Staphylococcus aureus Should be absent/gm Absent Absent Absent Absent Absent
Absent

Table 11

B.No. Specification Scale up & stability batch - 2
Initial (40°C / 75% RH) (30°C / 75% RH)
Test 3 Months 6 Months 6 Months 12 Months 24 Months
Description White to off white homogeneous gel White homogeneous gel White homogeneous gel White homogeneous gel White homogeneous gel White homogeneous gel White homogeneous gel
pH 5.0 to 7.5 6.28 6.27 6.31 6.44 6.57 6.39
Assay (By HPLC)
1. Pregabalin 90 - 110% of Label claim 103.10 102.60 102.53 103.27 98.56 99.60
2. Methyl Paraben 90 - 110% of Label claim 97.30 100.00 99.90 100.10 98.90 98.38
3. Propyl Paraben 90 - 110% of Label claim 100.30 98.60 98.80 98.70 98.60 97.47
Related Substances
1. Pregabalin Lactum Impurity NMT 0.5% Not Detected 0.16% 0.22% 0.044% 0.118% 0.205%
2. Any other individual Impurity NMT 1.0 % Not Detected Not Detected Not Detected Not Detected Not Detected Not Detected
3. Total Impurities other than Lactum Impurity NMT 2.5% NIL NIL NIL NIL NIL NIL
Microbial Limit Test
1. Total Viable Aerobic Count NMT 100 cfu/gm 35 cfu/gm 50 cfu/gm 55 cfu/gm 40 cfu/gm 40 cfu/gm
35 cfu/gm
2. Total combined yeast and mould count NMT 10 cfu/gm NIL NIL NIL NIL NIL
NIL
3. Pathogen
a.E.coli Should be absent/gm Absent Absent Absent Absent Absent
Absent
b. Salmonellae Should be absent/10gm Absent Absent Absent Absent Absent
Absent
c. Pseudomonas aeruginosa Should be absent/gm Absent Absent Absent Absent Absent
Absent
d. Staphylococcus aureus Should be absent/gm Absent Absent Absent Absent Absent
Absent

Table 12

B.No. Specification Scale up & stability batch - 3
Initial (40°C / 75% RH) (30°C / 75% RH)
Test 3 Months 6 Months 6 Months 12 Months 24 Months
Description White to off white homogeneous gel White homogeneous gel White homogeneous gel White homogeneous gel White homogeneous gel White homogeneous gel White homogeneous gel
pH 5.0 to 7.5 6.18 6.26 6.28 6.45 6.54 6.40
Assay (By HPLC)
1. Pregabalin 90 - 110% of Label claim 103.20 102.70 101.27 102.51 99.02 98.98
2. Methyl Paraben 90 - 110% of Label claim 99.90 100.20 100.00 100.40 99.20 98.29
3. Propyl Paraben 90 - 110% of Label claim 99.90 97.60 97.70 98.40 99.00 97.11
Related Substances
1. Pregabalin Lactum Impurity NMT 0.5% Not Detected 0.16% 0.227% 0.041% 0.130% 0.222%
2. Any other individual Impurity NMT 1.0 % Not Detected Not Detected Not Detected Not Detected Not Detected Not Detected
3. Total Impurities other than Lactum Impurity NMT 2.5% NIL NIL NIL NIL NIL NIL
Microbial Limit Test
1. Total Viable Aerobic Count NMT 100 cfu/gm 40 cfu/gm 50 cfu/gm 55 cfu/gm 45 cfu/gm 50 cfu/gm
30 cfu/gm
2. Total combined yeast and mould count NMT 10 cfu/gm NIL NIL NIL NIL NIL
NIL
3. Pathogen
a.E.coli Should be absent/gm Absent Absent Absent Absent Absent
Absent
b. Salmonellae Should be absent/10gm Absent Absent Absent Absent Absent
Absent
c. Pseudomonas aeruginosa Should be absent/gm Absent Absent Absent Absent Absent
Absent
d. Staphylococcus aureus Should be absent/gm Absent Absent Absent Absent Absent Absent

Conclusion:
After storage at 6 Months Accelerated stability at 40°C ± 2°C / 75% RH ± 5% RH and 24 Months long term stability at 30°C ± 2C / 75% RH ± 5% RH the Physical, Microbiological and Chemical stability of the product was well within limits and was satisfactory.

Pre-Clinical Study
The toxicity studies were conducted at Accuprec Research Labs Pvt. Ltd. which is approved for experiment on laboratory animals by Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA, New Delhi)

Example 5
ACUTE DERMAL TOXICITY STUDY
Acute Dermal Toxicity study test has been conducted through IAEC Protocol No. ARL/PT/176/2021
Test:
Pregabalin Gel 8% w/w was tested for Acute Dermal Toxicity Study in Wistar rats according to OECD guideline402; compliance with the requirements of OECD GLP.
Results:
Based on the results, single dermal application of ‘Pregabalin Gel 8% w/w’ in female Wistar rats at a dose level up to 2000mg/kg b.wt. did not produce any toxicity and any mortality under the conditions and procedures followed in the present study. Hence, considering globally harmonized system (GHS) for the classification of chemicals, the test item was classified under Category 5 or unclassified which anticipate that the LD50 of test item is not less than or equal to 2000mg/kg body weight.

Example 6
SUB -ACUTE DERMAL TOXICITY STUDY
28 Days Toxicity study test has been conducted through IAEC Protocol No. ARL/PT/543/2021
Test:
Pregabalin Gel 8% w/w was tested for repeated dose 28 days Dermal Toxicity Study in New Zealand White rabbits as per New Drugs and Clinical Trials Rules 2019 in compliance with the requirements of OECD GLP.
Results:
Based on the results, it could be concluded that the test item “Pregabalin Gel 8 % did not show any local reaction like signs of erythema and edema and did not produce any systemic toxicity or adverse effects upto the highest dose level (93mg/10cm2when applied topically for 28 consecutive days, under the conditions and procedures followed in the present study.
Based on the findings, the No Observed Adverse Effect Level (NOAEL) of ‘Pregabalin Gel 8% w/w was 93mg/10cm2in New Zealand White rabbits.

Example 7
SUB -ACUTE DERMAL TOXICITY STUDY
28 Days Toxicity study test has been conducted through IAEC Protocol No. ARL/PT/547/2021

Test:
Pregabalin Gel 8% w/w was tested for repeated dose 28 days Dermal Toxicity Study in Wistar Rats as per New Drugs and Clinical Trials Rules 2019 in compliance with the requirements of OECD GLP.
Results:
Based on the results, it could be concluded that the test item “Pregabalin Gel 8 % did not show any local reaction like signs of erythema and edema and did not produce any systemic toxicity or adverse effects upto the highest dose level (93mg/10cm2) when applied topically for 28 consecutive days, under the conditions and procedures followed in the present study.

Example 8
PHASE III CLINICAL STUDY
A phase III randomized, double blinded, double dummy, parallel group, placebo controlled, two arm, multicenter clinical study to evaluate the safety and efficacy of Pregabalin Gel 8 % w/w in comparison with Pregabalin Capsule as a standard of care in patients with diabetic neuropathic pain.
Test Arm (Group A): Pregabalin Gel 8 % w/w with Placebo Capsule.
Comparator Arm (Group B): Standard of care (Pregabalin Capsule) with Topical Placebo Gel.
Given the trend towards using topical medications to treat DNP, the present study SCR/001/PGB/2022 – Pregabalin Gel 8% w/w provides a promising option for the treatment of DNP. It gives information about the current knowledge regarding the physiopathology of DNP and the use of an effective option of topical pharmacological treatments.

PRIMARY END POINTS: As per analysis the change in mean VAS (Visual Analogue Scale) at baseline, after 8days, 36 days and 63 days of treatment was comparable between groups and the difference was not significant.

SECONDARY END POINTS:
According to the analysis, 43.1% of cases among Group A had =50% change in Leeds Assessment of Neuropathic Symptoms which was less as compared to 52.3% of cases among Group B, but the difference was not significant.

LABORATORY PARAMETERS:
All Hematology parameters and Biochemistry parameters were comparable at baseline and the difference was not significant. If compared the mean change in all treatment groups were comparable and the difference was not significant

OBSERVATIONS FROM CURRENT STUDY FINDINGS:
• The results demonstrated a progressive reduction in VAS scores with both topical and oral Pregabalin.
• With topical Pregabalin by 8 days of treatment 37.1% reduction in pain scores, 57.3% reduction in pain scores by day 36 and 73.8% reduction in pain scores by day 63. This indicates pain relief progressively increases over 2 months with topical Pregabalin without the need for adding oral Pregabalin underscoring the efficacy of topical Pregabalin and no development of tolerance to the analgesic effect of Pregabalin over long term use.
• The Leeds assessment of neuropathic symptoms and signs (LANSS) Pain Scale is based on analysis of sensory description and bedside examination of sensory dysfunction, and provides immediate information in clinical settings. It was developed in two populations of chronic pain patients (in patients with nociceptive and neuropathic pain, combined with an assessment of sensory function). In the current study both the treatment groups had comparable responders to the treatments and reduction in symptoms in the Leeds Pain scale.
These results indicate that topical Pregabalin is pharmacodynamically comparable in terms of reduction of neuropathic pain to oral Pregabalin.

• Assessment of the Patient’s global impression of pain indicated that 33.0% of cases among Group A had Moderately better, and a slight but noticeable change which was numerically (insignificant) more as compared to 24.3% cases among Group B.43.1% patients had definite improvement in the topical Pregabalin arm as compared to 43% in the oral Pregabalin arm. These findings indicate that the patient’s perception of pain relief was comparable with both topical and oral Pregabalin
• The CGI provides an overall clinician-determined summary measure that takes into account all available information, including a knowledge of the patient's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the patient's ability to function. In practice, the CGI captures clinical impressions that transcend mere symptom checklists the CGI can track clinical progress across time. The clinician makes a judgment about the total picture of the patient at each visit: the illness severity, the patient's level of distress and other aspects of impairment, and the impact of the illness on functioning. Evaluation of the Physicians’ global impression of pain relief indicated that both the treatment groups had comparable results in the CGI scale.
• In the quality-of-life domains, lesser number of patients had pain worsened by washing / showering / shaving as compared to oral Pregabalin. Topical Pregabalin also relieved tingling, numbness, feeling of cold sensation in the painful area. This relief was comparable to oral Pregabalin.
• 9.1% of the cases among Group B had Somnolence which was significantly more as compared to 2.7% of cases among Group A. This indicates that topical Pregabalin group had lower adverse effects as compared to oral Pregabalin. The expected key benefit of topical Pregabalin of lower adverse effects were confirmed in the current study.
• A greater number of patients in the topical Pregabalin group had less interference with daily work after treatment. Personal care improved comparably in all domains between the treatment groups.
The study concludes that Management of Diabetic Neuropathic Pain is often challenging and may require a multimodal approach. Oral Pregabalin has been demonstrated to relieve neuropathic pain in several clinical trials. But oral Pregabalin is associated with adverse effects such as dizziness, somnolence which interfere with daily activities.
The topical formulation of Pregabalin is expected to be better tolerated as it would undergo minimal systemic absorption after application.
The current study findings have proved that topical Pregabalin has analgesic efficacy comparable to oral Pregabalin (Non-inferior) but it is better tolerated. Topical Pregabalin was associated with significantly lesser somnolence as compared to oral Pregabalin.
Topical Pregabalin effectively balances analgesic efficacy with safety and improved tolerability profile as compared to oral Pregabalin over 63 days. Topical Pregabalin can be expected to improve patient adherence to treatment and thus would lead to improved pain relief and improved quality of life of the patients with diabetic neuropathic pain. No tolerance develops to the analgesic effects of topical Pregabalin. Topical Pregabalin retains its analgesic efficacy over long term use. Topical Pregabalin will be a useful addition to the therapeutic armamentarium of diabetic neuropathic pain.

CLAIMS:

1. A stable topical pharmaceutical composition comprising Pregabalin or its pharmaceutically acceptable derivatives in an amount of 8% w/w of the total composition along with one or more pharmaceutically acceptable excipients.

2. The stable topical pharmaceutical composition as claimed in claim 1, wherein the particle size of Pregabalin is in the range of 10 to 50 µm.

3. The stable topical pharmaceutical composition as claimed in claim 1 and 2, in the form of a Gel.

4. The stable topical pharmaceutical composition as claimed in claim 1, wherein one or more pharmaceutically acceptable excipients are selected from neutralizing agents, gelling agents, emulsifying agents, emollient bases, chelating agents, antioxidants, preservatives and vehicles and cosolvents.

5. The stable topical pharmaceutical composition as claimed in claim 4, wherein the neutralizing agents is selected from Sodium hydroxide (NaOH), Potassium hydroxide (KOH), Triethanolamine (TEA), Ammonia (28%) in amount ranging from 0.01 to 0.3%.

6. The stable topical pharmaceutical composition as claimed in claim 4, wherein the gelling agent is selected from the group consisting of Carbomer (Carbomer Homopolymer Type C), Xanthan Gum, Veegum, Hydroxypropyl Cellulose, Hydroxymethyl cellulose, Hydroxyethyl cellulose, Carboxymethyl Cellulose or their mixtures in amount ranging from 0.1% to 0.5%.

7. The stable topical pharmaceutical composition as claimed in claim 4, wherein the emulsifying agent is selected from the group consisting of Cetostearyl Alcohol, Cetomacrogol 1000, Cetyl Alcohol, Polysorbate 80, polysorbate 60, Sorbitan monooleate or their mixtures in amount ranging from 1% to 10%.

8. The stable topical pharmaceutical composition as claimed in claim 4, wherein the emollient bases isselected from the group consisting of White Soft paraffin, Light liquid paraffin, Hard paraffin or their mixtures in amount ranging from 5% to 15%.

9. The stable topical pharmaceutical composition as claimed in claim 4, wherein the chelating agents is from the group consisting of Disodium EDTA, Calcium Disodium EDTA in amount ranging from 0.05% to 1 %.

10. The stable topical pharmaceutical composition as claimed in claim 4, wherein the antioxidant is selected from the group consisting of Butylated Hydroxytoluene, Butylated Hydroxy Anisole, Vitamin C, Vitamin E in amount ranging from 0.01% to 0.05%.

11. The stable topical pharmaceutical composition as claimed in claim 4, wherein the preservative is selected from the group consisting of Benzyl Alcohol, Methyl paraben, Propyl Parabenor their mixtures in amount ranging from 0.01 to 0.3%.

12. The stable topical pharmaceutical composition as claimed in claim 4, wherein the vehicles and cosolvents are selected from Propylene Glycol, Glycerine and purified water or their mixtures in an amount ranging from 5% to 50%.

13. A stable topical pharmaceutical composition comprising 8%w/w of Pregabalin, 0.2%w/w of Carbomer (Carbomer Homopolymer Type C), 8% w/w of Cetostearyl Alcohol, 2%w/w of Cetomacrogol 1000, 6%w/w of Light liquid Paraffin, 12%w/w of White soft paraffin, 19% w/w of Propylene glycol, 0.10 % w/w of Disodium EDTA, 0.02 % w./w of Butylated hydroxytoluene, 0.20 % of Methyl Paraben, 0.02 % Propyl Paraben and Triethanolamine.

14. A process to prepare 8% w/w Pregabalin Gel stable topical pharmaceutical composition comprising:
Stage 1: - Preparation of Carbomer phase
Step- I: Preparation of the Soak
Adding Disodium EDTA to the heated Purified Waterandmixing to form a clear solution followed by addition of Carbomer(Carbomer Homopolymer Type C) under continuous stirring and hydrating till uniform dispersion is obtained and is soaked overnight.
Step-II: Neutralization process
Neutralizing the soak obtained in Step 1 with the 50% Triethanolamine solution to obtain a pHrange between 5.0 to 5.5.

Stage 2: Preparation of the Water phase
Adding Methyl paraben in purified water by heating the solution up to 75 -80? with continuous stirring, to obtain a clear solution.

Stage 3: Preparation of the Water and Soak Mixture
Mixing together the Soak prepared in Stage 1 and the Water Phase prepared in Stage 2 and heating the mixture of upto 75-80°C to obtain the Water Phase Soak Mixture.

Stage 4: Preparation of the Oil phase
Heating Cetostearyl Alcohol, Cetomacrogol 1000, Light liquid paraffin, White soft paraffin, Propyl paraben and Butylated Hydroxytoluene and heating the mixture upto 80°C under continuous stirring.

Stage 5: Preparation of the Drug phase
Adding Pregabalin slowly in vortex under continuous stirring into Propylene Glycol and mixing till a uniform dispersion is formed. (White slurry form).
Stage 6: Mixing phase
i) Adding the Water phase Soak mixture of Stage 3 under continuous stirring and maintaining the temperature between 75°C -85°C;
ii) Adding Oil phase (temperature 75°C -85°C) of Stage 4 into Water phase Soak mixture under continuous stirring;
iii) Adding the Drug phase of Stage 5 under continuous stirring in the mixture of step ii at temperature 40°C -50°C of emulsion;
iv) Adjusting the weight to the desired batch weight with Purified Water and stirring continuously till a white smooth homogeneous gel is formed.

15. The topical pharmaceutical composition as claimed in claims 1 to 13 comprising NMT 0.5 % of Pregabalin Lactum Impurity.

16. Use of the topical pharmaceutical composition comprising Pregabalin 8% w/w for treating Diabetic Neuropathic pain

17. The method of treating Diabetic Neuropathic Pain comprising applying the topical pharmaceutical composition as claimed in any one of the claims 1 to 13.