DESC:Present invention relates to a topical pharmaceutical formulations comprising of Crisaborole or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients and processes for the preparation of the pharmaceutical composition.
Present invention is to provide a stable topical pharmaceutical formulation comprising Crisaborole or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients wherein the classes of excipients are solvents, stiffening agents, stabilizers, emulsifier, antioxidants, and ointment base.
Present invention is to provide a stable topical pharmaceutical formulation comprising Crisaborole or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients wherein the excipients are selected from group of propylene glycol, hard paraffin, edetate calcium disodium, glyceryl mono stearate, antioxidants and ointment base.
Present invention is the process of preparation of a stable topical pharmaceutical formulation comprising Crisaborole or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients
Present invention is to provide a stable topical pharmaceutical formulation comprising Crisaborole or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients where in the topical formulation used for the treatment of atopic dermatitis.
The term "composition" or "formulation" or "dosage form" has been employed interchangeably for the purpose of the present invention and mean that it is a pharmaceutical composition which is suitable for administration to a patient or subject.
The subject can be an animal, preferably a mammal, more preferably a human. For the purpose of the present invention terms "immediate release" or "sustained release" or "extended release" or "prolonged release" have been used interchangeably and mean broadly that Crisaborole.
The term “pharmaceutically acceptable” as used herein means that which is useful in preparing a pharmaceutical composition that is generally safe and non-toxic.
The term “excipients” as used herein means a component of a pharmaceutical product that is not an active ingredient such as, for example, fillers, diluents, carriers and the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.
By the term “composition” as used herein refers to a topical formulation like ointments, cream, emulsion, lotions, lacquers, concentrate solution and gels.
According to the embodiments of the present invention, emulsifiers are selected from ethylene glycol monostearate, sorbitan tristearate, a mixture of PEG-6 stearate, glycol stearate and PEG-32 stearate and hydrogenated lecithin, ceto stearyl alcohol.
According to the embodiments of the present invention, surfactants are selected from the mono-olein sorbitan / propylene glycol oleate, Cs / Cw fatty acid mono- and diglycerides from coconut oil, soy lecithin, egg phosphatide, citric acid esters of monoglycerides, monoglyceride lactic acid esters, sucrose fatty acid esters, oleic acid polyglycolated glycerides, linoleic acid polyglycolated glycerides, fatty acid polyglycerol esters, including both long and medium chain fatty acids and these of polyglyceryl fatty acids of mixed fatty acids, and mixtures thereof. Preferably, the surfactants are polyglycolized glycerides of oleic acids, polysorbate 60 Glyceryl Mono Stearate.
According to the embodiments of the present invention, emollients are selected from white soft paraffin, fatty acids with 8 to 30 carbon atoms, fatty alcohols with 8 to 30 carbon atoms, fatty acid esters with from 8 to 30 carbon atoms, fatty acid amides with 8 to 30 carbon atoms, silicone waxes, and mixtures thereof. Preferably, low melting waxes are fatty alcohols with 8 to 30 carbon atoms. More preferably, a stearyl alcohol is selected from the fatty alcohols.
According to the embodiments of the present invention, water-dispersible or Solubilizer components are selected from polyethylene glycol 400, hexylene glycol, propylene glycol, methyl glycol ether, polypropylene glycol-10, ethoxydiglycol, capric / caprylic glyceride polyethylene glycol-6, monobutyl ether ethylene glycol, polyethylene glycol-8, capric / caprylic glycerides, 3-methoxy-3-methyl-1-butanol, dimethyl isosorbide and mixtures thereof. Preferably, the water-dispersible component is propylene glycol.
According to the embodiments of the present invention, antimicrobial preservatives are selected from polyethylene glycol 400, hexylene glycol, propylene glycol, benzoic acid, methyl glycol ether, polypropylene glycol 10, glycol ethoxy, capric / polyethylene glycol 6 caprylic glyceride, monobutyl ether ethylene glycol, polyethylene glycol 8 capric / caprylic glycerides, 3-methoxy-3-methyl-1-butanol, dimethyl isosorbide, Butylated Hydroxy Toluene and mixtures thereof.
According to the embodiments of the present invention a stabilizer/chelating agents is an excepients which would form stable water-soluble complexes with alkaline earth and heavy metal ions which are the cause for the degradation of the product and causes the increase in the level of impurities some of examples of stabilizers/chelating agents are ethylene diaminetetra acetic acid (EDTA), nitrilotriacetic acid, n-hydroxy ethylethylene diaminetriacetic acid (HEDTA), Edetate Calcium Disodium, hemoglobin, Chlorophyll, as well as several simple organic acids like Oxalic acid, Malic acid. Rubeanic acid and Citric acid.
According to the embodiments of the present invention an Ointment base is the wax that suitable for the dispersion topical drug for getting long-term of exposure of the affected area when applied the ointment bases examples are hard paraffin, soft paraffin bees wax steryl alcohol etc some of these waxes can also act as stiffening agents based on the concentration used in the formulation.
In one of the embodiments of the invention provides a stable topical pharmaceutical formulation comprising Crisaborole or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.
In one of the embodiments of the invention is to provide a stable topical pharmaceutical formulation comprising Crisaborole or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients wherein the classes of excipients are solvents, stiffening agents, stabilizers, emulsifier, antioxidants, and ointment base.
In one of the embodiments of the invention is the process of preparation of a stable topical pharmaceutical formulation comprising Crisaborole or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients
In one of the embodiments of the invention is to provide a stable topical pharmaceutical formulation comprising Crisaborole or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients wherein the excipients are selected from group of propylene glycol, hard paraffin, edetate calcium disodium, glyceryl mono stearate, white soft paraffin and hard paraffin.
In one of the embodiments of the invention is to provide a stable topical pharmaceutical formulation comprising Crisaborole or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients wherein the excipients are propylene glycol about 9%, hard paraffin 4%, edetate calcium disodium 0.0035%, glyceryl mono stearate 7%, white soft paraffin 78% and hard paraffin 4%.
In one of the embodiments of the invention relates to a process of preparation of a topical formulation of Crisaborole by dispensing the required quantity of glyceryl mono stearate, hard paraffin and white soft paraffin under stirring to get clear solution, add required quantity of butylated hydroxy Toluene, edetate calcium disodium to the above process and mix Crisaborole, perform the homogenization and cool the process, under stirring until a homogenous ointment is obtained.
Examples
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention

Example 1
Manufacturing Formula:
S. No. Ingredients Quantity (mg)
per 1000 mg % w/w
1. Crisaborole 20.00 2.000
2. Butylated Hydroxy Toluene 1.00 0.100
3. Edetate Calcium Disodium 0.035 0.0035
4. Propylene Glycol 90.00 9.000
5. Glyceryl Mono Stearate 70.00 7.000
6. Hard Paraffin 40.00 4.000
7. White Soft Paraffin 778.965 77.8965
Total 1000.00 100.00

Manufacturing Process:
Preservative Phase
i. Weigh required quantities of Glyceryl Mono Stearate, Hard Paraffin and White Soft Paraffin, transfer to SS vessel and heat at 75 ± 5 °C (70 °C to 80 °C) under stirring to get clear solution.
ii. Add required quantity of Butylated Hydroxy Toluene into step i and dissolve at 75 ± 5 °C (70 °C to 80 °C) under stirring to get clear solution.
iii. Cool down contents of step ii at 45 ± 5 °C (40 °C to 50 °C) under stirring.
Drug Solution Phase
iv. Weigh and add 9/10th of Propylene Glycol into another SS vessel and heat at 45 ± 5 °C (40 °C to 50 °C) under stirring. Remaining 1/10th of Propylene Glycol will be used for rinsing purpose.
v. Add required quantity of Edetate Calcium Disodium to step iv and disperse at 45 ± 5 °C (40 °C to 50 °C) under stirring.
vi. Add required quantity of Crisaborole into step v under stirring at 45 ± 5 °C (40 °C to 50 °C) to get clear solution.
Mixing and Homogenization
vii. Add drug solution phase step vi into step iii. Rinse step vi container using remaining 1/10th of propylene glycol.
viii. Homogenize step vii for 10 minutes under stirring at 45 ± 5 °C (40 °C to 50 °C).
Cooling
ix. Cool down step viii to 25 °C to 30 °C under stirring until a homogenous ointment is obtained.

Example: 2
Manufacturing Formula:
S. No. Ingredients Quantity (mg) per 1000 mg % w/w
1. Crisaborole 20.00 2.000
2. Propylene Glycol 90.00 9.000
3. Butylated Hydroxy Toluene 1.00 0.100
4. Mono- and Di-Glycerides 70.00 7.000
5. Stearyl Alcohol 50.00 5.000
6. White Petrolatum 768.965 76.8965
7. Edetate Calcium Disodium 0.035 0.0035
Total 1000.00 100.00

Manufacturing Process:
Oil Phase
i. Weigh required quantity of Mono- and Di-Glycerides, Stearyl Alcohol and White Petrolatum, transfer to SS vessel and heat at 70 °C to 80 °C to under stirring.
ii. Add required quantity of Butylated Hydroxy Toluene into step i and dissolve at 70 °C to 80 °C.
iii. Cool down contents of step ii under stirring at 40 °C to 50 °C.
Drug Solution Phase
iv. Weigh required quantities of Edetate Calcium Disodium and Propylene glycol into another SS vessel and heat at 40 °C to 50 °C under stirring.
v. Add required quantity of Crisaborole into step iv and dissolve at 40 °C to 50 °C under stirring.
Mixing and Homogenization
vi. Filter drug solution phase step v through 80 mesh filter and add into step iii.
vii. Homogenize step vi for 10 minutes under stirring at 40 °C to 50 °C.
viii. After homogenization, cool down step vii to 25 °C under stirring until a homogenous ointment is obtained.

Filling and Sealing
Fill the ointment into laminate tubes and seal the filled tubes.
,CLAIMS:1) A stable topical formulation comprising Crisaborole or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, where in the composition comprising Crisaborole about 0.5-3%
a) butylated hydroxy toluene about 0.10-1%
b) edetate calcium disodium about 0.035-1%
c) propylene glycol about 6-10%
d) glyceryl mono stearate about 5-9%
e) hard Paraffin about 2-7%
f) white soft paraffin about 60-80%.

2) The stable topical formulation as claimed in claim 1, where in the composition is a topical composition of cream or lotion or gel or ointment.

3) The process of the preparation of stable topical formulation of Crisaborole as claimed in claim 1, wherein the process comprises the steps of dispensing the required quantity of glyceryl mono stearate, hard paraffin and white soft paraffin under stirring to get clear solution, add required quantity of butylated hydroxy toluene, edetate calcium disodium to the above process and mix Crisaborole, perform the homogenization and cool the process, under stirring until a homogenous ointment is obtained.