DESC:Field of Invention:
The present invention provides a novel drug delivery composition comprising Dydrogesterone to overcome the problems associated with conventional drug delivery system and more particularly to provide a stable parenteral formulation comprising Dydrogesterone and pharmaceutically acceptable excipients for effective 5 treatment of female associated reproductive cycle disorders.
Background of the invention:
Dydrogesterone is a synthetic hormone and have similar activity as that of natural hormone progesterone therefore it acts as a selective progesterone receptor agonist. Since dydrogesterone structurally and pharmacologically similar to natural 10 progesterone, it is often used to treat progesterone deficiency. It helps in maintaining of pregnancy and in normal shedding of endometrial lining during menstrual period, thus it is indicated for irregular menstrual cycle, infertility, recurrent miscarriages and has no effect on ovulation process. Dydrogesterone is clinically approved since 40 years and found to be safe and have better tolerability profile. Oral Dydrogestrone is 15 marketed as DUPHASTON which is available in 10 and 20 mg tablet.
The use of oral Dydrogesterone is already known in the art and has been used since many years. Conventionally formulated Dydrogesterone is limited to oral dosage form only, however oral drug delivery has certain limitation such as:
„h It delays the onset of action as first drugs get absorbed and then transported 20 through bloodstream to target site.
„h Oral delivery may contraindicate with people having gastrointestinal disorder.
„h The absorption of drugs may get affected by certain factors such as presence of food, other drugs.
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„h Absorption of certain drugs via gastric or intestinal mucosa may causes undesirable side effects such as nausea, vomiting, abdominal pain, constipation, and diarrhea.
Thus there is a need in the art to provide a novel drug delivery system of Dydrogesterone which overcome the disadvantages associated with oral dosage 5 forms for the effective treatment of disorders associated with progesterone deficiency. Accordingly, to overcome the difficulties associated with oral drug delivery, the present invention provides an alternative drug delivery system for Dydrogesterone and wherein the alternative delivery system is delivery of Dydrogesterone in parenteral form. The parenteral drug delivery of the present 10 invention provides rapid onset action with improved bioavailability, surpass first pass metabolism, and can be easily administered to unconscious patient and patient who have difficulty in swallowing oral dosage forms.
Objective:
An objective of the present invention provides a pharmaceutical composition 15 comprising dydrogesterone for effective treatment of conditions associated with progesterone deficiency more particularly for effective treatment of female reproductive cycle disorder such as irregular menstruation, infertility, premenstrual syndrome, dysmenorrhea, endometriosis, or miscarriages.
Another objective of the present invention is to provide a novel drug delivery system 20 comprising Dydrogesterone and pharmaceutically acceptable excipients to overcome the problems associated with oral drug delivery system.
Yet another objective of the present invention provides a novel parenteral pharmaceutical composition comprising Dydrogesterone and pharmaceutically
4
acceptable excipients for effective treatment of conditions associated with progesterone deficiency.
Summary:
The present invention provides a drug delivery system comprising Dydrogesterone. The present invention provides a solution to address the problems associated with 5 oral dosage form. In an aspect, the present invention is directed to pharmaceutical composition for parenteral administration, comprising Dydrogesterone or pharmaceutically acceptable salt as the active ingredient. In another embodiment, the present invention provides a process of preparation of present parenteral formulation. 10
In another embodiment, the present invention provides a stable parenteral composition comprising Dydrogesterone wherein parenteral drug delivery can be administered in form of intravenous, intramuscular, subcutaneous, intradermal, intra-arteria, intraperitoneal injection.
In yet another embodiment, the present invention provides a novel parenteral 15 composition comprising Dydrogesterone in form of dry powder, solution, suspension and emulsion.
Description
Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that 20 the present disclosure includes all such variations and modifications. The disclosure also includes all such compositions, components of the composition, referred to or indicated in this specification, individually or collectively and all combinations of any or more of such components or composition.
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5
Definitions
For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have their meanings recognized and 5 known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
The articles ¡§a¡¨, ¡§an¡¨ and ¡§the¡¨ are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. 10
The terms ¡§comprise¡¨ and ¡§comprising¡¨ are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as ¡§consists of only¡¨.
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Throughout this specification, unless the context requires otherwise the word ¡§comprise¡¨, and variations such as ¡§comprises¡¨ and ¡§comprising¡¨, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.
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The term ¡§including¡¨ is used to mean ¡§including but not limited to¡¨. ¡§Including¡¨ and ¡§including but not limited to¡¨ are used interchangeably.
Unless defined 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 this 25 disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the
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preferred methods, and materials are now described. All publications mentioned herein are incorporated herein by reference.
The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. 5 Functionally equivalent products and processes are clearly within the scope of the disclosure, as described herein.
The term ¡§pharmaceutical composition¡¨ refers to delivery system in which active agents are delivered to the patients. This could be in the form of tablet, capsule, 10 injection, liquid etc.
The term ¡§pharmaceutically acceptable excipient¡¨ refers to inert substances other than active ingredients which are used in the preparation of pharmaceutical products.
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The term ¡§parenteral¡¨ refers to drug delivery system in which the active agent(s) are directly administered into blood stream in form of injection surpassing first pass metabolism.
The term ¡§excipients¡¨ as used herein means a component of a pharmaceutical product that is not an active ingredient. The excipients that are useful in preparing a 20 pharmaceutical composition are generally safe and non-toxic. The present invention relates to novel drug delivery system comprising Dydrogesterone and pharmaceutical acceptable salts thereof and process of manufacturing thereof.
The term ¡§solubilizing agents¡¨ as used herein means to include, solubilizers, co-solubilizers, surfactants, co-surfactants and likes thereof. 25
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In an embodiment the present invention provides a stable parenteral formulation comprising dydrogesterone or pharmaceutical acceptable salts thereof to overcome the limitations associated with oral drug delivery system. The stable parenteral composition provides rapid onset of action, improved bioavailability and patient compliance for those who are unable to swallow tablet or patient who is suffering 5 from nausea and vomiting.
In an another embodiment, the present invention provides a stable parenteral formulation for the treatment of disorders or conditions associated with progesterone deficiency more preferably for the treatment of irregular menstrual cycle, premenstrual syndrome, infertility, menstrual distress (Dysmenorrhea), 10 miscarriages, dysfunctional uterine bleeding or other female related reproductive cycle disorders.
In an embodiment the novel dosage form comprising Dydrogesterone as an active agent and pharmaceutically acceptable excipients wherein said novel dosage form being suitable for parenteral administration. 15
In an another embodiment parenteral formulation are suitable in form of intravenous, intramuscular, subcutaneous, intradermal, intra-arterial administration.
In an embodiment the parenteral formulation can be present in form of aqueous or non-aqueous solution, emulsion, suspension, dry powder or lyophilized powder. In a preferred embodiment the parenteral formulation is present in the form of aqueous 20 solution.
In an embodiment the parenteral formulation can be present in the form of vial, ampoule, pre-filled syringe or the likes thereof.
In an another embodiment the present formulation comprises pharmaceutical acceptable excipients selected from stabilizer, pH regulator, buffering agents, 25
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solvents, chelating agents, antioxidants, preservatives, surfactants, tonicity modifying agents, dispersing agents.
In a preferred embodiment the present formulation comprises excipient selected from solubilizing agents and solvents.
The present invention relates to parenteral composition comprising an effective 5 amount of Dydrogesterone and/or pharmaceutically acceptable salts thereof.
In an embodiment the solubilizing agents are selected from monohydric or polyhydric alcohol, glycofurol, Polyethylene glycol, propylene glycol, Dimethylacetamide, Hydroxypropyl Betadex, Polyoxyethylene hydrogenated castor oil, polyoxyl 40 hydrogenated castor oil, Polyethylene glycol 400. 10
In an embodiment, Dydrogesterone is present in an amount present ranging from 2 to 40 mg/ml.
In preferred embodiment, Dydrogesterone is present in an amount ranging from 2.5 to 10 mg/ml.
In an embodiment, the present invention is directed to pharmaceutical composition 15 for parenteral administration comprising Dydrogesterone or a pharmaceutically acceptable salt thereof in the range of 0.1 % to 20% w/v of the composition, preferably in the range of 0.1% to 10%, more preferably in the range of 0.2% to 5% w/v of the composition.
Accordingly, to the present invention provide an aqueous solution for parenteral 20 administration comprising 0.25 to 1% Dydrogesterone.
In an embodiment water soluble cyclodextrin derivative may be added selected from group consisting of hydroxypropyl-£]-cyclodextrin, sulfobutyl-£]-cyclodextrin, and glucosyl-£]-cyclodextrin. The water-soluble cyclodextrin derivative used is preferably hydroxypropyl-£]-cyclodextrin also known as Hydroxypropyl betadex. The water 25
9
soluble cyclodextrin derivative are added to increase the solubility of Dydrogesterone wherein the inventors of the present invention have found that Dydrogesterone and a water-soluble cyclodextrin derivative are dissolved in water.
In a preferred embodiment hydroxypropyl-£]-cyclodextrin is present in an amount ranging from 5-50% w/v. 5
In an embodiment the present invention provides a parenteral aqueous solution comprising
a. 0.25 to 1% w/v Dydrogesterone and;
b. 10 to 35% w/v hydroxypropyl-£]-cyclodextrin or Hydroxypropyl Betadex
In an another embodiment the parenteral composition may optionally comprises one 10 or more co-solubilizing agent can be incorporated which can be selected from Poloxamer, Polysorbates, Polyethoxylated castor oil, polyethylene glycol or combinations thereof.
In an another embodiment the co-solubilizing agent is Polyethoxylated castor oil present in an amount ranging from 1 to 10% w/v. 15
In an another embodiment Polyethoxylated castor oil present is present in amount ranging from 2 to 6% w/v.
In an embodiment the present invention provides a parenteral composition comprising:
a. 0.25 to 1% w/v Dydrogesterone and; 20
b. 10 to 35% w/v hydroxypropyl-£]-cyclodextrin or Hydroxypropyl Betadex
c. 2 to 6% w/v Polyethoxylated castor oil
In an another embodiment the co-solubilizing agent is Polyethylene glycol present in an amount ranging from 10 to 30% w/v.
10
In an another embodiment polyethylene glycol is present in an amount about 20% w/v.
In an embodiment the present invention provides a parenteral composition comprising: 5
a. 0.25 to 1% w/v Dydrogesterone and;
b. 10 to 35% w/v hydroxypropyl-£]-cyclodextrin or Hydroxypropyl Betadex
c. 20% w/v Polyethylene glycol
In an another embodiment the present invention provides a method of preparing a stable aqueous parenteral composition which is convenient for industrial mass 10 production and simple in process, and comprises the following steps:
1. Heat water for injection in suitable container at temperature 45-50¢XC and add solubilizing agent with continuous stirring for 1 hour.
2. Add Dydrogesterone in above solution with continuous stirring for atleast 30 minutes and volume make up with water for injection and continue stirring for 15 at least 120 minutes.
3. Filter the solution obtained in step 2 and filled in sterile container.
In an embodiment, the present invention provides a process for producing a pharmaceutical composition for parenteral administration, wherein the process involves the following steps 20
1. Dispensing of Raw materials
2. Take water for injection in suitable SS container (25-30oC)
3. Add solubilizing agent with stirring to get clear solution
4. Add Dydrogesterone with stirring to get clear solution
5. Make up the volume to the required quantity 25
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6. Send sample for analysis
7. Aseptic filtration through pre-filter & final filter cartridge filter using nitrogen after bulk release from QC
8. Vial filling & sealing
9. Sterilization of filled & sealed vials 5
In another embodiment the present invention provides a parenteral pharmaceutical composition wherein the pH of the formulation is 4.0 to 8.0, preferably 5.0 to 7.5
In a preferred embodiment the pH of aqueous solution suitable for parenteral administration is 5.6
In another embodiment the present invention provides a parenteral pharmaceutical 10 composition wherein the osmolality of the formulation is between 240-450 preferably between 280-380 osmole.
The present invention is described with reference to the following examples, which are given by way of illustration and should not be construed to limit the scope of the present invention. The solutions are prepared with different concentration of 15 Dydrogesterone in different solubilizing agent.
Example 1
Table 1: Composition details of Dydrogesterone in concentration 0.25% (2.5 mg/ml)
Ingredients
Role
Amount
Dydrogesterone
Active Agent
0.25%
Hydroxypropyl Betadex
Solubilizing agent
15%
Water of Injection
Solvent
Q.S.
Take Water for Injection in a suitable S.S container and Maintain temp 45-50¢XC. Then add Hydroxypropyl Betadex under the continue stirring, stirring continue for 1 hrs. 20
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Add the Dydrogesterone with continuous stirring for at least 30 minutes. Make up the volume with Water for Injection and continue stirring for at least 120 minutes.
Example-2
Table 2: Composition details of Dydrogesterone in concentration 0.25% (2.5 mg/ml)
Ingredients
Role
Amount
Dydrogesterone
Active Agent
0.25%
Hydroxypropyl Betadex
Solubilizing agent
12.5%
Water of Injection
Solvent
Q.S.
5
Example-3
Table 3: Composition details of Dydrogesterone in concentration 0.25% (2.5 mg/ml)
Ingredients
Role
Amount
Dydrogesterone
Active Agent
0.25%
Hydroxypropyl Betadex
Solubilizing agent
10%
Water of Injection
Solvent
Q.S.
Example 4
Table 4: Composition details of Dydrogesterone in concentration 0.5 % (5 mg/ml) 10
Ingredients
Role
Amount
Dydrogesterone
Active Agent
0.5
Hydroxypropyl Betadex
Solubilizing agent
30%
Water of Injection
Solvent
QS
Take Water for Injection in a suitable S.S container and Maintain temp 45-50¢XC. Then add Hydroxypropyl Betadex under the continue stirring, stirring continue for 1 hrs.
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Add the Dydrogesterone with continuous stirring for at least 30 minutes. Make up the volume with Water for Injection and continue stirring for at least 120 minutes
Example 5
Table 5: Composition details of Dydrogesterone in concentration 0.5 % (5 mg/ml)
Ingredients
Role
Amount
Dydrogesterone
Active Agent
0.5
Hydroxypropyl Betadex
Solubilizing agent
25%
Water of Injection
Solvent
QS
5
Example 6
Table 6: Composition details of Dydrogesterone in concentration 0.5 % (5 mg/ml)
Ingredients
Role
Amount
Dydrogesterone
Active Agent
0.5
Hydroxypropyl Betadex
Solubilizing agent
20%
Water of Injection
Solvent
QS
Example 7
Table 7: Composition details of Dydrogesterone in concentration 1 % (10 mg/ml) 10
Ingredients
Role
Amount
Dydrogesterone
Active Agent
1.0%
Hydroxypropyl Betadex
Solubilizing agent
31%
Water of Injection
Solvent
Q.S
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Add hydroxypropyl Betadex in water of injection with continuous stirring to obtain a clear solution. To this clear solution, add Dydrogesterone with continuous stirring to get clear solution. Volume make up the clear solution with water for injection and filter the solution.
The filtered solution was filled in vial or ampoule. 5
Example 8
Table 8: Composition details of Dydrogesterone in concentration 1 % (10 mg/ml)
Ingredients
Role
Amount
Dydrogesterone
Active
1.0%
Hydroxypropyl Betadex
Solubilizing agent
25%
Polyoxyethylene Hydrogenated Castor Oil
Co-Solubilizing agent
2.0%
Water of Injection
Solvent
QS
Add hydroxypropyl Betadex and Polyoxyethylene hydrogenated castor oil in water of injection with continuous stirring to obtain a clear solution. To this clear solution, add 10 Dydrogesterone with continuous stirring to get clear solution. Volume make up the clear solution with water for injection and filter the solution.
The filtered solution was filled in vial or ampoule.
Example 9
Table 9: Composition details of Dydrogesterone in concentration 1 % (10 mg/ml) 15
Ingredients
Role
Amount
Dydrogesterone
Active
1.0%
Hydroxypropyl Betadex
Solubilizing agent
25%
15
Polyethylene glycol
Co-solubilizing agent
20%
Water of Injection
Solvent
QS
Add hydroxypropyl Betadex and Polyethylene glycol in water of injection with continuous stirring to obtain a clear solution. To this clear solution, add Dydrogesterone with continuous stirring to get clear solution. Volume make up the clear solution with water for injection and filter the solution. 5
The filtered solution was filled in vial or ampoule.
Example 10
Table 10: Composition details of Dydrogesterone in concentration 1 % (10 mg/ml)
Ingredients
Role
Amount
Dydrogesterone
Active Agent
1.0%
Hydroxypropyl Betadex
Solubilizing agent
32%
Polyoxyethylene Hydrogenated Castor Oil
Co-solubilizing agent
6.0%
Water of Injection
Solvent
QS
Add hydroxypropyl Betadex and Polyoxyl 40 hydrogeneted castor oil in water of 10 injection with continuous stirring to obtain a clear solution. To this clear solution, add Dydrogesterone with continuous stirring to get clear solution. Volume make up the clear solution with water for injection and filter the solution.
The filtered solution was filled in vial or ampoule.
Example 11: Stability study 15
Table 11 (a) -Dydrogesterone 5 mg/ml were stored and analyzed for stability at temperature 50¢XC ¡Ó 2 ¢XC prepared from Example-4
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Test
Acceptance criteria
Initial testing
After 07 days
After 14 days
After 21 days
Description
Clear colorless solution filled in 2 ml clear glass vial
Clear colorless solution filled in 2 ml clear glass vial
Clear colorless solution filled in 2 ml clear glass vial
Clear colorless solution filled in 2 ml clear glass vial
Clear colorless solution filled in 2 ml clear glass vial
Weight per ml
Between 0.99919 gm/ml to 1.2123 g/ml
1.095
1.0831
1.0794
1.0709
Related substances
Impurity A
Not more than 0.3%
0.054
BDL*
BDL
BDL
Impurity B
Not more than 0.15%
Not detected
BDL
BDL
BDL
Impurity C
Not more than 0.3%
0.043
0.073
0.053
0.061
Unknown impurity
Not more than 0.2%
Not detected
BDL
BDL
Not detected
Total
Not more than 1%
0.054
0.054
0.053
0.061
Assay
Each ml contains:
Dydrogesterone IP 5 mg
NLT 4.625 and NMT 5.375 mg
(NLT 92.5% and NMT 107.5% of labeled claim)
5.049 mg
(100.98%)
5.007 mg
(100.14%)
4.98 mg
(99.50%)
5.04 mg
(100.76%)
Table 11 (b) -Dydrogesterone 2.5 mg/ml were stored and analyzed for stability at temperature 50¢XC ¡Ó 2 ¢XC prepared from example 1.
Test
Acceptance criteria
Initial testing
After 07 days
After 14 days
After 21 days
Description
Clear colorless solution filled in 2 ml clear glass vial
Clear colorless solution filled in 2
Clear colorless solution filled in 2
Clear colorless solution filled in 2
Clear colorless solution filled in 2
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ml clear glass vial
ml clear glass vial
ml clear glass vial
ml clear glass vial
Weight per ml
Between 0.99919 gm/ml to 1.2123 g/ml
1.0423
1.0864
1.0492
1.0394
Related substances
Impurity A
Not more than 0.3%
Not detected
BDL
BDL
Not detected
Impurity B
Not more than 0.15%
Not detected
BDL
Not detected
Not detected
Impurity C
Not more than 0.3%
BDL
0.067
0.055
BDL
Unknown impurity
Not more than 0.2%
0.057
BDL
BDL
0.077
Total
Not more than 1%
0.057
0.067
0.055
0.077
Assay
Each ml contains:
Dydrogesterone IP 5 mg
NLT 4.625 and NMT 5.375 mg
(NLT 92.5% and NMT 107.5% of labeled claim)
2.50 mg
(99.4%)
2.517 mg
(100.69%)
2.52 mg
(100.64%)
2.51 mg
(100.53%)
* BDL= Below disregard limit
From the data in both tables 11(a) and 7(b) it can be seen a clear liquid solution is provided. The physical appearance is obtained after 21 days of storage even when stored at 50¢XC ¡Ó 2 ¢XC shows stable aqueous solution with no crystal formation and 5 the impurities levels of Dydrogesterone is very low. ,CLAIMS:A parenteral composition comprising an effective amount of Dydrogesterone and/or pharmaceutically acceptable salts thereof.
2. A parenteral composition as claimed in claim 1, is an aqueous solution comprising 5 Dydrogesterone present in an amount ranging from 0.1 % to 20% w/v.
3. An aqueous solution for parenteral administration as claimed in claim 2, further comprises one or more solubilizer.
4. An aqueous solution as claimed in claim 3, wherein solubilizer is water soluble cyclodextrin derivative selected from hydroxypropyl-ß-cyclodextrin, sulfobutyl-ß-10 cyclodextrin, and glucosyl-ß-cyclodextrin.
5. An aqueous solution as claimed in claim 4 comprises 5 to 50% w/v hydroxypropyl-ß-cyclodextrin or Hydroxypropyl Betadex
6. An aqueous solution for parenteral administration as claimed in claim 1-5 comprising
a) 0.25 to 1% w/v Dydrogesterone and; 15
b) 10 to 35% w/v hydroxypropyl-ß-cyclodextrin or Hydroxypropyl Betadex
7. An aqueous solution for parenteral administration as claimed in claim 3 may optionally comprises one or more co-solubilizer selected from Polyethoxylated castor oil or polyethylene glycol
8. An aqueous solution as claimed in claim 7 wherein Polyethoxylated castor oil is 20 present in an amount 2 to 6% w/v and polyethylene glycol is present in an amount 20% w/v.
9. An aqueous solution as claimed in claim 6, wherein pH of composition is 5.0 to 7.5.
10. A method of preparing a stable aqueous parenteral composition comprising:
a) Heat water for injection in suitable container at temperature 45-50°C and add 25 solubilizing agent with continuous stirring for 1 hour.
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b) Add Dydrogesterone in above solution with continuous stirring for atleast 30 minutes and volume make up with water for injection and continue stirring for at least 120 minutes.
c) Filter the solution obtained in step 2 and filled in sterile container.