DESC:
4. . DESCRIPTION

FIELD OF INVENTION

The present invention relates to a stabilized composition comprising folic acid derivatives including pharmaceutically acceptable salt thereof, the invention also relates to dosage
5 form, composition and the process for preparing pharmaceutical film compositions, which are comparable to immediate release solid oral dosage forms. Said dosage forms may be useful as a nutritional supplement or for the treatment of various medical conditions.

More specifically, the present invention relates to oral dispersible film composition comprising L-Methylfolate as a supplement for folate deficiency and to treat depressive
10 disorders.

BACKGROUND OF THE INVENTION

Majority of the pharmaceutically active molecules are administered through oral route as tablet or capsule dosage form. But, owing to their bitter taste, unpleasant odour or size of the solid dosage form, the patient compliance is modest, especially in paediatrics and
15 geriatrics.

Considering these limitations, an alternative patient centric dosage form can be investigated for the effective delivery of the pharmaceutical compositions. One such dosage form of interest is the Oral dispersible film, that is placed in the mouth and allowed to disperse there itself letting the release of active component.
20

Such film dosage forms are beneficial for several reasons, including ease of administration, particularly to those individuals who have difficulty swallowing pills or tablets.

Research and studies indicate that more than 4% of the population are affected with depression worldwide and it is an illness prevalent in all countries. Statistics show 5.0%
25 among adults and 5.7% among adults older than 60 years are affected by depression disorders. It is generally believed that there is some kind of association between folate deficiency and depression which in turn is the myriad spirit of megaloblastic anaemia.

Mental health is important and cannot be ignored because not all treatment regimens are effective for all individual, there is a strong need to identify a composition and processing
method thereof that can facilitate the selection of an appropriate treatment regimen for

individuals with depression.

Megaloblastic anaemia is a form of anaemia characterized by very large red blood cells and a decrease in the number of those cells. Anaemias are blood disorders that occur when the
5 body has fewer red blood cells than normal. Red blood cells carry oxygen throughout the body using a protein called haemoglobin. If there aren’t enough of these cells or this protein, anaemia results.

Usually, megaloblastic anaemia is due to acquired deficiency in vitamin B12 or folic acid. The deficiency can be related to inadequate dietary intake of these B vitamins or poor
10 intestinal absorption. Rarely, megaloblastic anaemias are the result of medications or inherited defects in the transport/metabolism of vitamin B12 or folic acid.

Folic acid is the man-made form of folate. Folate is a B-vitamin naturally found in some foods. It is needed to form healthy cells, especially red blood cells. Folic acid supplements may come in different forms (such as L-methylfolate, levomefolate,
15 methyltetrahydrofolate). They are used to treat or prevent low folate levels. Low folate levels can lead to certain types of anaemia. Conditions that can cause low folate levels include poor diet, pregnancy, alcoholism, liver disease, certain stomach/intestinal problems, kidney dialysis, among others. Women of childbearing age should receive adequate amounts of folic acid either through their diet or as supplements to
20 prevent infant spinal cord birth defects.

In 2004, the European Food Safety Authority (EFSA) issued an opinion on calcium l- methylfolate (EFSA AFC Panel, 2004) concluding that its use as a source of folate in foods for particular nutritional uses, food supplements and foods intended for the general population, at level of 1 mg/adult person/day does not raise safety concerns in line with the
25 tolerable upper level (UL) for folic acid for adults defined by the Scientific Committee on

Food (2000).

Generally, Folic acid, N-[4-[[(2-amino-1,4-dihydro-4-oxo-6-pteridinyl) methyl] amino] benzoyl]-L-glutamic acid is widely used for the treatment of mental health. It is a water- soluble synthetic form of Vitamin B9 and the precursor of dihydrofolic acid and
5 tetrahydrofolic acid. It is essential that folic acid is reduced to its metabolically active tetrahydrofolate form within the cell. The enzymatic conversion process consists of folic acid converting into dihydrofolate (DHF), DHF converting into Tetrahydrofolate (THF), THF converting into 5,10-methylene THF, and finally, 5,10-methylene THF converting into l-Methylfolate.

10 Hence, there are several inventions which have addressed the issue and have customized treatment regimen based on the need of each individual and the stage of the said disorder. The patent application US20210085685A1 relates to methods of treating, preventing, and improving disorders and conditions related to certain metabolic abnormalities using metabolically active folate compounds, optionally in combination with methylcobalamin,
15 including methods of improving blood lipid profiles and methods of treating fibromyalgia; erectile dysfunction; diseases associated with certain HLA-DQ gene alleles and/or gluten intolerance, including Celiac Disease; headaches and/or migraines; muscle recovery and/or repair in athletes; as well as idiopathic neuropathy, inability to sleep, inability to concentrate, and/or neurological development issues in children.

20 Similarly, the PCT application WO2019000101A1 discloses novel extended-release formulations of L-Methylfolate (“5- methyltetrahydrofolate” or “5-MTHF”). The extended-release compositions and formulations provided herein may be used to treat a variety of disorders associated with folate deficiencies, including central nervous system (CNS) disorders such as, seizures, ataxia, neuropathy, developmental delay, cognitive
25 dysfunction (as in dementia) and psychiatric disorders as well as cerebral folate deficiency

(CFD). Also provided herein are methods of diagnosing and/or treating a disease or
disorder in a subject by administering extended-release compositions or formulations

comprising 5-MTHF.

Similarly, the patent application US2016207925A1 is directed to salts of L-Methylfolate. The invention also relates to a process for the preparation of salts of l-Methylfolate.
5 Furthermore, the invention also relates to medicaments and nutritional supplements comprising salts of l-Methylfolate.

Despite the existence of several dosage forms of L-methyl folate and its salts thereof, there is an unmet (patient centric) need for the development of L-methyl folate and its salts thereof oral film dosage forms to be used a supplement for folate deficiency and to treat depressive disorders.

10 OBJECTIVE OF THE INVENTION

The main objective of our invention is the development of an oral dispersible film comprising L-methyl folate and its salts thereof composition and method of processing thereof.

SUMMARY OF THE INVENTION

The following summary is provided to facilitate a clear understanding of the new features

15 in the disclosed embodiment, and it is not intended to be a full, detailed description. A detailed description of all the aspects of the disclosed invention can be understood by reviewing the full specification, and the claims and the abstract, as a whole.

The present invention relates to develop a rapidly dissolving oral dispersible film comprising L-methyl folate and its salts thereof composition and method of processing thereof. In one embodiment, the present invention discloses the composition and process for the preparation oral dispersible film of L-methyl folate and its salts thereof to be used as a food/nutrient supplement.

In another embodiment, the present invention discloses a simple, inexpensive, and efficient process, for the preparation of oral dispersible film of and its salts thereof to be used in the treatment of a depressive disorders. In another embodiment, the present invention discloses the compositions and preparation for oral dispersible film of L-methyl folate and its salts thereof, having higher stability.
In addition to the actives, the film composition of the present invention may further comprise of polymers, plasticizers, flavours, colours, and sweeteners.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides improved methods and dosage form for oral administration

5 of active molecules. In some embodiments, the active component (or “drug”) is delivered to the user via an oral dispersible film. The design of formulation composition in these non- limiting examples can be varied and are merely cited to illustrate at least one embodiment of the invention, without limiting the scope thereof.

The embodiments disclosed herein can be expressed in different forms and should not be

10 considered as limited to the listed embodiments in the disclosed invention. The various embodiments outlined in the subsequent sections are construed such that it provides a complete and a thorough understanding of the disclosed invention, by clearly describing the scope of the invention, for those skilled in the art.

The present invention provides a composition in the form of a film for oral administration,

15 including a composition having a uniformly distributed L-methyl folate and its salts thereof, combination of a polymer, a flavouring agent, a polar solvent, a sweetening agent, a colouring agent, and a therapeutically active molecule.

In one of the embodiments, the present invention includes a method of processing an oral dispersible film of L-methyl folate and its salts thereof. The processing steps comprises of

20 1. Weigh required quantity of purified water in a container.

2. Add L-Methylfolate Calcium to step 1 and stir for 2 min.

3. Add Maltodextrin to step 2 and stir for 2min.

4. Add Sucralose to step 3 and stir manually for 1min.

5. Add Polyethylene glycol to step 4 and stir manually for 1min.

25 6. Add required quantity of Hydroxypropyl methylcellulose to step 5 and stir manually for 5min.
7. Add flavour to step 6 and stir manually for 2min.

8. Add colour to step 7 and stir manually for 2min.

9. Cast the slurry at process parameters of Dr. Knife thickness of 470 to 525 microns;

30 Temperature 95±3°C; In-direct drying for 18 min.
10. Slit the dried casted film into 15mm x 25mm (3.75 cm2) Example 1
L- Methylfolate Oral Dispersible Film 1mg

S. No Ingredients %w/w mg/unit Function
1 L-Methylfolate Calcium 2.5 1.00 Active
2 Maltodextrin 30 12.20 Diluent
3 Sucralose 2 0.80 Sweetening agent
4 Polyethylene glycol 400 12.5 5.00 Plasticizer
5 Hydroxypropyl methylcellulose 37.5 15.00 Polymer
6 Flavour 12.5 5.00 Flavouring agent
7 Color 2.5 1.00 Colouring agent
8 Purified water Qs to 100 39.06 Vehicle
Dry film weight (mg) 40.00

5 In another embodiment of the present invention, the processing of an oral dispersible film of

L-Methylfolate comprises of following steps:

1. Weigh required quantity of purified water in a container.
2. Add L-Methylfolate Calcium to step 1 and stir for 2 min.
3. Add Maltodextrin to step 2 and stir for 2min.
10 4. Add Sucralose to step 3 and stir for 1min.
5. Add Polyethylene glycol to step 4 and stir manually for 1min.
6. Add required quantity of Hydroxypropyl methylcellulose to step 5 and stir for 5min.
7. Add Flavour to step 6 and stir for 2min.
8. Add colour to step 7 and stir for 2min.
15 9. Cast the slurry at process parameters of Dr. Knife thickness of 470 to 525 microns;
Temperature 100±3°C; In-direct drying for 18 min.
10. Slit the dried casted film into 30mm x 25mm (7.5 cm2) for 15mg dose.

11. Slit the dried casted film into 15mm x 25mm (3.75 cm2) for 7.5mg dose.

Example 2

20 L-Methylfolate Oral Dispersible Film 7.5 / 15 mg

S. No Ingredients %w/w mg/unit Function
1 L-Methylfolate Calcium 9.375 - 18.75 7.5 - 15.00 Active

2 Maltodextrin 22.75 – 16.5 18.20 - 13.20 Diluent
3 Sucralose 2 1.60 Sweetening agent
4 Polyethylene glycol 12.5 10.00 Plasticizer
5 Hydroxypropyl methylcellulose 37.5 30.00 Polymer
6 Flavour 6.25 5.00 Flavouring agent
7 Colour 0.25 0.20 Colouring agent
8 Purified water Qs to 100 Qs to 80 Vehicle
Dry film weight (mg) 80.00

In another embodiment of the present invention, the processing of an oral dispersible film of L-Methylfolate comprises of following steps:
1. Weighed quantity of purified water was taken in a ss container and kept under stirring at 350 RPM.
2. Weighed quantity of L-Methylfolate Calcium was added to step- 1 under stirring at 350 RPM for 2 min.
3. Weighed quantity of Maltodextrin was added to step- 2 under stirring at 350 RPM for 2 min.
4. Weighed quantity of Sucralose was added to step- 3 under stirring at 350 RPM for 2 min.
5. Weighed quantity of Polyethylene glycol was added to step- 4 under stirring at 350 RPM for 2 min.
6. Weighed quantity of Dicalcium phosphate was added to step- 5 under stirring at 350 RPM for 2 min.
7. Weighed quantity of Hydroxypropyl methylcellulose was added to step- 6 under stirring at 500rpm for 10mins.
8. Weighed quantity of Flavor was added to step- 7 under stirring at 500 RPM for 3 min.
9. Weighed quantity of Colour was added to step- 8 under stirring at 500 RPM for 3 min.
10. The wet slurry after completion of mixing subjected to vacuum degassing for 15mins to obtain bubble free slurry.
11. Wet slurry was casted at process parameters of Dr. Knife thickness of 470 to 525 microns; Temperature 90±3°C; In-direct drying for 18 min.
12. The dried casted film was Slitted into 15mm x 25mm.
The films were evaluated for disintegration time, folding endurance, Assay Dissolution, and impurities. The films were subjected to stability study under 40°C ± 2°C and 75% ± 5% RH condition for six months and evaluated above test parameters and results are tabulated.

Results:
S. No. Test Parameters Limits Results
Initial 1month 3months 6months
1 Disintegrating time NMT 60sec 30sec 32sec 34sec 35sec
2 Folding Endurance NLT 10 60 folds 54 folds 52 folds 46 folds
3 Water content NMT 10% 6.28 6.81 7.62 8.27
4 Assay 90 - 110% 102.42 101.1 99.2 98.7
5 Dissolution (water Media) NLT 75% in 30 min 99.2 99.0 98.6 97.4

The comparative invitro data for LMF is depicted in the table below:

S.no Drug product Release in official media (water)
1. Tetrafol 109% in 10 mins
2. LMF (In-house) 107% in 10 mins


The present invention addresses the gap on the existence of several dosage forms of L-methyl folate and its salts thereof, where there is an unmet (patient centric) need for the development of L-methyl folate and its salts thereof oral film dosage forms to be used a supplement for folate deficiency and to treat depressive disorders.
The present invention has a release rate of 99% in water when compared to the existing drug product Tetrafol.

The present invention was tested against existing marketed drugs and the comparative results are provided for each media and how effective the current invention is proven.

WORKING EXAMPLE 1:
Media: Water
REFERENCE PRODUCT TEST PRODUCT
Name of product : L-Methylfolate Tablet 7.5 mg (Tetrafol) L-Methylfolate Calcium ODF 15mg
Batch No. : SID0646A LME/P/ODF/0026-IPD/014
Manufactured by Sun pharma laboratories ltd LN Laboratotries Pvt. Ltd
Mfg. Date : Mar-22 Oct-22
Exp.Date : Feb-24 _

Time Intervals Reference Product Test Product
0 0 0
10 107 109
15 108 109
20 108 109
30 109 109
45 109 108

WORKING EXAMPLE 2:
Media: 1.2 Buffer

REFERENCE PRODUCT TEST PRODUCT
Name of product : L-Methylfolate Tablet 7.5 mg (Tetrafol) L-Methylfolate Calcium ODF 15mg
Batch No. : SID0646A LME/P/ODF/0026-IPD/014
Manufactured by Sun pharma laboratories ltd LN Laboratotries Pvt. Ltd
Mfg. Date : Mar-22 Oct-22
Exp.Date : Feb-24 _

Time Intervals Reference Product Test Product
0 0 0
10 105 105
15 107 108
20 108 109
30 106 108
45 106 108

WORKING EXAMPLE 2:
Media: 4.5 Buffer

REFERENCE PRODUCT TEST PRODUCT
Name of product : L-Methylfolate Tablet 7.5 mg (Tetrafol) L-Methylfolate Calcium ODF 15mg
Batch No. : SID0646A LME/P/ODF/0026-IPD/014
Manufactured by Sun pharma laboratories ltd LN Laboratotries Pvt. Ltd
Mfg. Date : Mar-22 Oct-22
Exp.Date : Feb-24 _

Time Intervals Reference Product Test Product
0 0 0
10 106 107
15 107 106
20 108 106
30 109 105
45 109 106

WORKING EXAMPLE 3:
Media: 6.8 Buffer

REFERENCE PRODUCT TEST PRODUCT
Name of product : L-Methylfolate Tablet 7.5 mg (Tetrafol) L-Methylfolate Calcium ODF 15mg
Batch No. : SID0646A LME/P/ODF/0026-IPD/014
Manufactured by Sun pharma laboratories ltd LN Laboratotries Pvt. Ltd
Mfg. Date : Mar-22 Oct-22
Exp.Date : Feb-24 _

Time Intervals Reference Product Test Product
0 0 0
10 108 105
15 108 100
20 109 105
30 107 107
45 108 108

The invention should not be limited by the above-described embodiment, method, and examples, but by all embodiments and methods within the scope and spirit of the invention as claimed.
,CLAIMS:
5. CLAIMS

I/We Claim

1. An oral dispersible film composition comprising:

5 an active molecule wherein the said active molecule is L-methyl folate and its salts thereof and is 1%

w/w to about 20% w/w of the film composition;

a polymeric carrier wherein the said polymer is hydroxypropyl methylcellulose is about 25% w/w to about 50% w/w of the film composition;
a water-soluble diluent wherein the said water-soluble diluent is maltodextrin and

10 is 10% w/w to 35% w/w of the film composition;

a plasticizer polyethylene glycol is about 7.5% w/w to about 20% w/w of the film composition; and
excipients selected from flavouring, colouring and sweetening agent

15 2. The oral dispersible film composition as claimed in claim 1 wherein the said polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose and cellulose derivatives, and mixtures thereof.

3. The oral dispersible film composition as claimed in claim 1 where said plasticizer is

20 selected from the group consisting of Polyethylene glycol, Glycerol, Propylene glycol and mixtures thereof.

4. The oral dispersible film composition as claimed in claim 1 wherein the oral dispersible dosage form is an oral dispersible film of L-methyl folate and its salts thereof.
25

5. The oral dispersible film composition as claimed in claim 1 wherein the oral dispersible dosage form is a solid dosage form comprising L-methyl folate and its salts thereof and a polymer matrix network carrying the L-methyl folate and its salts thereof, the polymer matrix network being comprised of a water-soluble polymer and/or water-soluble diluent material that is inert towards L-
30 Methyl folate.

6. A method of processing an orally dispersible film composition comprising the steps of: Weighing required quantity of purified water.
Addition of L-Methylfolate Calcium to above water and stirring for 2 min.

Addition of Maltodextrin to above active solution and stir for 2min followed by the addition of Sucralose and stirring for 1min.

Addition of Polyethylene glycol to above solution and stirring for 1 min.

5 Addition of Hydroxypropyl methylcellulose and stirring for 5 min.

Addition of flavouring and colouring agents to above resultant mixture and stirring

for 2 min sequentially.

Casting the above active matrix at a process parameters of Dr. Knife thickness of

470 - 525 microns and drying the wet film at a Temperature 100±3°C for 18 min

10 using indirect heating mode.

Post drying, slitting the film into 15mm x 25mm (3.75 cm2) and 30mm x 25mm (7.5 cm2) for 7.5 mg and 15 mg dose respectively.

6. DATE AND SIGNATURE

15 Dated this 11th day of November 2022

Signature

(Mr. Srinivas Maddipati)

20 IN/PA 3124

Agent for Applicant