CLIAMS:We Claim:
1. A water soluble salt composition of L-2-Oxothiazolidine-4-carboxylic acid (a) with 2,4-Diamino pyrimidine-3-oxide derivatives of the formula (b).
Where R can be, Hydrogen, Alkyl of from 1 to 8 carbon atoms, heterocyclic moieties containing either Nitrogen or Nitrogen and Oxygen.
2. R can be heterocyclic moieties like pyrrolidine, piperidine, piperazine, morpholine etc.

3. The water soluble salt as claimed in claim 1, wherein salt is prepared by reacting stoichiometric quantities of (a) and (b) by conducting the reactions in water, organic solvents or by simply mixing the two in a suitable vehicle.
4. A composition suitable for topical application containing a water soluble salt as claimed in claim 1.
5. The composition as claimed in claim 4, can be in the form of lotion, cream, spray, gel, solution or ointment.
6. The composition as claimed in claim 4, can contain the salt from 0.1 to 15% of the composition.
7. The composition as claimed in claim 4, can contain water up to 95% of the composition.
8. The composition as claimed in claim 4, can further contain a suitable vehicle and /or other excipients.
9. A method for preventing hair loss and stimulating hair growth comprising the steps of administering to a patient who has at least the experience of hair loss and requires new hair growth using an effective amount of a composition of claim 4.
10. We claim that the formulations made from water soluble salts as claimed in claim 3, are therapeutically superior to the formulations made using formula b alone showing marked synergism between formulae (a) and (b) with increased mRNA values
,TagSPECI:WATER SOLUBLE COMPOSITIONS FOR
TREATING HAIR LOSS & PROMOTING HAIR GROWTH
FIELD OF INVENTION
[001] The present invention relates, in general, to the field of hair loss treatment and, in particular, relates to novel water soluble compositions which are capable of preventing hair loss and stimulating hair regrowth. Such compositions comprise a hair growth stimulant and a multifunctional compound.
BACKGROUND AND PRIOR ART
[002] In human beings, hair growth and shedding is random and not seasonal or cyclical. At any given time, a random number of hairs will be in one of three stages of growth and shedding: anagen, catagen, and telogen. The anagen phase or growth phase, during which the hair lengthens, lasts several years. The catagen phase, which succeeds the anagen phase, is very short and lasts only a few weeks. The telogen phase, which lasts several months, corresponds to a period of rest of the follicle, where the hair finishes by falling out.
[003] The natural loss of the hair can be estimated, on average, at a few hundred hairs per day for a normal physiological state. However, it happens that the hair cycle can go wrong and that hair loss accelerates and results in a temporary or definitive loss of the hair known as alopecia.
[004] Hair loss, particularly in men, mainly after middle age, can be attributed to several factors or a combination of them. The factors can be medication, genetics, stress, malnutrition, hormonal imbalance, reduced blood flow to hair follicles etc.
[005] Even though several active ingredients are known for hair loss treatment, Minoxidil is the only active chemical ingredient that is approved by FDA for generating new hair growth.
[006] A disadvantage of Minoxidil is that it is practically insoluble in water which limits its use to such formulations having relatively low proportion of water. Formulations containing high concentrations of alcohol or poly alcohol are in general not well tolerated and alcohol present in topical preparation may dry the scalp resulting in dandruff, rash and itchiness.
[007] When the vehicle evaporates, formation of crystalline Minoxidil occurs. But the water soluble formulation enhances the transdermal delivery or penetration of Minoxidil in comparison with solvent based.
[008] Hence there exists a need in the prior art to develop a composition which is water soluble, which not only prevents hair loss but stimulates new hair growth also and overcomes the disadvantages of known hair growth compositions.
OBJECTS OF THE INVENTION:
[009] Some of the objects of the present disclosure are described herein below:
[0010] A main object of the present invention is to provide novel compositions which can prevent hair loss and stimulate hair growth.
[0011] Another object of the present invention is to provide novel compositions containing a hair growth stimulant and a multifunctional compound.
[0012] Yet another object of the present invention is to provide water soluble salts prepared by hitherto unknown combination of a hair growth stimulant and a multifunctional compound, which not only prevents hair loss but also stimulates new hair growth.
[0013] Still another object of the present invention is to provide novel hair growth compositions which do not cause any side effect when applied on scalp.
[0014] Another object of the present invention is to provide novel hair growth compositions which can provide the required nutrients to hair follicles for hair growth.
[0015] The other objects and advantages of the present invention will be apparent from the following description when read in conjunction with the accompanying drawings which are incorporated for illustration of preferred embodiments of the present invention and are not intended to limit the scope thereof.
SUMMARY OF THE INVENTION:
[0016] In view of the foregoing, the embodiment herein provides hitherto unknown hair growth compositions comprising a hair growth stimulant and a multifunctional compound which not only prevents hair loss but stimulates new hair growth also.
[0017] According to an embodiment, hair growth compositions comprising hair growth stimulants and a multifunctional compound to form water soluble salts, wherein the hair growth stimulants selected are pyrimidine-3-oxide derivatives.
[0018] In an embodiment, a water soluble salt is prepared with a combination of L-2-Oxothiazolidine-4-carboxylic acid and 2,4-Diamino-6-piperidinopyrimidine-3-oxide. In another embodiment, a water soluble salt is prepared with a combination of L-2-Oxothiazolidine-4-carboxylic acid and 2,4-Diamino-6-pyrrolidinopyrimidine-3-oxide. In yet another embodiment, a water soluble salt is prepared with a combination of L-2-Oxothiazolidine-4-carboxylic acid and 2,4-Diamino pyrimidine-3-oxide. Accordingly, the novel water soluble compositions of the active ingredients can be used for the treatment of human alopecia and calvities.
[0019] According to an embodiment, a method for preparing water soluble salt is provided. Accordingly, the salts may be prepared in water by reaction of the actives with L-2-Oxothiazolidine-4-carboxylic acid in a stoichiometric ratio. In another embodiment, the salts can also be prepared by using other solvents such as Methanol, Ethanol, Isopropanol etc. Further, the two components, the actives and the acid, can also be mixed uniformly in stoichiometric ratio. The salts or formulae may be isolated by using conventional techniques such as evaporation of solvent, precipitation with non-solvents etc.
[0020] According to an embodiment, a method for preventing hair loss and stimulating new hair growth is disclosed herein. Accordingly, a person suffering from hair loss or requiring new hair stimulation is provided with a water soluble composition, which includes a hair growth stimulant and a cyclic amino acid, preferably L-2-Oxothiazolidine-4-carboxylic acid that acts as an intracellular cysteine source.
[0021] These and other aspects of the embodiments herein will be better appreciated and understood when considered in conjunction with the following description and the accompanying drawings. It should be understood, however, that the following descriptions, while indicating preferred embodiments and numerous specific details thereof, are given by way of illustration and not of limitation. Many changes and modifications may be made within the scope of the embodiments herein without departing from the spirit thereof, and the embodiments herein include all such modifications.
DETAILED DESCRIPTION OF EMBODIMENTS
[0022] The embodiments herein and the various features and advantageous details thereof are explained more fully with reference to the non-limiting embodiments that are illustrated in the accompanying drawings and detailed in the following description. Descriptions of well-known components and processing techniques are omitted so as not to unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those skilled in the art, to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.
[0023] The disclosure is directed to water soluble salt compositions for treating hair loss and stimulating hair growth. More particularly the disclosure is directed to water soluble salt compositions which are suitable for topical use. These water soluble compositions significantly enhance the transdermal delivery of the active / multifunctional compound. The disclosure also gives methods for preparing the salts and use of the same in treating hair loss and promoting hair growth.
[0024] According to an embodiment, the multifunctional compound is a Cysteine source and a stimulator of intracellular Glutathione. Cysteine is the major amino acid component of hair and plays a very important role by contributing to hair growth and hair loss prevention.

[0025] In an embodiment, a water soluble salt [structure I] is prepared with a combination of L-2-Oxothiazolidine-4-carboxylic acid and 2,4-Diamino-6-piperidinopyrimidine-3-oxide.

[0026] In another embodiment, a water soluble salt [structure II] is prepared with a combination of L-2-Oxothiazolidine-4-carboxylic and 2,4-Diamino-6-pyrrolidinopyrimidine-3-oxide.

[0027] In yet another embodiment, a water soluble salt [structure III] is prepared with a combination of L-2-Oxothiazolidine-4-carboxylic acid and 2,4-Diamino pyrimidine-3-oxide.

[0028] According to an embodiment, the acid compound used in salt preparation is based on L-2-Oxothiazolidine-4-carboxylic acid. These water soluble compositions contain high percentage of water and enhance the transdermal delivery of the actives and the glutathione precursor.
[0029] According to present invention, water soluble compositions of the active ingredients can be used for the treatment of human alopecia and calvities.
[0030] According to present invention, the multifunctional compound particularly L-2-Oxothiazolidine-4-carboxylic acid considerably enhances the properties of the active ingredients with respect to the treatment of hair loss, more specifically preventing hair loss and stimulating new hair growth.
[0031] It has been observed that L-2-Oxothiazolidine-4-carboxylic acid added provides the necessary ingredients for the healthy growth of hair. Further, L-2-Oxothiazolidine-4-carboxylic acid can provide the necessary nutrients to increase the strength and stability of hair–scalp bond. Additionally, L-2-Oxothiazolidine-4-carboxylic acid being an excellent “Antioxidant”, it can prevent or limit toxic alopecia also.
[0032] Further, it has been observed that the present water soluble composition can also be used in the treatment of Alopecia resulting from oxidative stress as L-2-Oxothiazolidine-4-carboxylic acid is a good antioxidant. L-2-Oxothiazolidine-4-carboxylic acid has been proved to be an excellent radical scavenger. Hence the water soluble combinations can also be used in the treatment of alopecia induced by the use of chemotherapeutic agents.
[0033] Moreover, L-2-Oxothiazolidine-4-carboxylic acid blocks the formation of dihydro testosterone [DHT] which is the main cause of destruction of hair follicles, by preventing the reaction of 5-Alpha reductase on the male hormone testosterone.
[0034] According to an embodiment, the water soluble salts of the actives and L-2-Oxothiazolidine-4-carboxylic acid are for topical use which may be administered in gel, cream, lotion, ointment, solutions or sprays.
[0035] In an embodiment, the water soluble formulations of this invention may contain other active ingredients with complimentary activity, as well as small quantities of conventionally used vehicles and excipients such as fragrances, stabilizers, colours etc.
[0036] It has been found that the formulations made from the salts are therapeutically superior to the formulations made using active ingredients alone. This showed marked synergism between the actives and the multifunctional compound.

Example 1
[0037] 20 gm of L-2-Oxothiazolidine-4-carboxylic acid was added to a suspension of 30 gm of 2,4-Diamino-6-piperidinopyrimidine-3-oxide in 450 gm water. The solution becomes clear after stirring for 1 hr. The resulting solution can be used directly for the preparation of compositions suitable for topical applications. The solution was analyzed for the contents present.
Example 2
[0038] 20 gm of L-2-Oxothiazolidine-4-carboxylic acid and 30 gm of 2,4-Diamino-6-piperidinopyrimidine-3-oxide was dissolved in 1.0 ltr of 95% alcohol. The solvent was evaporated to give the desired solid. Alternatively the solid can also be obtained by partial distillation of the solvent and precipitation of the same with a suitable solvent. The solid can be analyzed using techniques known in the art.
Example 3
[0039] 21.5gm of L-2-Oxothiazolidine-4-carboxylic acid was added to a suspension of 28.5gm of 2,4-Diamino-6-pyrrolidino pyrimidine 3-oxide in 450gm water. The solution becomes clear after stirring for 1 hr. The resulting solution can be used directly for the preparation of compositions suitable for topical applications. The solution was analyzed for the contents present.
Example 4
[0040] 21.5 gm of L-2-Oxothiazolidine-4-carboxylic acid and 28.5gm of 2,4-Diamino-6-pyrrolidinopyrimidine-3-oxide was dissolved in 1.0 ltr of 95% alcohol. The solvent was evaporated to give the desired solid. Alternatively the solid can also be obtained by partial distillation of the solvent and precipitation of the same with a suitable solvent. The solid can be analyzed using techniques known in the art.
Example 5
[0041] 8.67gm of L-2-Oxothiazolidine-4-carboxylic acid was added to a suspension of 7.33 gm of 2,4-Diamino pyrimidine-3-oxide in 484 gm water. The solution becomes clear after stirring for 1 hr. The resulting solution can be used directly for the preparation of compositions suitable for topical applications. The solution was analyzed for the contents present.
Example 6
[0042] 8.67gm of L-2-Oxothiazolidine-4-carboxylic acid and 7.33 gm of 2,4-Diamino pyrimidine-3-oxide was dissolved in 1.0 ltr of 95% alcohol. The solvent was evaporated to give the desired solid. Alternatively the solid can also be obtained by partial distillation of the solvent and precipitation of the same with a suitable solvent. The solid can be analyzed using techniques known in the art.
[0043] IR and NMR analysis of all the above salts confirmed their desired structures.
Example I
[0044] Formulation of water soluble salt of 2,4-Diamino-6-piperidinopyrimidine-3-oxide with L-2-Oxothiazolidine-4-carboxylic acid is shown in Table 1.
Ingredient Amount
Salt 5 gm
Tween 20 0.5 gm
Alcohol 10.0 gm
Fragrance q.s
Colour q.s
Water q.s to 100
Table 1

Example II
[0045] Formulation of water soluble salt of 2,4-Diamino-6-pyrrolidinopyrimidine-3-oxide with L-2-Oxothiazolidine-4-carboxylic acid is shown in Table 2.
Ingredient Amount
Salt 5.27gm
Tween 20 0.5 gm
Alcohol 10.0 gm
Fragrance q.s
Colour q.s
Water q.s to 100
Table 2
Example III
[0046] Formulation of water soluble salt of 2,4-Diaminopyrimidine-3-oxide with L-2-Oxothiazolidine-4-carboxylic acid is shown in Table 3.
Ingredient Amount
Salt 3.26 gm
Tween 20 0.5 gm
Alcohol 10.0 gm
Fragrance q.s
Colour q.s
Water q.s to 100
Table 3
[0047] pH of all the above water soluble compositions were adjusted to 4.5 - 5.5 using mild bases (organic / inorganic) known in the art.
[0048] Open label, phase II, clinical study was carried out, to evaluate the safety and efficacy of topical application of the above 3 compositions and conventional 5% solution of 2,4-Diamino-6-piperidinopyrimidine-3-oxide (Minoxidil) available in market, for the treatment of mild to moderate androgenic alopecia in male patients.

Hair density and hair growth results of Minoxidil 5% (market sample) on subjects tested:

mRNA levels % Improvement after month 4
5% Minoxidil
(Market sample) 6.3%

Hair density and hair growth results of water soluble salt of L-2-Oxothiazolidine-4-carboxylic acid with 2,4-Diamino-6-piperidinopyrimidine-3-oxide (Minoxidil) on subjects tested :

mRNA levels % Improvement after month 4
Salt of L-2-Oxothiazolidine-4-carboxylic acid with 2,4-Diamino-6-piperidinopyrimidine-3-oxide 18%

Hair density and hair growth results of water soluble salt of L-2-Oxothiazolidine-4-carboxylic acid with 2,4-Diamino-6-pyrrolidinoyrimidine-3-oxide on subjects tested :

mRNA levels % Improvement after month 4
Salt of L-2-Oxothiazolidine-4-carboxylic acid with 2,4-Diamino-6-pyrrolidinopyrimidine-3-oxide 13.5%

Hair density and hair growth results of water soluble salt of L-2-Oxothiazolidine-4-carboxylic acid with 2,4-Diamino pyrimidine-3-oxide on subjects tested :

mRNA levels % Improvement after month 4
Salt of L-2-Oxothiazolidine-4-carboxylic acid with 2,4-Diamino pyrimidine-3-oxide 12.6%

[0049] Few research papers disclosed that mRNA levels have been co-related to hair growth. More the mRNA value, better is the effectiveness of the formulation in hair growth. According to above clinical study, the water soluble salts showed increased mRNA values. Particularly, the water soluble composition of 2,4-Diamino-6-piperidinopyrimidine-3-oxide (Minoxidil) with L-2-Oxothiazolidine-4-carboxylic acid showed almost 3 times mRNA value when compared with 5% solution of 2,4-Diamino-6-piperidinopyrimidine-3-oxide (Minoxidil) available in market as shown in Table 4.

Sl.No Composition mRNA values
1 5% Minoxidil
(market) 6.3%
2 Water soluble salt of Minoxidil 18%
3 Water soluble salt of 2,4-Diamino-6-pyrrolidinopyrimidine-3-oxide 13.5%
4 Water soluble salt of 2,4-Diamino pyrimidine-3-oxide 12.6%
Table 4
[0050] The foregoing description of the specific embodiments will so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and therefore, such adaptations and modifications are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modifications within the spirit and scope of the appended claims.