WO2018070940A1 - An injectable composition for localized controlled and sustained delivery system - Google Patents

Abstract

The present disclosure is directed to an injectable composition which is capable of delivering a controlled and sustained amount of at least one 5α-reductase inhibitor to a subject. The injectable composition comprises a polymer solution comprising a biocompatible and biodegradable polymer dissolved in at least one biocompatible solvent under a non-aqueous condition, the polymer solution further comprising at least one 5α-reductase inhibitor dissolved, dispersed or suspended therein, wherein the dissolved biocompatible and biodegradable polymer is capable of solidifying into a gel-like state under an aqueous condition by the elution of the at least one biocompatible solvent from the polymer solution and the solidified biocompatible and biodegradable polymer entraps the at least one 5α-reductase inhibitor therein. Uses of the injectable composition are also disclosed.

Description

AN INJECTABLE COMPOSITION FOR LOCALIZED CONTROLLED AND

SUSTAINED DELIVERY SYSTEM

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority of Singapore Patent Application No. 10201608607R, filed on 14 October 2016, the contents of it being hereby incorporated by reference in its entirety for all purposes.

TECHNICAL FIELD

[0002] The present disclosure refers generally to the field of controlled and sustained delivery systems, specifically an in situ polymer precipitation system. In particular, the disclosure is directed to an injectable composition which is capable of delivering a controlled and sustained amount of at least one 5a-reductase inhibitor to a subject.

BACKGROUND

[0003] Hair loss, also known as alopecia or baldness, refers to a loss of hair from the head.

Androgenic Alopecia

[0004] Androgenic alopecia (AGA) is the most common cause of balding in males, which increases in frequency and severity with age. The prevalence is highest in Caucasians, around 50% for men in their 50s, with a lower prevalence rate in Chinese (30% for men above 50 years). It was estimated that approximately 80% of Caucasians show signs of balding by the age of 70. Females are affected by patterned baldness too but at a lesser rate of about 25%. Though the disease displayed more apparent effects in older people, the thinning of hair is known to initiate amongst people as young as 12 to 40 years of age. The prevalence of the disease is also evident from the astounding 1.5 billion USD expended on combating hair loss in the United States each year. While it may be a cosmetic concern, many studies have shown that AGA causes much psychological distress to patients, so much so that it is one of the top 10 conditions seen in National Skin Centre yearly. To date there is no universally successful treatment for AGA; the most successful being an oral medication, finasteride. However, oral finasteride has multiple side effects (like erectile dysfunction, reduced sperm count, depression and post finasteride syndrome) due to its systemic absorption.

5a-reductase inhibitor

[0005] 5a-reductase inhibitor competes with testosterone at the binding site of type II 5a- reductase and prevents the conversion of testosterone to dihydrotestosterone (DHT). High levels of DHT would result in follicular miniaturization and shortening of the anagen phase in the hair growth cycle, progressively leading to Androgenic Alopecia (AGA). Another consequence of high levels of DHT is the enlargement of the prostate gland in men, leading to benign prostatic hyperplasia (BPH). Hence, the inhibiting action of 5a-reductase inhibitor helps in the lowering of DHT levels to alleviate the conditions of AGA and BPH.

Finasteride

[0006] Finasteride is a type of 5a-reductase inhibitor. It is an FDA approved oral drug for the treatment of AGA and BPH in men only, due to the associated teratogenic risk in women. Currently, an oral dose of lmg/day and 5mg/day is administered to patients in the treatment of AGA and BPH respectively. Specifically for AGA, this dose has shown to be clinically efficacious with prolonged treatment and proven to be well tolerated in man. Even though it had been reported that adverse side effects such as sexual disorders including suppressed libido, erectile dysfunction and ejaculation disorder can arise from the consumption of finasteride at lmg/day, the percentage of patients thus affected is not large. A clinical study also showed that the prolonged treatment or cessation of the treatment usually led to the disappearance of these side effects. Nevertheless, since finasteride does not target the underlying genetic reasons for the cause of AGA, cessation of the treatment would result in a resumption of the balding condition.

[0007] Therefore, a dedicated life-long treatment is mandatory to maintain a cosmetic response, and this often leads to poor patient compliance.

[0008] It is an object of the present disclosure to provide a composition which alleviates, or at least ameliorates, the effects of baldness, for example. It is another object of the present disclosure to provide a composition which is biocompatible. It is a further object of the present disclosure to provide a controlled delivery system for a bioactive agent, such as a 5a-reductase inhibitor, against hair loss, with a sustained release over a long period of time, in order to improve patient's compliance. It is yet another object of the present disclosure to provide for a sustained and localized delivery option for a 5a-reductase inhibitor, such as finasteride and dutasteride, which will significantly improve efficacy and reduce side-effects through reducing systemic absorption of finasteride. It is yet a further object of the present disclosure to develop subcutaneous delivery of effective molecules to manage this common condition.

SUMMARY

[0009] The components of the present disclosure include a biocompatible and biodegradable polymer dissolved in at least one biocompatible solvent and further include a bioactive agent, such as a 5a-reductase inhibitor, to form a polymer solution which is injectable through commonly available syringes and needles to a localized target site or area.

[0010] In a first aspect, there is provided an injectable composition comprising a polymer solution comprising a biocompatible and biodegradable polymer dissolved in at least one biocompatible solvent under a non-aqueous condition, the polymer solution further comprising at least one 5a-reductase inhibitor dissolved, dispersed or suspended therein, wherein the dissolved biocompatible and biodegradable polymer is capable of solidifying into a gel-like state under an aqueous condition by the elution of the at least one biocompatible solvent from the polymer solution and the solidified biocompatible and biodegradable polymer entraps the at least one 5 a- reductase inhibitor therein.

[0011] An advantage of the present disclosure is the biodegradable nature of the biocompatible and biodegradable polymer in the injectable composition which allows the solidified polymer gel (or solid depot as used interchangeably) formed to be hydrolyzed or dissolved or eroded away with time which can be over a period of 1 week, 1 month, 3 months, 6 months, 1 year or 2 years. During biodegradation of the polymer gel, the at least one 5a-reductase inhibitor entrapped therein under aqueous conditions, is slowly released by diffusion along with the biodegradation of the polymer. The reduction in mass and volume of the polymer gel allows the repeated injection of the injectable composition if desired or required. This may occur, for example, when the release rate of the at least one 5a-reductase inhibitor is known to fall below effective levels or when a clinical positive result is not observed due to suspected depletion of the at least one 5 a- reductase inhibitor reservoir.

[0012] Another advantage is that the injectable composition may be suitable to transform conventional oral administration of the at least one 5a-reductase inhibitor into a controlled and sustained delivery system to help improve patients' compliance by reducing the frequency of administration.

[0013] Hence, another advantage is a controlled and sustained delivery of the at least one 5a- reductase inhibitor, which mitigates the wide fluctuations of the at least one 5a-reductase inhibitor in blood concentration commonly associated with a single oral dose. A stable and consistent concentration of the at least one 5a-reductase inhibitor in blood would be able to reach and maintain effective levels in a shorter period of time and for a prolonged period.

[0014] In a second aspect, there is provided an injectable composition as described above for use in a cosmetic treatment.

[0015] In a third aspect, there is provided a method of treating baldness comprising administering to a subject an effective amount of an injectable composition as described above.

[0016] In a fourth aspect, there is provided a method of implanting an injectable composition as described above into a subject, comprising injecting the injectable composition into the subject by using a needle. Advantageously, subcutaneous delivery has the advantage of delivering the at least one 5a-reductase inhibitor directly to the site of action, resulting in better efficacy with minimal systemic side effects. Such systems will also be able to deliver more than one 5a- reductase inhibitor that will work synergistically to achieve better results.

[0017] In a fifth aspect, there is provided use of an injectable composition as described above in the manufacture of a cosmetic formulation for the cosmetic treatment of baldness.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] In the drawings, like reference characters generally refer to the same parts throughout the different views. The drawings are not necessarily drawn to scale, emphasis instead generally being placed upon illustrating the principles of various embodiments. In the following description, various embodiments are described with reference to the following drawings.

[0019] Fig. 1 shows schematically a method of using the injectable composition, wherein: Figure la shows the 5a-reductase inhibitor loaded polymer solution (1) injected into the subcutaneous tissues (2) via a needle (3). Figure lb shows the process of phase inversion, whereby water (4) from surrounding tissues enters into the polymer solution and solvents (5) elute out of the polymer solution. This causes the polymer to precipitate forming a gel or solid depot loaded with 5a-reductase inhibitor. Figure l c shows the depot acting as a 5a-reductase inhibitor reservoir and providing localized, controlled and sustained release of 5a-reductase inhibitor (6) to the surrounding tissues over a prolonged period. Figure Id shows that the polymeric depot (7) biodegrades over time and the 5a-reductase inhibitor gets released into the tissue and exhausted from the depot.

[0020] Fig. 2 shows a schematic of formulating the 5a-reductase inhibitor into an "in situ" gelling system that can be injected subcutaneously. The numbers in the scheme correspond to the following components: 1 shows the at least one 5a-reductase inhibitor, 2 shows one biocompatible solvent, 3 shows a second biocompatible solvent, 4 shows the biocompatible and biodegradable polymer, wherein components 1 to 4 form the injectable composition shown as 5. For in situ gelling, this composition is injected by syringe into a buffer 6, at a pH value of 7.4.

[0021] Fig. 3 shows an in vitro release profile for the injectable composition with one biocompatible solvent.

[0022] Fig. 4 shows an in vitro release profile for the injectable composition with two biocompatible solvents.

[0023] Fig. 5 shows the results from a concept trial involving two monkeys, as evidenced by hair weight (Fig. 5a) and hair density (Fig 5b).

DESCRIPTION

[0024] The following detailed description refers to the accompanying drawings that show, by way of illustration, specific details and embodiments in which the disclosure may be practised. These embodiments are described in sufficient detail to enable those skilled in the art to practise the invention. Other embodiments may be utilized and structural and logical changes may be made without departing from the scope of the disclosure. The various embodiments are not necessarily mutually exclusive, as some embodiments can be combined with one or more other embodiments to form new embodiments.

[0025] Injectable compositions have been developed according to various embodiments. The injectable composition according to the present disclosure may be injected into a subject in need of a treatment. The subject may be in need of a medical treatment. Alternatively, the subject may be in a desirable need of a cosmetic treatment. In one disclosed embodiment, the subject may be suffering from baldness, and may be perceived to be in a desirable need of a cosmetic treatment. The injectable composition, when injected, may represent an in situ polymer precipitation system and refers to a type of in situ forming delivery system that characteristically converts from sol to gel through a stimulus known as phase inversion. In a physiological setting, the presence of water in the environment or tissue is the stimulus which triggers the phase inversion, whereby water from the surrounding tissue enters into the injected composition and the at least one biocompatible solvent from the injected composition elutes or diffuses out, causing the precipitation of the biocompatible and biodegradable polymer into a solid depot or polymer gel. In cases where bioactive agents such as cosmetic agents, for example 5a-reductase inhibitors, are present in the injectable composition, the bioactive agent may be entrapped in the polymer gel upon phase inversion. This results in a reservoir of the bioactive agent for the controlled and sustained release of the bioactive agent into the surroundings of the site of injection. The initial release kinetics of the bioactive agent is governed by the rate of phase inversion. Upon the formation of the polymer gel, the release kinetics are dependent on the rate of diffusion of water into, and the rate of diffusion of bioactive agent out of the polymer gel, until the onset of polymer biodegradation where the release profile is less predictable due to the increasing number of interplaying factors.

[0026] Accordingly, in a first aspect, the present disclosure refers to an injectable composition comprising a polymer solution comprising a biocompatible and biodegradable polymer dissolved in at least one biocompatible solvent under a non-aqueous condition, the polymer solution further comprising at least one 5a-reductase inhibitor dissolved, dispersed or suspended therein, wherein the dissolved biocompatible and biodegradable polymer is capable of solidifying into a gel-like state under an aqueous condition by the elution of the at least one biocompatible solvent from the polymer solution and the solidified biocompatible and biodegradable polymer entraps the at least one 5a-reductase inhibitor therein.

[0027] Advantageously, the biocompatible polymer is biodegradable. A 'biodegradable' polymer, in the context of the present disclosure, refers to a polymeric material, which is hydrolyzed, dissolved and/or eroded away under physiological conditions, which are essentially aqueous conditions, within a limited time period. The term 'polymer' or 'polymeric' in the context of the present disclosure refers to the biocompatible and biodegradable polymer, which is used in the injectable composition. The biocompatible and biodegradable polymers used in the present disclosure are generally considered insoluble in aqueous medium but are considered to be soluble in a water-miscible organic solvent (defined below). When injected into physiological environment or in contact with any aqueous medium, phase inversion occurs whereby the at least one biocompatible solvent elutes or diffuses out from the polymer solution and water from the aqueous environment diffuses into the injected composition causing the precipitation of the biocompatible and biodegradable polymer in the injected composition. A sol-gel transition occurs and a polymer gel is formed, temporarily entrapping the bioactive agents, such as at least one 5a-reductase inhibitor, within the polymer gel. The at least one 5a-reductase inhibitor, under aqueous conditions, is slowly released into the surrounding environment, dependent on the rate of diffusion. The surrounding environment may be a physiological surrounding, such as a mammal body. Preferably, the environment is a subcutaneous region, more preferably in the scalp region of a human. 'Temporarily entrapped', in the context of the present disclosure, refers to the at least one 5a-reductase inhibitor being entrapped within the polymer gel, and being slowly released from the polymer gel either during the phase inversion or through diffusion after the phase inversion is completed. The release rate may be measured in mg/day and may be about 0.1 to about 5 mg/day, or about 0.5 to about 3 mg/day, or about 1 to about 2 mg/day, if the total amount of 5a-reductase inhibitor injected is about 100 mg.

[0028] Examples of the biocompatible and biodegradable polymers suitable for the present injectable composition include, but are not limited to, polylactides, polyglycolides, polycaprolactones, poly anhydrides, polyure thanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(maleic anhydride), and copolymers, terpolymers, and combinations or mixtures thereof.

[0029] A 'biocompatible polymer', or 'biocompatible solvent', in the context of the present disclosure, refers to polymer or solvent made out of a material which does not cause any, or negligible, irritations when brought into contact with a body, in particular subcutaneous tissue. The biocompatible and biodegradable polymer is dissolved in at least one biocompatible solvent. Dissolved, in the context of the present disclosure, refers to the polymer being substantially miscible with the at least one biocompatible solvent, when the injectable composition is not exposed to aqueous conditions, as for example physiological conditions. In the context of the present disclosure, the at least one 5a-reductase inhibitor is dissolved, dispersed or suspended in the polymer solution of the injectable composition. The biocompatible and biodegradable polymer and the at least one biocompatible solvent may therefore serve as a vehicle or a carrier system for the at least one 5a-reductase inhibitor, from which the at least one 5a-reductase inhibitor is released through slow diffusion out of the polymer gel upon exposure to physiological conditions. '5a-reductase inhibitor' refers to any compound which can inhibit the action of 5a-reductase which primarily role includes but is not limited to the conversion of testosterone into dihydrotestosterone. 'Non-aqueous condition', in the context of the present disclosure, refers to conditions wherein the injectable composition is not exposed to a significant amount of water. A significant amount of water may not include humidity from ambient air. 'Aqueous conditions', in the context of the present disclosure, refers to conditions wherein the composition is exposed to significant amounts of water. A significant amount of water may include the composition being surrounded by water, or comprising water. Aqueous conditions are, for example, physiological conditions in a body. The body may be that of a mammal, preferably a human.

[0030] The term 'biocompatible solvent' refers to pharmaceutically acceptable organic solvents including but not restricted to N-methyl-2-pyrrolidone, methoxypolyethylene glycol, alkoxypolyethylene glycol, polyethylene glycol esters, glycofurol, glycerol formal, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decylmethylsulfoxide, benzyl benzoate, ethyl benzoate, triacetin, diacetin, tributyrin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethylglycerides, triethyl phosphate, diethyl phthalate, diethyl tartrate, ethyl lactate, propylene carbonate, ethylene carbonate, butyrolactone, and l-dodecylazacyclo-heptan-2-one, and any combinations thereof.

[0031] In various embodiments, the injectable composition comprises about 20 to about 90 wt% of the at least one biocompatible solvent, based on the total weight of the injectable composition. For example, about 35 to 90 wt%, or about 25 to 60 wt%, or about 40 to 90 wt%, or about 60 to 90 wt%, or about 55 to 90 wt%, or about 20 to 80 wt%, and preferably about 60 to 80 wt% of the at least one biocompatible solvent may be comprised in the injectable composition.

[0032] In various embodiments, the at least one biocompatible solvent may comprise a first biocompatible solvent and a second biocompatible solvent. The first biocompatible solvent may be miscible in water. Advantageously, the first biocompatible solvent being miscible with water increases the diffusion of the first biocompatible solvent into the body and allows for the polymer precipitation, thereby supporting the phase inversion of the polymer solution under aqueous conditions in contrast to non-aqueous conditions.

[0033] In various embodiments, the injectable composition comprises about 25 to about 60 wt%, or about 25 to about 50 wt%, or about 40 to about 60 wt% of the first biocompatible solvent, based on the total weight of the injectable composition. Advantageously, these weight ranges are particularly advantageous in keeping the biocompatible and biodegradable polymer dissolved under non-aqueous conditions, and supporting solidification under aqueous conditions, while entrapping the at least one 5a-reductase inhibitor. For example, about 45 to about 55 wt%, or about 30 wt%, or about 50 wt% of the first biocompatible solvent may be comprised in the injectable composition.

[0034] The first biocompatible solvent may be a coordinating solvent, i.e. it may comprise electron lone pairs, preferably in the form of an amine (primary, secondary or tertiary) or an ether moiety. Preferably, the first biocompatible solvent may be selected from a group consisting of, but not being limited to, N-methyl-2-pyrrolidone (NMP), methoxypolyethylene glycol, alkoxypolyethylene glycol, polyethylene glycol esters, glycofurol, glycerol formal, tetrahydrofuran, and any combination thereof. In one example, the first biocompatible solvent is N-methyl-2-pyrrolidone.

[0035] The second biocompatible solvent may be a glyceride, which may be a monoglyceride, a diglyceride or a triglyceride. Advantageously, a glyceride provides, due to its three optionally esterified hydroxyl functionalities, electronic interactions with the remaining components of the injectable composition which are beneficial in the phase inversion. The introduction of a second biocompatible solvent, as for example triacetin, may also be advantageous in reducing the overall toxicity, as it may have a higher biocompatibility than some of the first biocompatible solvents, such as NMP. The second biocompatible solvent may have no negative effect on the properties associated with the sustained and controlled release which is related to the phase inversion (as can be seen from Fig. 4). Hence, the second biocompatible solvent may be selected from a group consisting of, but not being limited to, triacetin, diacetin, tributyrin, triethylglycerides, and any combination thereof. In one example, the second biocompatible solvent is triacetin. [0036] In various embodiments, the injectable composition comprises about 15 to about 40 wt%, or about 15 to about 35 wt%, or about 20 to about 40 wt%, or about 20 to about 30 wt% of the second biocompatible solvent, based on the total weight of the injectable composition. Advantageously, these weight ranges are particularly advantageous in keeping the biocompatible and biodegradable polymer dissolved under non-aqueous conditions, and supporting solidification under aqueous conditions, while entrapping the at least one 5a-reductase inhibitor. For example, about 20 to about 25 wt%, or about 20 wt% or about 30 wt% of the second biocompatible solvent may be comprised in the injectable composition.

[0037] The biocompatible and biodegradable polymer may have an inherent viscosity of about 0.2 dL/g to about 0.6 dL/g under non-aqueous conditions. Advantageously, this viscosity range is beneficial, under non-aqueous conditions, for injectability and under aqueous conditions, after phase inversion, for the release rate of the at least one 5a-reductase inhibitor. Preferably, the biocompatible and biodegradable polymer may have an inherent viscosity of about 0.3 dL/g to about 0.5 dL/g, or about 0.2 dL/g or about 0.4 dL/g under non-aqueous conditions. In one embodiment, the biocompatible and biodegradable polymer may be a copolymer of glycolic acid and lactic acid (PLGA).

[0038] The biocompatible and biodegradable polymer may be a polylactide. In one embodiment, the biocompatible and biodegradable polymer may be a polylactide. A polylactide polymer is a polymer based on lactic acid or a copolymer of glycolic acid and lactic acid (PLGA), including poly(D,L-lactide-co-glycolide) and poly(L-lactide-co-glycolide).

[0039] In some embodiments, the biocompatible and biodegradable polymer may comprise an acidic end group.

[0040] In some embodiments, the biocompatible and biodegradable polymers comprising polylactides may have a weight average molecular weight of about 1,000 to about 120,000, or about 10,000 to about 100,000, or about 20,000 to about 80,000, or about 50,000 to about 60,000. In one embodiment, PLGA is used as the biocompatible and biodegradable polymer, and the average molecular weight for PLGA is related to the inherent viscosity and therefore may be expressed with this value. The monomer ratios of lactic acid to glycolic acid may be about 15:85 to 100:0, or about 35:65 to 100:0, or about 45:55 to 100:0, or about 55:45 to 100:0, or about 40:60 to 60:40, or it may be about 50:50. [0041] In various embodiments, the injectable composition comprises about 10 to about 80 wt% of the biocompatible and biodegradable polymer, based on the total weight of the injectable composition. In preferred embodiments, about 10 to about 60 wt%, or about 10 to about 30 wt%, or about 10 to about 40 wt% of the biocompatible and biodegradable polymer may be comprised in the injectable composition.

[0042] In a preferred embodiment, the injectable composition comprises about 20 to about 40 wt% of the biocompatible and biodegradable polymer, based on the total weight of the injectable composition. Advantageously, in this particular percentage by weight range, it is possible to obtain a near zero order release profile, while still keeping the composition injectable. At higher polymer concentrations, the polymer composition may not be injectable anymore, in particular when long chain polymers are used. At lower polymer concentrations, the polymer composition may not form a sufficiently solidified depot, in particular when short chain polymers are used (the depot would be too liquid).

[0043] For the embodiment wherein the biocompatible and biodegradable polymer is PLGA, the combination of a particular inherent viscosity, for example in the range of 0.2 dL/g to 0.4 dL/g, and a particular percentage by weight range, for example about 20 to about 40 wt% of PLGA, may result in a substantially zero order release profile (as shown in Figs. 3 and 4) while keeping the composition injectable.

[0044] In certain embodiments, the at least one 5a-reductase inhibitor may be finasteride or dutasteride. Additional bioactive agents, such as prostaglandin, may also be included in the injectable composition. In one embodiment, the at least one 5a-reductase inhibitor may be dissolved or dispersed or suspended in the polymer solution. In various embodiments, the injectable composition comprises about 0.1 to about 20 wt% of the at least one 5a-reductase inhibitor, based on the total weight of the injectable composition. Preferably, about 0.1 to about 10 wt%, or about 0.2 to about 5 wt%, or about 0.5 to about 2 wt%, or about 1 to 2 wt% or about 1.5 wt% of the at least one 5a-reductase inhibitor is comprised in the injectable composition.

[0045] In another embodiment, the at least one 5a-reductase inhibitor may be encapsulated in a microparticle. The microparticle may be the biocompatible and biodegradable polymer.

[0046] In a second aspect, there is provided an injectable composition as described in the first aspect, for use in a cosmetic treatment. A therapeutic treatment is explicitly excluded from this definition. The injectable composition may not have a therapeutic effect, as it is injected locally into the hair region of the head. Therefore, the treatment area is localized to the hair region and restricted to the cosmetic treatment of baldness.

[0047] The cosmetic treatment may be for balding, or hair loss.

[0048] In a third aspect, there is provided a method of treating baldness comprising administering to a subject an effective amount of an injectable composition as described in the first aspect. The administration may be in the form of a subcutaneous injection.

[0049] In a preferred embodiment, the subject may be a mammal. The mammal may be a human. It may be a male human. Alternatively, it may be a female human. Advantageously, the treatment may also be applicable for female humans. This is because there is minimal systemic absorption. In particular, due to the localized treatment, the liver is minimally involved. As a comparison, oral finasteride is currently not approved for use in women for female patterned hair loss, due to teratogenic side effects arising from oral administration.

[0050] An effective amount of the injectable composition may be about 0.5 to about 6 g, or about 1 to about 4 g, or about 2 to about 3 g.

[0051] In various embodiments, the effective amount of the injectable composition may comprise an amount of 30 to 60 mg of the at least one 5a-reductase inhibitor, which may be based on a daily dosage of 1 to 2 mg released over a period of about one month. In a weight percentage range of, for example, 1 to 2 wt% of the at least one 5a-reductase inhibitor, based on the weight of the at least one biocompatible solvent together with the biocompatible and biodegradable polymer, the effective amount of the composition to be administrated may be 1.5 g to 6 g. For example, the effective amount may be administrated as a composition comprising 1.2g of a polylactide (PLGA 5002A), 1.8g of NMP, and 45 mg of the at least one 5a-reductase inhibitor (1.5 wt%).

[0052] In the in vitro and animal studies, 0.2 mL (approximately 200 mg) of the injectable composition was typically injected, with approximately 3 mg of the at least one 5a-reductase inhibitor (1.5 wt%). This effective amount may be extrapolated for the treatment in humans.

[0053] The effective amount may be administered at a frequency of about once a month to about once every four months, or about once a month to about once every three months, or about once a month to about once every two months.

[0054] As mentioned above, the treatment may be applied subcutaneously. Advantageously, the treatment may be applied to the hair region of the head (scalp area). [0055] The treatment may further comprise topical administration of an additional cosmetic hair loss agent. The additional cosmetic hair loss agent may be selected from Minoxidil, Prostaglandin E2 and a combination thereof.

[0056] In a fourth aspect, there is provided a method of implanting an injectable composition according to the first aspect into a subject as defined above, comprising injecting the injectable composition into the subject by using a needle. One advantage of the disclosure is the injectable nature of the composition, which allows it to be injected into sites including subcutaneous, intramuscular, intramyocardial, adventitial, intratumoral, or intracerebral portion, or body cavity of a human or animal. The injectable nature of the composition may be a result of the particular weight percentage ranges disclosed for the biocompatible and biodegradable polymer and the at least one biocompatible solvent. Advantageously, the injection is carried out in the subcutaneous region of the skin. Further advantageously, this implanting method provides for a localized treatment, which results in minimal systemic absorption.

[0057] In a fifth aspect, there is provided a use of an injectable composition of the first aspect in the manufacture of a cosmetic formulation for the cosmetic treatment of baldness.

[0058] In the approach described in the present disclosure, three points were addressed:

1) Develop a delivery system that is able to carry up to 3 bioactive agents for delivery into the site of action (dermal-epidermal junction) via subcutaneous injection.

2) The delivery system would then release the bioactive agents slowly over the course of up to 4 months while the carrier system undergoes spontaneous biodegradation into nontoxic protein molecules.

3) Bioactive agents, such as finasteride, prostaglandins etc, will thus be released into the sites of action at a constant rate over up to 4 months with little/no systemic absorption.

[0059] The injectable nature of the composition allows for localized treatment by directing the composition directly or closer to the site in need of the bioactive ingredient. It was discovered specifically, in the treatment of AGA, that a subcutaneously injected composition in the scalp tissues may allow for a better treatment of AGA, by virtue of enhanced bioavailability of the at least one 5a-reductase inhibitor. A subcutaneous injection of the sustained delivery system into the scalp allows the localized delivery of the at least one 5a-reductase inhibitor to the hair follicles. Such close proximity also allows for a faster positive clinical observation by supplying the at least one 5a-reductase inhibitor directly to the target site, diminishing chances of elimination of the 5a-reductase inhibitor by external factors.

[0060] The localized release (in the case of subcutaneous injection in treatment of AGA) and high bioavailability (due to the bypass of the liver) of the at least one 5a-reductase inhibitor allows the use of a lower dose for the same clinical efficacy as compared to conventional oral administration, minimizing the risk of systemic side effects.

[0061] The use of a biodegradable vehicle also allows zero residues to be left behind upon full degradation of the polymer via gradual systemic clearance.

[0062] The disappearance of the polymer gel, as a result of its biodegradable nature, allows for regular injection at the same site without overcrowding issues.

EXAMPLES

[0063] The following examples provide a description of the fabrication of the injectable composition and are provided solely for purposes of illustration, and should not be construed as limiting the scope of the invention in any manner.

Example 1: Fabrication of polymer solution

[0064] 12mg of finasteride is dissolved in 3g of N-methyl-2-pyrrolidone and stirred for 4 hours. Subsequently, 1.2g of triacetin and 1.8g of PLGA with an inherent viscosity of 0.4dL/g and an acid end group are added and the final polymeric solution is left to stir overnight.

[0065] In a typical in vitro experiment, about 0.15 to about 1.5 wt% of the at least one 5a- reductase inhibitor was used. All weight percentages stated in this section are based on the total weight of the biocompatible and biodegradable polymer with the at least one biocompatible solvent and excluding the at least one 5a-reductase inhibitor in the 100%.

[0066] Another formulation according to the disclosure is labelled as F460 and has the following composition: 2.4g of PLGA 5002A is added to 3.6g of NMP. This makes up 6g in total for weight of polymer and solvent. For 1.5 wt% loading of the at least one 5a-reductase inhibitor, 90mg is added to the formulation.

[0067] Typically, 0.2 ml of gel is injected for each sample in in vitro studies and for each dose in animal studies. 0.2 ml of gel is approximately 200 mg; for 1.5 wt% 5a-reductase inhibitor loading the weight of 5a-reductase inhibitor loaded is approximately 3mg. Example 2: Carrier System

[0068] A carrier system was developed and loaded with at least one 5a-reductase inhibitor (Fig. 2). It was demonstrated, in vitro, that the system has acceptable pharmacokinetic profiles and release patterns (in Figs. 3 and 4). The carrier system is schematically shown in Fig. 2 and depicts an in-situ gelling system - a solution of the at least one 5a-reductase inhibitor and the biocompatible and biodegradable polymer in a pharmaceutically-acceptable solvent, which may be injected subcutaneously, whereupon the composition immediately gels, and subsequently slowly releases the at least one 5a-reductase inhibitor.

Example 3: Sustained and controlled in vitro release

[0069] Examples of the sustained and controlled in vitro release of two of the proposed formulations are depicted in Figs. 3 and 4. Upon injection into a buffer (that mimics subcutaneous tissue environment), the release profiles shown in Figs 3 and 4 were obtained. Fig. 3 shows the release profile for a formulation without triacetin (F460), while Fig. 4 shows that of a formulation with triacetin (F433). All in all, both formulations are representative of the release profile that can be achieved by changing the solvent ratios.

*The amount of finasteride is based on 100% of a total weight of PLGA 5002A, NMP and Triacetin.

Example 4: Clinical Trial

[0070] There was conducted an initial proof of concept trial involving two monkeys. In this proof-of-concept trial, the Formulation F433 was used. A left-right, placebo controlled trial was designed whereby the scalp of the monkeys was divided into two equal halves. Baseline hair density and caliber was determined using conventional folliculoscope (whereby a magnified photograph of a predetermined region was taken and the number of hairs per cm² and average thickness of hairs in the defined region was determined through computer image analysis.) At monthly intervals, finasteride loaded into the carrier system was injected into the right side of the scalp of the monkey (active side) while the carrier system without finasteride was injected into the left side of the scalp (placebo side). Hair density, hair weight as well as caliber was measured and compared. The results are shown in Fig 5. In summary, the side that was injected with carrier-loaded finasteride has twice as much hair and the hair caliber was thicker than on the placebo side.

Claims

1. An injectable composition comprising a polymer solution comprising a biocompatible and biodegradable polymer dissolved in at least one biocompatible solvent under a nonaqueous condition, the polymer solution further comprising at least one 5a-reductase inhibitor dissolved, dispersed or suspended therein, wherein the dissolved biocompatible and biodegradable polymer is capable of solidifying into a gel-like state under an aqueous condition by the elution of the at least one biocompatible solvent from the polymer solution and the solidified biocompatible and biodegradable polymer entraps the at least one 5a-reductase inhibitor therein.

2. The injectable composition of claim 1, wherein the at least one 5a-reductase inhibitor comprises finasteride or dutasteride.

3. The injectable composition of any one of the preceding claims, wherein the injectable composition further comprises prostaglandin.

4. The injectable composition of any one of the preceding claims, wherein the at least one biocompatible solvent comprises a water-miscible organic solvent.

5. The injectable composition of claim 4, wherein the at least one biocompatible solvent is selected from the group consisting of N-methyl-2-pyrrolidone, methoxypolyethylene glycol, alkoxypolyethylene glycol, polyethylene glycol esters, glycofurol, glycerol formal, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decylmethylsulfoxide, benzyl benzoate, ethyl benzoate, triacetin, diacetin, tributyrin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethylglycerides, triethyl phosphate, diethyl phthalate, diethyl tartrate, ethyl lactate, propylene carbonate, ethylene carbonate, butyrolactone, 1- dodecylazacyclo-heptan-2-one, and a mixture thereof.

6. The injectable composition of any one of the preceding claims, wherein the injectable composition comprises about 20 to about 90 wt% of the at least one biocompatible solvent, based on the total weight of the injectable composition.

7. The injectable composition of any one of the preceding claims, wherein the at least one biocompatible solvent comprises a first and a second biocompatible solvent.

8. The injectable composition of claim 7, wherein the injectable composition comprises about 25 to about 60 wt% of the first biocompatible solvent, based on the total weight of the injectable composition.

9. The injectable composition of claim 7 or 8, wherein the injectable composition comprises about 20 to about 30 wt% of the second biocompatible solvent, based on the total weight of the injectable composition.

10. The injectable composition of any one of the preceding claims, wherein the biocompatible and biodegradable polymer is selected from the group consisting of polylactide, polyglycolide, polycaprolactone, polyanhydride, polyurethane, polyesteramide, polyorthoester, polydioxanone, polyacetal, polyketal, polycarbonate, polyorthocarbonate, polyphosphazene, polyhydroxybutyrate, polyhydroxy valerate, polyalkylene oxalates, polyalkylene succinate, poly(malic acid), poly(maleic anhydride), a copolymer thereof, a terpolymer thereof, and a combination thereof.

11. The injectable composition of any one of the preceding claims, wherein the injectable composition comprises about 10 to about 80 wt% of the biocompatible and biodegradable polymer, based on the total weight of the injectable composition.

12. The injectable composition of any one of the preceding claims, wherein the at least one 5a-reductase inhibitor is encapsulated in a microparticle.

13. The injectable composition of any one of the preceding claims for use in a cosmetic treatment.

14. A method of treating baldness comprising administering to a subject an effective amount of an injectable composition according to any one of claims 1 to 13.

15. The method of claim 14, wherein the subject is a mammal.

16. The method of claim 15, wherein the mammal is a male human.

17. The method of claim 15, wherein the mammal is a female human.

18. The method of any one of claims 14 to 17, wherein the effective amount is about 0.5 to about 6 g.

19. The method of any one of claims 14 to 18, wherein the effective amount is administered in a frequency of about once a month to about once every four months.

20. The method of any one of claims 14 to 19, wherein the treatment is applied subcutaneously.

21. The method of any one of claims 14 to 20, wherein the treatment further comprises topical administration of an additional cosmetic hair loss agent.

22. A method of implanting an injectable composition according to any one of claims 1 to 13 into a subject, comprising injecting the injectable composition into the subject by using a needle.

23. Use of an injectable composition of any one of claims 1 to 13 in the manufacture of a cosmetic formulation for the cosmetic treatment of baldness.