Polymeric films and methods of preparation thereof

Abstract

The present disclosure relates to polymeric films comprising a high viscosity hydroxypropylmethyl cellulose and a low viscosity hydroxypropylmethyl cellulose, methods of preparing such polymeric films and uses thereof. The polymeric films may be loaded with pharmaceutically active agents and may find particular application in the controlled delivery of such pharmaceutically active agents. In particular, the polymeric films may be suitable for vaginal administration.

Description

[0001] Polymeric films and methods of preparation thereof

[0002] FIELD

[0003] The present disclosure relates to polymeric films comprising a high viscosity hydroxypropylmethyl cellulose and a low viscosity hydroxypropylmethyl cellulose, methods of preparing such polymeric films and uses thereof. The polymeric films may be loaded with pharmaceutically active agents and may find particular application in the controlled delivery of such pharmaceutically active agents. In particular, the polymeric films may be suitable for vaginal administration.

[0004] BACKGROUND

[0005] Intravaginal administration of a drug can offer several advantages and can be particularly useful in the administration of hormones and the treatment of many conditions which require local action of such hormones.

[0006] Whilst hormones (and other drugs) can be delivered by other routes, such as intramuscular and oral, the intravaginal route has several advantages. In particular, it allows for the possibility of self-administration and the avoidance of hepatic first-pass metabolism. In addition, the rich blood supply and relatively high permeability of the vaginal mucosa can facilitate uptake and local action (e.g. the intravaginal administration can provide higher levels of the drug in the endometrial tissue, due to the direct transport through the vaginal epithelium into the uterine circulation). By way of example, when the hormone progesterone is administered intravaginally, it can directly reach the uterus and the systemic circulation, without undergoing first-pass metabolism. Whilst the intravaginal administration can sometimes result in lower plasma concentrations of progesterone compared to an intramuscular administration, the local effect of hormone can induce endometrial transformation, with a reduction in the systemic side effects. Progesterone- based treatments can be of relatively long duration (often lasting from weeks to months) and so it is particularly important to provide dosage forms for intravaginal administration that can be consistently and comfortably used by patients.

[0007] Many vaginal dosage forms take the form of creams and gels. Such semi-solid products may not provide an exact and / or consistent dose due to non-uniform distribution and also loss of the cream or gel in the applicator and during the administration step.

[0008] In particular, soft gel capsules have been associated with messiness, and leakage and generally require high frequency of administration. Additionally, such gel capsules often comprise oil (typically peanut oil) and so there can be issues with irritation. A gel product (Crinone®) is also known for the delivery of progesterone. However, there have been reports of gel accumulation in the vaginal cavity after several administrations, resulting in a plug formation. This can cause patient discomfort, can hamper an insemination process, and sometimes requires a periodic removal of the gel from the vaginal cavity.

[0009] Other dosage forms of progesterone include tablets and rings. There are also drawbacks associated with these dosage forms. For example, tablets have been associated with leakage and require a relatively high frequency of administration. Additionally, ring forms are known to be not well-tolerated by all patient groups, and can have issues with insertion, removal and / or involuntary expulsions.

[0010] Polymeric films can provide an alternative dosage form for intravaginal administration of drugs, such as hormones. In particular, such films can be retained in the vagina for relatively long periods of time, offer the potential to avoid issues such as messiness and / or product loss during the application process, avoid leakage and / or can be a comfortable dosage form to promote patient compliance.

[0011] An example of a progesterone-containing polymeric film is described in Chinese Patent Publication No. CN100486581C. The polymeric film described in this document comprises progesterone, a film forming material and a surfactant.

[0012] Other examples of polymeric films comprising hormones include: “A Comparative Study of Progesterone and Lidocaine Hydrochloride Release from Poly(L-lactide) Films”, Mashak et al, Pharmaceutical Sciences, September 2015, 21 , 77-85; “Design and Development of a mucoadhesive buccal film bearing progesterone”, Jain et al, Pharmazie, 63, 2008, pages 129-135; and “Mucoadhesive Buccal Film of Estradiol for Hormonal Replacement Therapy: Development and In-Vivo Performance Prediction”, Abdella et al, Pharmaceutics, 2022, 12, page 542.

[0013] Polymeric films suitable for intravaginal administration of a drug (such as progesterone) should ideally show good content uniformity, be thin and / or flexible (to promote comfort and patient compliance), and be robust enough to withstand the administration step. Polymeric films are generally produced by way of a solvent casting process and issues can also be encountered during the manufacture where films can deform during the drying process, or show low peelability after drying. There remains a need for further polymeric films that can address one or more of the problems noted above. In particular, polymeric films that are particularly suited for intravaginal administration of pharmaceutically active agents such as progesterone.

[0014] SUMMARY

[0015] The present disclosure is based on the identification of new polymeric films that are particularly amenable for use in the intravaginal administration of pharmaceutically active agents. In particular, the present inventors have identified a cohort of polymeric films that have mechanical properties that render it particularly suitable for this mode of administration, including good levels of flexibility and mechanical strength. The polymeric films of the present disclosure may also be loaded with relatively high levels of pharmaceutically active agents and show good levels of content uniformity. When loaded with the pharmaceutically active agent, the polymeric films can be used to provide a sustained and / or controlled delivery of such agents.

[0016] Accordingly, in a first aspect, disclosed herein is a polymeric film comprising:

[0017] (a) a high viscosity hydroxypropylmethyl cellulose in an amount from about 0.01 % w / w to about 20% w / w based on a total weight of the polymeric film; and

[0018] (b) a film former, wherein the film former comprises a low viscosity hydroxypropylmethyl cellulose in an amount from about 5% w / w to about 50% w / w based on a total weight of the polymeric film; wherein: the polymeric film further comprises a pharmaceutically active agent, which is a hormone; and the pharmaceutically active agent is present in an amount from about 15% w / w to about 35% w / w based on the total weight of the polymeric film.

[0019] The hormone may be selected from progesterone, estradiol and testosterone. In some embodiments, the hormone is progesterone.

[0020] The high viscosity hydroxypropylmethyl cellulose may comprise a viscosity from about 2000 to about 5500 mPa.s, at 20°C at 2% w / w in water. The low viscosity hydroxypropylmethyl cellulose may comprise a viscosity from about 0.5 mPa.s to about 10 mPa.s at 20°C at 2% w / w in water. The viscosities can be determined by using a rotational method. For example, in accordance with “Viscosity - Rotating Viscometer Method" section 2.2.10 described in the European Pharmacopoeia 11.0, or in accordance “Viscosity - Rotational Methods” with General Chapter 912 of the United States Pharmacopeia - National Formulary (USP-NF) (version USP41-NF36).

[0021] The film former may further comprise hydroxypropyl cellulose.

[0022] The polymeric film may further comprise a plasticizer, a wetting agent, water, one or more agents to control a rate of release, a pharmaceutically active agent, or combinations thereof.

[0023] In a second aspect, disclosed herein is a polymeric film comprising:

[0024] (a) a high viscosity hydroxypropylmethyl cellulose in an amount from about 0.01% w / w to about 20% w / w based on a total weight of the polymeric film; and

[0025] (b) a film former, wherein the film former comprises a low viscosity hydroxypropylmethyl cellulose in an amount from about 5% w / w to about 50% w / w based on a total weight of the polymeric film and a low viscosity hydroxypropyl cellulose from about 1% w / w to about 25% w / w based on the total weight of the polymeric film.

[0026] In some embodiments, the low viscosity hydroxypropyl cellulose comprises a viscosity from about 1 to about 10 mPa.s, from about 2 to about 8 mPa.s, from about 3 to about 6.5 mPa.s, or from about 6 to about 6.5 mPa.s at 20 °C at 2% w / w in water.

[0027] There is further disclosed a method of making a polymeric film as described herein. The method may comprise:

[0028] (i) providing a dispersion comprising:

[0029] (a) a high viscosity hydroxypropylmethyl cellulose in a concentration range from about 0.01 % w / w to about 2.0% w / w of the dispersion; and

[0030] (b) a film former, wherein the film former comprises a low viscosity hydroxypropylmethyl cellulose in a concentration range from about 2% w / w to about 10% w / w of the dispersion;

[0031] (ii) casting the dispersion onto a surface; and

[0032] (iii) drying the dispersion to provide the polymeric film.

[0033] The disclosure further extends to polymeric films obtained or obtainable by the methods described herein.

[0034] The polymeric films of the present disclosure may find particular utility in the delivery of pharmaceutically active agents.

[0035] Accordingly, there is disclosed the polymeric film as described above or herein, or obtained or obtainable in accordance with the methods described above or herein, for use as a medicament or for use in therapy. In particular, the polymeric films described herein can facilitate the delivery of progesterone to a subject in need thereof. Consequently, the polymeric films of the disclosure (when loaded with progesterone) may find use in any of the following:

[0036] (i) the treatment or prevention of a condition associated with reduced levels of progesterone or a progesterone deficiency;

[0037] (ii) supplementing progesterone levels in a subject undergoing an assisted reproductive technology (ART) procedure, such as in vitro fertilization (IVF);

[0038] (iii) the treatment or prevention of a condition selected from infertility, miscarriage, pre-term labour, endometriosis, adenomyosis, irregular menstruation, dysfunctional uterine bleeding, endometrial hyperplasia and amenorrhea;

[0039] (iv) reducing the risk of miscarriage or pre-term labour; or

[0040] (v) the treatment or prevention of symptoms associated with the menopause; or

[0041] (vi) a method of hormone replacement therapy.

[0042] The present disclosure also extends to methods of treating a subject in need thereof for any one of (i) to (vi) with the disclosed polymeric films. The present disclosure further extends to the use of the disclosed polymeric films in the manufacture of a medicament for use in any one of (i) to (vi).

[0043] In any of the compositions for use, the methods, and the uses described above, the composition may be administered to the subject in a therapeutically effective amount.

[0044] DESCRIPTION

[0045] The current disclosure relates to, in first aspect, a polymeric film comprising:

[0046] (a) a high viscosity hydroxypropylmethyl cellulose in an amount from about 0.01 % w / w to about 20% w / w based on a total weight of the polymeric film; and

[0047] (b) a film former, wherein the film former comprises a low viscosity hydroxypropylmethyl cellulose in an amount from about 5% w / w to about 50% w / w based on a total weight of the polymeric film; wherein: the polymeric film further comprises a pharmaceutically active agent, which is a hormone; and the pharmaceutically active agent is present in an amount from about 15% w / w to about 35% w / w based on the total weight of the polymeric film.

[0048] The present inventors have particularly identified that a polymeric film based on a combination of high viscosity hydroxypropylmethyl cellulose and low viscosity hydroxypropylmethyl cellulose can provide films with good levels of mechanical strength and flexibility and / or provide peelable films (that facilitates the manufacture and handling of such films). Furthermore, this combination can facilitate the incorporation of relatively high concentrations of a pharmaceutically active agent, i.e., a hormone, e.g,. progesterone.

[0049] Additionally, in a second aspect, the current disclosure relates to a polymeric film comprising:

[0050] (a) a high viscosity hydroxypropylmethyl cellulose in an amount from about 0.01% w / w to about 20% w / w based on a total weight of the polymeric film; and

[0051] (b) a film former, wherein the film former comprises a low viscosity hydroxypropylmethyl cellulose in an amount from about 5% w / w to about 50% w / w based on a total weight of the polymeric film and a low viscosity hydroxypropyl cellulose from about 1% w / w to about 25% w / w based on the total weight of the polymeric film.

[0052] As above, the present inventors have particularly identified that a polymeric film based on a combination of high viscosity hydroxypropylmethyl cellulose and low viscosity hydroxypropylmethyl cellulose can provide films with good levels of mechanical strength and flexibility and / or provide peelable films. A film further comprising hydroxypropyl cellulose also contributes to this fine balance of properties that is otherwise challenging to achieve.

[0053] For the avoidance of doubt, all embodiments described herein apply to both the first and second aspects of the invention, mutatis mutandis.

[0054] Film former

[0055] As used herein, the film former refers to constituents that may be used to form a polymeric film, e.g. the main components or base of the polymeric matrix that forms the polymeric film. The film former comprises at least the low viscosity hydroxypropylmethyl cellulose but may additionally comprise other components.

[0056] In some embodiments, the film former is present in an amount from about 5% w / w to about 75% w / w, from about 15% w / w to about 60%, from about 20% w / w to 50% w / w, or from about 30% w / w to about 40% w / w based on a total weight of the polymeric film.

[0057] Hydroxypropylmethyl cellulose

[0058] Hydroxypropylmethyl cellulose (HPMC) is a cellulose derivative in which some of the hydroxyl groups in the repeating glucose units have been methylated and hydroxypropylated. It may sometimes be referred to as hypromellose. Hydroxypropymethyl cellulose may be considered as a partly O-methylated and 0-(2- hydroxypropylated) cellulose ether derivative.

[0059] As described herein, hydroxypropylmethyl cellulose may be provided in a range of viscosities, including both high viscosity and low viscosity (as described in further detail herein). The viscosity of a hydroxypropylmethyl cellulose may be dependent upon a number of factors including molecular weight, polymer chain length and / or size, degree of branching, and degree of substitution of methoxy and hydroxypropyl groups. In some examples, the viscosity of a hydroxypropylmethyl cellulose may be largely impacted by the degree of polymerization and molecular weight. When the hydroxypropylmethyl cellulose is in a solution, the viscosity of the polymer in the solution may be mainly affected by the degree of polymerization of the polymer, molecular weight, the concentration of the polymer in the solution, the shear rate and the temperature of the solution.

[0060] Low viscosity hydroxypropylmethyl cellulose

[0061] As used herein, the term “low viscosity hydroxypropylmethyl cellulose” may refer to a hydroxypropylmethyl cellulose comprising a viscosity from about 0.5 mPa.s to about 10 mPa.s, at 20°C at 2% w / w in water. In some embodiments, low viscosity hydroxypropylmethyl cellulose may comprise a viscosity from about 1 mPa.s to about 7.5 mPa.s, from about 2 mPa.s to about 5 mPa.s, from about 2 to about 4 mPa.s, or from about 3 to about 4 mPa.s at 20°C at 2% w / w in water. The viscosity can be determined by using a rotational method. For example, in accordance with “Viscosity - Rotating Viscometer Method" section 2.2.10 described in the European Pharmacopoeia 11.0, or in accordance “Viscosity - Rotational Methods” with General Chapter 912 of the United States Pharmacopeia - National Formulary (USP-NF) (version USP41-NF36).

[0062] In some embodiments, the low viscosity hydroxypropylmethyl cellulose may comprise one or more, or all, of the following properties: an average molecular weight of 20 kDa, from about 28% to about 30% methoxyl substitution, and from about 7% to about 12% hydroxypropoxyl substitution.

[0063] In some embodiments, the low viscosity hydroxypropylmethyl cellulose is HPMC E3. By way of example, the HPMC E3 may be Pharmacoat® 603 as obtained from Shin- etsu. The chemical and physical properties (e.g., viscosity) of various grades of HPMC, including the Pharmacoat® range, may be found in the manufacturers’ technical brochures and websites (for example, at https: / / www.metolose.jp / en / pharmaceutical / tc- 5.html).

[0064] As stated above, the low viscosity hydroxypropylmethyl cellulose may be present in an amount from about 5% w / w to about 50% w / w based on the total weight of the polymeric film. In some embodiments, the low viscosity hydroxypropylmethyl cellulose may be present in an amount from about 10% w / w to about 40% w / w, or from about 15% w / w to about 30% w / w based on the total weight of the polymeric film. In some embodiments, the low viscosity hydroxypropylmethyl cellulose may be present in an amount from about 20% w / w to about 30% w / w based on the total weight of the polymeric film.

[0065] High viscosity hydroxypropylmethyl cellulose

[0066] As used herein, the term “high viscosity hydroxypropylmethyl cellulose” may refer to a hydroxypropylmethyl cellulose comprising a viscosity from about 2000 to about 5500 mPa.s, or from about 2200 to about 5040 mPa.s,1at 20°C at 2% w / w in water.

[0067] The viscosity can be determined by using a rotational method. For example, in accordance with “Viscosity - Rotating Viscometer Method" section 2.2.10 described in the European Pharmacopoeia 11 .0, or in accordance “Viscosity - Rotational Methods” with General Chapter 912 of the United States Pharmacopeia - National Formulary (USP-NF) (version USP41-NF36).

[0068] In some embodiments, the high viscosity hydroxypropylmethyl cellulose may comprise one or more, or all, of the following properties: an average molecular weight of 400 kDa, from about 20% to about 24% methoxyl substitution, and from about 7% to about 12% hydroxypropoxyl substitution.

[0069] In some embodiments, the high viscosity hydroxypropylmethyl cellulose is HPMC K4M. By way of example, the HPMC K4M may be Benecel™ K4M as obtained from Ashland. The chemical and physical properties (e.g., viscosity) of various grades of HPMC, including the Benecel™ range, may be found in the manufacturers’ technical brochures and websites (for example, at https: / / www.ashland.com / ).

[0070] As stated above, the polymeric film may comprise the high viscosity hydroxypropylmethyl cellulose in an amount from about 0.01% w / w to about 20% w / w. In some embodiments, the polymeric film may comprise the high viscosity hydroxypropylmethyl cellulose in an amount from about 0.1 % w / w to about 15% w / w, or from about 0.5% w / w to about 12% w / w. In some embodiments, the high viscosity hydroxypropylmethyl cellulose may be present in an amount from about 3% w / w to about 10% w / w. In the above embodiments, the amount given as %w / w is based on a total weight of the polymeric film.

[0071] Hydroxypropyl cellulose (HPC)

[0072] In some embodiments, the film former may further comprise hydroxypropyl cellulose (HPC).

[0073] As used herein, hydroxypropyl cellulose (HPC) is a derivative of cellulose in which some of the hydroxyl groups in the repeating glucose units have been hydroxypropylated forming -OCH2CH(OH)CH3 groups.

[0074] As described herein, hydroxypropyl cellulose may be provided in a range of viscosities, including both high viscosity and low viscosity (as described in further detail herein). The viscosity of a hydroxypropyl cellulose may be dependent upon a number of factors including molecular weight, polymer chain length and / or size, degree of branching and degree of substitution of hydroxypropoxyl groups. However, the viscosity of hydroxypropyl cellulose is largely dependent upon the molecular weight. The chemical and physical properties (e.g., viscosity) of various grades of HPC (such as VH, H, M, L, SL, and SSL) may be found in manufacturers’ technical brochures and websites (for example, at https: / / www.nissoexcipients.com / hpc-e / medical_stable.php).

[0075] In some embodiments, the hydroxypropyl cellulose is a low viscosity hydroxypropyl cellulose. In some embodiments, the low viscosity hydroxypropyl cellulose comprises a viscosity from about 0.5 to about 15 mPa.s, from about 1 to about 10 mPa.s, from about 2 to about 8 mPa.s, from about 3 to about 6.5 mPa.s, or from about 6 to about 6.5 mPa.s at 20°C at 2% w / w in water.

[0076] In some embodiments, the low viscosity HPC may comprise one or more, or all, of the following properties: an average molecular weight of 100,000 g / mol and from about 60% to 80% hydroxypropoxyl substitution (e.g. about 73.5% hydroxypropoxyl substitution) and a viscosity of from about 3 to about 5.9 mPa.s at 20°C at 2% w / w in water.

[0077] The viscosity can be determined by using a rotational method. For example, in accordance with “Viscosity - Rotating Viscometer Method" section 2.2.10 described in the European Pharmacopoeia 11 .0, or in accordance “Viscosity - Rotational Methods” with General Chapter 912 of the United States Pharmacopeia - National Formulary (USP-NF) (version USP41-NF36). In some embodiments, the low viscosity hydroxypropyl cellulose is HPC-SL. In some embodiments, the hydroxypropyl cellulose may comprise an average molecular weight from about 50,000 g / mol to about 150,000 g / mol, or from about 75,000 g / mol to about 125,000 g / mol, e.g. about 100,000 g / mol.

[0078] In some embodiments, the polymeric film comprises a low viscosity hydroxypropyl cellulose in an amount from about 1 % w / w to about 25% w / w, from about 5% w / w to about 20% w / w, or from about 10% w / w to about 15% w / w based on the total weight of the polymeric film. In some embodiments, the low viscosity hydroxypropyl cellulose is present in an amount from about 10% w / w to about 15% w / w (e.g. about 10% w / w, about 11 % w / w, or about 12% w / w) based on the total weight of the polymeric film.

[0079] Where the films additionally comprise low viscosity HPC, in some embodiments, the polymeric film may comprise: the high viscosity hydroxypropylmethyl cellulose in an amount from about 7% w / w to about 10% w / w (e.g. about 8% w / w or 9% w / w); the low viscosity hydroxypropylmethyl cellulose in an amount from about 20% w / w to about 30% w / w (e.g. about 25% w / w); and the low viscosity hydroxypropyl cellulose in an amount from about 10% w / w to about 15% w / w (e.g. about 10% w / w, about 11 % w / w, or about 12% w / w); wherein the values in %w / w are given based on the total weight of the polymeric film.

[0080] Plasticizer

[0081] In some embodiments, the polymeric film may further comprise a plasticizer. The plasticizer may be any suitable plasticizer that can be added to the polymeric film to increase the softness and / or flexibility of the polymeric film.

[0082] In some embodiments, the plasticizer may be selected from low molecular weight polyethylene glycols, glycerol, propylene glycol, triacetin, triethyl citrate, acetyltributyl citrate, acetyltriethyl citrate, benzyl benzoate, cellulose acetate phthalate compatible, chlorbutanol, dextrin, dibutyl phthalate, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, glycerin monostearate, mannitol, mineral oil, lanolin alcohols, palmitic acid, petrolatum and lanolin alcohols, pyrrolidone, sorbitol, tributyl citrate, triethanolamine and vitamin E, or combinations thereof. In some embodiments, the plasticizer may be or comprise one or more, or all, of a low molecular weight polyethylene glycol (e.g. PEG400), glycerol and propylene glycol. In some embodiments, the polymeric film may comprise low molecular weight polyethylene glycol (e.g. PEG400), optionally in an amount from about 1 % w / w to about 25% w / w based on a total weight of the polymeric film. In some embodiments, the polymeric film may comprise low molecular polyethylene glycol in an amount from about 1 .5% w / w to about 20% w / w, or from about 2% w / w to about 15% w / w.

[0083] In some embodiments, the polymeric film may comprise glycerol, optionally in an amount from about 1 % w / w to 25% w / w based on a total weight of the polymeric film. In some embodiments, the glycerol may be present in an amount from about 2% w / w to 20% w / w, or from about 5% w / w to 15% w / w.

[0084] In some embodiments, the polymeric film may comprise propylene glycol, optionally in an amount from about 1 % w / w to 25% w / w based on a total weight of the polymeric film. In some embodiments, the polymeric film may comprise propylene glycol in an amount from about 1 .5% w / w to about 20% w / w, or from about 2% w / w to about 15% w / w.

[0085] In some examples, the polymeric film may comprise PEG400 and glycerol, optionally in the amounts described above.

[0086] Water

[0087] The polymeric film may comprise water. The presence of water in the polymeric film may assist in providing a flexible film and / or a film that is not brittle.

[0088] In particular, when the polymeric film has been prepared in accordance with a solvent casting method (using water as the solvent), the polymeric film may be dried to provide a desired water content.

[0089] In some embodiments, the polymeric film may comprise water in an amount from about 0.1 % w / w to about 20% w / w, from about 1 % w / w to about 15% w / w, or from about 5% w / w to about 10% w / w based on a total weight of the polymeric film.

[0090] In some embodiments, the polymeric film may comprise water in an amount from about 6% w / w to about 8% w / w based on a total weight of the polymeric film.

[0091] Additional components (to control rate of release)

[0092] The polymeric film may comprise one or more additional components to control a rate of release, e.g. the rate of release of an active agent comprised and / or loaded in the polymeric film. In particular the one or more additional components may modulate a rate of release of a pharmaceutically active agent from the polymeric film, e.g. increase the rate of release or decrease the rate of release. For example, the one or more additional components may act to decrease and / or delay the rate of release of a pharmaceutically active agent from a polymeric film. The one or more additional components may be added in an amount suitable to provide a desired or targeted pharmacokinetic profile.

[0093] The one or more additional components to control a rate of release may facilitate or promote gel formation, may form a gel (such as a hydrogel), and / or may be a thickener. In some embodiments, the one or more additional components to control a rate of release may be selected from carbomers, polycarbophil, alginate (e.g. sodium alginate) and metal chloride (e.g. calcium chloride), or combinations thereof.

[0094] In some embodiments, the polymeric film may comprise a polycarbophil, optionally Noveon®-AA-1 . In some embodiments, the polymeric film may comprise an alginate (e.g. sodium alginate) and calcium chloride.

[0095] In some embodiments, the one or more additional components is present in an amount from about 0.05% w / w to about 20% w / w, such as an amount from about 0.1% w / w to about 15% w / w based on the total weight of the polymeric film.

[0096] By way of further example, where the one or more additional components is a polycarbophil (e.g. Noveon®-AA-1 ), it may be present in an amount from about 0.1 % w / w to about 3% w / w, e.g. about 0.8% w / w based on the total weight of the polymeric film.

[0097] By way of yet further example, where the polymeric film comprises an alginate (e.g. sodium alginate) and calcium chloride, the alginate may be present in an amount from about 5% w / w to about 15% w / w, such as from about 8% w / w to about 12% w / w (e.g. from about 9% w / w to about 10% w / w) based on the total weight of the polymeric film. Additionally or alternatively, the calcium chloride may be present in an amount from about 0.05% to about 0.5% w / w based on the total weight of the polymeric film.

[0098] Pharmaceutically active agents

[0099] The polymeric film may comprise a pharmaceutically active agent. In particular, the polymeric film may be loaded with a pharmaceutically active agent such that the pharmaceutically active agent is substantially uniformly dispersed throughout a polymeric matrix forming the polymeric film.

[0100] In some embodiments, the pharmaceutically active agent may be a relatively insoluble active agent, e.g. it may be relatively insoluble, show relatively low solubility in water and / or be hydrophobic. In some embodiments, the pharmaceutically active agent is a hormone. As used herein, the term “hormone” may encompass naturally occurring hormones and synthetic hormones. In particular, the pharmaceutically active agent may be a hormone selected from progesterone, estradiol and testosterone, or combinations thereof.

[0101] In some embodiments, the pharmaceutically active agent is progesterone. Progesterone (also known as pregn-4-ene-3, 20-dione and sometimes referred to as P4) is an endogeneous steroid and progestogen sex hormone involved in the menstrual cycle. The structure of progesterone is shown below:

[0102] In some embodiments, the progesterone may be provided in the form of microparticles. For example, the progesterone may be provided in micronized form. As used herein, microparticles may refer to particles from about 0.1 pm to about 100 pm in size. Thus, in some embodiments, the progesterone microparticles that are dispersed or loaded in the polymeric film typically comprise a particle size from about 0.01 pm to about 100 pm, or from about 0.1 pm to about 50 pm. In some embodiments, the progesterone microparticles may comprise a particle size from about 1 pm to about 25 pm, or from about 1 pm to about 20 pm, e.g. less than or equal to about 15 pm.

[0103] In some embodiments, the ranges described above may refer to a mean or average particle size diameter (e.g. a volume mean diameter).

[0104] In some embodiments, the progesterone microparticles may comprise a particle size distribution such that a D90 value is from about 0.01 pm to about 50 pm, from about 0.1 pm to about 25 pm, or from about 1 pm to about 20 pm. In some embodiments, the D90 value is less than or equal to about 16 pm. As used herein, a D90 value may refer to a particle size diameter wherein ninety percent of the distribution of the particles has a smaller diameter and ten percent has a larger diameter than the stated value.

[0105] In some embodiments, the progesterone microparticles may comprise a particle size distribution such that a D50 value is from about 0.01 pm to about 25 pm, from about 0.1 pm to about 20 pm, or from about 1 pm to about 12 pm. In some embodiments, the D50 value is less than or equal to about 10 pm. As used herein, a D50 value may refer to a particle size diameter where fifty percent of the distribution of the particles has a smaller diameter and fifty percent has a larger diameter than the stated value.

[0106] In some embodiments, the progesterone microparticles may comprise a particle size distribution such that a D10 value is from about 0.01 pm to about 20 pm, from about 0.1 pm to about 15 pm, or from about 1 pm to about 10 pm. In some embodiments, the D10 value is less than or equal to about 6 pm. As used herein, a D10 value may refer to a particle size diameter where ten percent of the distribution of the particles has a smaller diameter and ninety percent has a larger diameter than the stated value.

[0107] The polymeric films of the present disclosure may be particularly useful in that they can be loaded with relatively high amounts of the pharmaceutically active agents and so can be useful in delivering higher dosages of such pharmaceutically active agents to a subject. In particular, the inventors have identified that polymeric films of the present disclosure may be loaded with relatively high concentrations of pharmaceutically active agents and show good levels of content uniformity.

[0108] In some embodiments, the pharmaceutically active agent is present in amount from about 5% w / w to about 50% w / w based on a total weight of the polymeric film. In some embodiments, the pharmaceutically active agent is present in an amount from about 10% w / w to about 40% w / w, or from about 15% w / w to about 35% w / w based on a total weight of the polymeric film.

[0109] By way of further example, the polymeric film may comprise progesterone in an amount from about 10% w / w to about 40% w / w, or from about 15% w / w to about 35% w / w based on a total weight of the polymeric film.

[0110] In some embodiments, the polymeric film may comprise progesterone in an amount from 25% w / w to about 35% w / w, or from about 28% w / w to about 32% w / w, such as about 30% w / w based on a total weight of the polymeric film.

[0111] In some embodiments, the polymeric film may comprise progesterone in an amount from 15% w / w to about 25% w / w, or from about 18% w / w to about 22% w / w, such as about 20% w / w based on a total weight of the polymeric film.

[0112] Wetting agents

[0113] The polymeric film may further comprise a wetting agent. In particular, where a pharmaceutically active agent is relatively insoluble in water and / or is hydrophobic, a wetting agent may be added to assist in providing better homogeneity and / or better levels of content uniformity in the polymeric film. By way of example, where the pharmaceutically active agent is a hormone, such as progesterone, the polymeric film may further comprise a wetting agent.

[0114] Suitable wetting agents may be selected from polysorbates (such as polysorbate 80), poloxamers and metal lauryl sulfate (e.g. sodium lauryl sulfate), or combinations thereof. In some embodiments, the wetting agent is a polysorbate, e.g. polysorbate 80.

[0115] In some embodiments, the wetting agent is present in an amount from about 0.1 % w / w to about 10% w / w based on a total weight of the polymeric film. In some embodiments, the wetting agent is present from about 1 % w / w to about 5% w / w, or from about 2% w / w to about 4% w / w based on a total weight of the polymeric film.

[0116] By way of further example, the wetting agent may be a polysorbate (such as polysorbate 80) and may be present in an amount from about 1% w / w to about 5% w / w, or from about 2% w / w to about 4% w / w based on a total weight of the polymeric film.

[0117] Preservatives

[0118] In some embodiments, the polymeric film may further comprise a preservative. The preservative may be any suitable preservative. In some embodiments, the preservative may be selected from, benzalkonium chloride, propylparaben and methylparaben, and phenol, or combinations thereof. The preservative may be present in an amount from about 0.01 % w / w to about 5% w / w based on a total weight of the polymeric film.

[0119] Film properties

[0120] The polymeric films of the present disclosure show a number of properties that may facilitate their use as intravaginal delivery devices.

[0121] In some embodiments, the polymeric films have been shown to provide relatively thin, robust and / or flexible films.

[0122] In some embodiments, the polymeric film has a thickness from about 25 pm to about 400 pm. In some embodiments, the polymeric film has a thickness from about 50 pm to about 300 pm. In some embodiments, the polymeric film has a thickness from about 75 pm to about 280 pm. By way of particular example, the polymeric films of the present disclosure may comprise a thickness from about 100 pm to about 250 pm.

[0123] In some embodiments, the polymeric films disclosed herein are relatively flexible. This flexibility can facilitate their use intravaginally as it can assist in the insertion of the film and improve patient comfort. In particular, the polymeric films of the present disclosure may show greater levels of flexibility than those films used in other applications (e.g. buccal films). In some embodiments, the polymeric film comprises a flexibility of at least about 10% or at least about 15%.

[0124] In some embodiments, the polymeric films disclosed herein are relatively robust. For example, the polymeric films may show rupture strength (e.g. good puncture resistance and / or mechanical resistance). In some embodiments, the polymeric film comprises a rupture strength of at least about 2 N / mm2, or at least about 3 N / mm2.

[0125] The flexibility and rupture strength of the polymeric film may be determined in accordance with the following method. In particular, the method may comprise using a Texture Analyser with a spherical head. The method may comprise fixing the polymeric film between two plates with a cylindrical hole of 10mm diameter. The Texture Analyzer may be moved forwards using a velocity of 1.0mm / s. Measurement may start when the probe contacts the sample film. The probe may be moved on at a constant speed until the film breaks apart. The applied force and displacement (penetration depth) may be recorded. The method may be conducted at room temperature (e.g. about 21 °C), at atmospheric pressure and / or about 40% relative humidity. In particular, the flexibility and rupture strength may be determined in accordance with the mechanical strength test described in Preis et al, International Journal of Pharmaceutics, 461 (2014), 22-29, using probe C as described in that document (see, in particular, section 3.4 “Mechanical strength test”), the contents of which are herein incorporated by reference. In particular, the elongation to break as described in this document provides a measure of flexibility.

[0126] When polymeric films are to be administered intravaginally, this typically involves folding the film during the insertion step. In some embodiments, the polymeric films disclosed herein show good resistance to folding, or repeated folding. In particular, the polymeric films may maintain their structural integrity and / or withstand repeated folding. In some embodiments, the polymeric films may comprise a folding endurance of greater than 30.

[0127] The folding endurance may be determined in accordance with the following method. A sample of film was repeatedly folded at 90° along the same axis. The number of folds until break was recorded. The samples of film tested comprised a size of 3 cm by 5 cm. The film samples typically comprised thicknesses in the range from about 100 pm to about 280 pm (or a thickness as described herein).

[0128] In some embodiments, the polymeric films may be appropriately dimensioned to facilitate insertion and / or placement in the vagina. The polymeric films may comprise any size and / or shape, in particular any size and / or shape to facilitate insertion and / or placement in the vagina. In particular, the films may be configured to be easily folded, such as in half, or in four, to facilitate administration.

[0129] In some embodiments, the polymeric films may comprise a generally circular, rectangular, square, or other polygonal shape. In some embodiments, the polymeric film may comprise a generally rectangular or square shape with a length from about 1 cm to about 10 cm, and a width from about from about 1 cm to about 10 cm. In some embodiments, the polymeric film may comprise a generally rectangular shape, having a length from about 2 cm to about 4 cm, and a width from about 4 cm to about 6 cm (e.g. the film may comprise a length of about 3 cm and a width of about 5 cm).

[0130] In some embodiments, the surface area of an upper surface or a lower surface of the polymeric film (or of each of these surfaces) may be in the range from about 1 cm2to about 100 cm2, such as from 1 cm2to about 50 cm2, e.g. from about 10 cm2to about 20 cm2, such as about 15 cm2. In some embodiments, the surface area of each of the upper surface and the lower surface of the polymeric film may be in the ranges defined above.

[0131] Methods of preparing polymeric films

[0132] The present disclosure further extends to methods of preparing the polymeric films described herein. In particular, the present disclosure provides a method of preparing the polymeric films by way of a solvent casting method. In such solvent casting methods, the various components of the polymeric film may be provided in a dispersion. The resulting dispersion may be cast onto a surface and then dried to provide the polymeric film.

[0133] Accordingly, as stated previously, the method of making the polymeric film may comprise:

[0134] (i) providing a dispersion comprising:

[0135] (a) a high viscosity hydroxypropylmethyl cellulose at a concentration from about 0.01 % w / w to about 2.0% w / w of the dispersion; and

[0136] (b) a film former, wherein the film former comprises a low viscosity hydroxypropylmethyl cellulose at a concentration from about 2% w / w to about 10% w / w of the dispersion;

[0137] (ii) casting the dispersion onto a surface; and

[0138] (iii) drying the dispersion to provide the polymeric film.

[0139] In some embodiments, the dispersion may comprise a solvent. In such embodiments, the high viscosity HPMC and low viscosity HPMC may be dispersed in the solvent. In some embodiments, the dispersion may comprise an aqueous solvent. In particular, in some embodiments, the dispersion may comprise water.

[0140] In some embodiments, the dispersion may be prepared by mixing the various components of the polymeric film (as described herein) in a solvent, e.g. water. The method may comprise mixing the components for a period of time such that the dispersion is substantially homogeneous.

[0141] As noted above, the dispersion may be cast onto a surface. The surface may be substantially planar, may be substantially flat, and / or may be substantially smooth.

[0142] In some embodiments, the dispersion may be cast onto a surface as a layer, e.g. a layer having a substantially uniform thickness. In some embodiments, the dispersion may be cast onto a surface using an automatic film applicator. In some embodiments, the dispersion may be cast onto a surface at a thickness from about 1000 pm to about 2000 pm, from about 1200 pm to about 1900 pm, such as about 1500 pm.

[0143] In some embodiments, the step of drying the dispersion may comprise removing, or substantially removing, the solvent. For example, the step of drying the dispersion may comprise using heat and / or reduced pressure to remove or substantially remove the solvent.

[0144] In some embodiments, the step of drying the dispersion may comprise heating at a temperature to remove or substantially remove the solvent, e.g. at a temperature from about 30 °C to about 130 °C, or from about 50 °C to about 120 °C. In some embodiments, the step of drying the dispersion may comprise heating at a temperature of about 70 °C.

[0145] In some embodiments, the step of drying the dispersion may comprise heating for a period of time to remove or substantially remove the solvent. In some embodiments, the the step of drying may comprise heating for a period of up to 3 hours, e.g. up to about 2 hours, up to about 1 hour.

[0146] In some embodiments, the step of drying the dispersion may comprise reducing the solvent content such that the polymeric film comprises less than or equal to: about 20% w / w, about 15% or about 10% w / w of solvent in the polymeric film. In some embodiments, the solvent content is reduced to from about 5% w / w to about 10% w / w, or from about 6% w / w to about 10% w / w.

[0147] In some embodiments, where the dispersion comprises water, the step of drying the dispersion may comprise reducing the water content such that the polymeric film comprises from about 5% w / w to about 10% w / w, or from about 6% w / w to about 10% w / w of water. For example, the step of drying the dispersion may comprise reducing the water content such that the polymeric film comprises from about 5% w / w to about 8% w / w, e.g. about 6% w / w, or about 7% w / w of water.

[0148] Dispersions

[0149] As noted above, the polymeric films described herein may be prepared using a solvent casting method from a dispersion.

[0150] As described herein, the dispersions comprise the high viscosity hydroxypropylmethyl cellulose and the low viscosity hydroxypropylmethyl cellulose which are dispersed in a liquid (e.g. a solvent such as water). The dispersions may comprise one or more additional components as described herein. For example, the dispersions may further comprise hydroxypropyl cellulose, one or more additional components to control a rate of release, a plasticiser, a pharmaceutically active agent, a wetting agent, a preservative, or combinations thereof. Further details of each of these components are disclosed herein in the context of the polymeric film, but it should be appreciated that the earlier description of each of these components is equally applicable to the method of making such films.

[0151] The present inventors were looking to identify a film that could support relatively high loads of an active agent but that would also be amenable to the manufacturing process (e.g. a solvent casting process). The present inventors unexpectedly identified that a dispersion comprising a high viscosity hydroxypropyl methyl cellulose and a low viscosity hydroxypropylmethyl cellulose could be used to provide a matrix with a higher polymeric concentration (facilitating the retention of a higher load in the polymeric film), but could also provide a dispersion with a suitable viscosity to facilitate the manufacturing process.

[0152] In some embodiments, the dispersion (comprising the high viscosity hydroxypropylmethyl cellulose and the low viscosity hydroxypropylmethyl cellulose, and optionally any other components of the polymeric film as described herein) may comprise a viscosity from about 1000 mPa.s to about 7500 mPa.s, or from about 1500 mPa.s to about 5000 mPa.s when measured at a shear rate of 10 s-1at 20°C.

[0153] As noted above, the dispersion may comprise the high viscosity hydroxypropylmethyl cellulose at a concentration from about 0.01% w / w to about 2.0% w / w of the dispersion. In some embodiments, the dispersion may comprise the high viscosity hydroxypropylmethyl cellulose at a concentration from about 0.05% to about 1.75% w / w. In some embodiments, the dispersion may comprise the high viscosity hydroxypropylmethyl cellulose at a concentration from about 0.10% to about 1.5% w / w. In some embodiments, the dispersion may comprise the high viscosity hydroxypropylmethyl cellulose at a concentration from about 1 % w / w to about 2% w / w in the dispersion (e.g. about 1.5% w / w). In some embodiments, the dispersion may comprise the high viscosity hydroxypropylmethyl cellulose at a concentration from about 0.05% w / w to about 1.5% w / w, or from about 0.1 % w / w to about 1 % w / w, (e.g. about 0.10% w / w or about 0.85% w / w).

[0154] In some embodiments, the film former is present in the dispersion at a concentration from about 0.5% w / w to about 15% w / w, from about 1 % w / w to about 10% w / w, from about 2% w / w to about 9% w / w, or from about 3% w / w to about 8.5% w / w. In some embodiments, the film former is present in the dispersion at a concentration from about 6% w / w to about 7% w / w, e.g. about 6.5% w / w or about 7% w / w.

[0155] As noted above, the film former comprises low viscosity hydroxypropylmethyl cellulose. The dispersion may comprise the low viscosity hydroxypropylmethyl cellulose at a concentration from about 2% w / w to about 10% w / w. In some embodiments the dispersion may comprise the low viscosity hydroxypropylmethyl cellulose at a concentration from about 2.5% w / w to about 9% w / w, or from about 3% w / w to about 8% w / w. In some embodiments, the dispersion may comprise the low viscosity hydroxypropylmethyl cellulose at a concentration from about 3% w / w to about 5% w / w (e.g. about 3.5% w / w, about 4% w / w or about 4.5% w / w).

[0156] In some embodiments, the film former additionally comprises hydroxypropyl cellulose (e.g. low viscosity HPC). In some embodiments, the dispersion may comprise a low viscosity hydroxypropyl cellulose at a concentration from about 0.5% w / w to about 7% w / w, from about 1 % w / w to about 5% w / w, from about 1.5% w / w to about 4% w / w, or from about 2% w / w to about 3.5% w / w. In some embodiments, the dispersion may comprise a low viscosity hydroxypropyl cellulose at a concentration from about 2% w / w to about 2.5% w / w in the dispersion. In some embodiments, the dispersion may comprise a low viscosity hydroxypropyl cellulose at a concentration about 2% w / w, about 2.5% w / w, about 3% w / w, or about 3.5% w / w.

[0157] In some embodiments, the dispersion may comprise the low viscosity hydroxypropylmethyl cellulose and low viscosity hydroxypropyl cellulose in the concentrations as described above. In some embodiments, the dispersion may comprise the low viscosity hydroxypropylmethyl cellulose at a concentration from about 3% w / w to about 5% w / w and a low viscosity hydroxypropyl cellulose at a concentration from about 1 .5% w / w to about 3.5% w / w.

[0158] In some embodiments, the dispersion may comprise:

[0159] (i) the high viscosity hydroxypropylmethyl cellulose at a concentration from about 0.1 % w / w to about 2% w / w in the dispersion (e.g. about 1.5% w / w);

[0160] (ii) the low viscosity hydroxypropylmethyl cellulose at a concentration from about 3% w / w to about 5% w / w in the dispersion (e.g. about 4.5% w / w); and

[0161] (iii) a low viscosity hydroxypropyl cellulose at a concentration from about 1 .5% w / w to about 4% w / w in the dispersion (e.g. about 2% w / w).

[0162] The dispersions may additionally comprise one or more other components as described herein, e.g. one or more components to control a rate of release, a plasticiser, a pharmaceutically active agent, a wetting agent, a preservative, or combinations thereof. The concentrations of each of these components that may be present in the dispersions used to make the polymeric films are described in further detail below.

[0163] In some embodiments, where the one or more components to control a rate of release is present, it may be present in the dispersion at a concentration from about 0.001 % w / w to about 3% w / w, or from about 0.005% w / w to about 2.5% w / w, such as from about 0.1 % w / w to about 2% w / w. In some embodiments, where the dispersion comprises an alginate (e.g. sodium alginate), the alginate may be present in a concentration from about 1 .5% w / w to about 2% w / w, e.g. about 1 .8% w / w. In some embodiments, where the dispersion comprises calcium chloride, the calcium chloride may be present at a concentration from about 0.01 %w / w to about 0.10% w / w, e.g. about 0.05% w / w. In some embodiments, where the dispersion comprises polycarbophil (e.g. Novean® AA-1), the polycarbophil may be present at a concentration from about 0.05% w / w to about 0.50% w / w, e.g. about 0.15% w / w.

[0164] In some embodiments, the dispersion further comprises a plasticizer as disclosed herein. In some embodiments, the plasticizer may be present in the dispersion at a concentration from about 0.1% w / w to about 5% w / w, e.g. at a concentration of about 3% w / w or about 3.5% w / w.

[0165] In some embodiments, the dispersion further comprises low molecular weight polyethylene glycol (e.g. PEG400), optionally at a concentration in the dispersion from about 0.1 % w / w to about 2.5% w / w, or from about 0.2% w / w to about 2% w / w, such as about 0.5% w / w, 1% w / w or 2% w / w. In some embodiments, the dispersion further comprises glycerol, optionally at a concentration in the dispersion from about 0.1 % w / w to about 5% w / w, from about 0.2% w / w to about 4% w / w, or from about 0.5% w / w to about 3% w / w, such as about 1 %, about 2%, or about 3% w / w. In some embodiments, the dispersion further comprises propylene glycol, optionally at a concentration in the dispersion from about 0.1% w / w to about 5% w / w, from about 0.5% w / w to about 4% w / w, or from about 1 % w / w to about 3% w / w, such as about 1 % w / w or about 2% w / w.

[0166] In some embodiments, the dispersion may comprise:

[0167] (i) low molecular weight polyethylene glycol (e.g. PEG400) at a concentration in the dispersion from about 0.2% w / w to about 2% w / w, such as about 0.5% w / w, about 1 % w / w, or about 2% w / w; and

[0168] (ii) glycerol at a concentration in the dispersion from about 1 % w / w to about 3% w / w, such as about 1 %, about 2%, or about 3% w / w.

[0169] In some embodiments, the dispersion further comprises a pharmaceutically active agent as described herein (e.g. a hormone such as progesterone). In some embodiments, the pharmaceutically active agent is present in the dispersion at a concentration less than or equal to: about 15% w / w, about 10%, about 7.5% or about 6 % w / w. In some embodiments, the pharmaceutically active agent is present in the dispersion at a concentration from about 0.01 % w / w to about 10% w / w, from about 0.1 % w / w to about 7.5% w / w, or from about 0.5% w / w to about 6% w / w. In some embodiments, the dispersion further comprises progesterone at a concentration from about 3% w / w to about 7% w / w, such as about 3.5% or about 6% w / w.

[0170] In some embodiments, the dispersion further comprises a wetting agent as described herein (e.g. a polysorbate such as polysorbate 80). In some embodiments, the wetting agent is present in the dispersion at a concentration from about 0.1 % w / w to about 3% w / w, or from about 0.25% w / w to about 1% w / w, such as about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, or about 0.9% w / w.

[0171] In some embodiments, the dispersion further comprises a preservative. Where present, the preservative may be present in the dispersion at a concentration from about 0.01 % w / w to about 0.5% w / w.

[0172] Therapeutic Uses / Methods

[0173] The polymeric films as disclosed herein (including those polymeric films obtained or obtainable via the methods disclosed herein) may comprise and / or be loaded with a pharmaceutically active agent. Such films may find use as medicaments and / or may be used in therapy. In particular, the polymeric films may be used for the intravaginal administration of the pharmaceutically active agent.

[0174] In some embodiments, the polymeric films may comprise or be loaded with a hormone such as progesterone. Where progesterone is present in the polymeric film, it can be administered intravaginally and be used as a means to provide a controlled and / or sustained delivery of progesterone to a subject in need thereof. As such, when the polymeric films comprise progesterone, they may find application in the treatment and / or prevention in any disease or condition that is associated with reduced levels of progesterone, or a progesterone deficiency. In some embodiments, the polymeric films may be of use in reducing the risk of any disease or condition that is associated with reduced levels of progesterone or a progesterone deficiency.

[0175] In some embodiments, the polymeric films may be for use in supplementing progesterone levels in a subject undergoing an assisted reproductive technology (ART) procedure, such as in vitro fertilization (IVF).

[0176] In some embodiments, the polymeric films may be for use in the treatment or prevention of a condition selected from infertility, miscarriage, pre-term labour, endometriosis, adenomyosis, irregular menstruation, dysfunctional uterine bleeding, endometrial hyperplasia and amenorrhea.

[0177] In some embodiments, the polymeric films may be for use in reducing the risk of miscarriage or pre-term labour.

[0178] In some embodiments, the polymeric films may be for use in the treatment or prevention of one or more symptoms associated with the menopause. Representative symptoms may include, but are not limited to, hot flushes, night sweats, sleep disturbances, and bone loss.

[0179] In some embodiments, the polymeric films may be used in a method of hormone replacement therapy.

[0180] The present disclosure further extends to methods of treatment and / or prevention of such diseases and conditions, and also the use of the polymeric films in the manufacture of medicaments for the treatment and / or prevention of such diseases and conditions.

[0181] Accordingly, there is provided a method of treating and / or preventing any disease or condition that is associated with reduced levels of progesterone, or a progesterone deficiency. In some embodiments, the method may comprise reducing the risk of any disease or condition that is associated with reduced levels of progesterone or a progesterone deficiency. The method may comprise administering a polymeric film comprising progesterone as described herein to a subject in need thereof in a therapeutically effective amount.

[0182] In some embodiments, the method may comprise:

[0183] (i) supplementing progesterone levels in a subject undergoing an assisted reproductive technology (ART) procedure, such as in vitro fertilization (IVF);

[0184] (ii) treating or preventing a condition selected from infertility, miscarriage, pre-term labour, endometriosis, adenomyosis, irregular menstruation, dysfunctional uterine bleeding, endometrial hyperplasia and amenorrhea;

[0185] (iii) reducing the risk of miscarriage or pre-term labour; or

[0186] (iv) treating or preventing one or more symptoms associated with the menopause; or

[0187] (v) a method of hormone replacement therapy.

[0188] Uses of the polymeric films described herein, in the manufacture of a medicament, are further encompassed within the present disclosure. Accordingly, there is further provided a use of a polymeric film comprising progesterone as described herein, in the manufacture of a medicament for treating or preventing a condition associated with reduced levels of progesterone or a progesterone deficiency in a subject in need thereof.

[0189] In some embodiments, the use may comprise the:

[0190] (i) use of a polymeric film comprising progesterone as described herein, in the manufacture of a medicament for progesterone supplementation in a subject undergoing an assisted reproductive technology (ART) treatment, such as in vitro fertilization (IVF);

[0191] (ii) use of a polymeric film comprising progesterone as described herein, in the manufacture of a medicament for treating or preventing a condition selected from infertility, miscarriage, pre-term labour, endometriosis, adenomyosis, irregular menstruation, dysfunctional uterine bleeding, endometrial hyperplasia and amenorrhea in a subject in need thereof;

[0192] (iii) use of a polymeric film comprising progesterone as described herein, in the manufacture of a medicament for reducing the risk of miscarriage or pre-term labour in a subject in need thereof;

[0193] (iv) use of a polymeric film comprising progesterone as described herein, in the manufacture of a medicament for treating or preventing one or more symptoms associated with the menopause; or

[0194] (v) use of a polymeric film comprising progesterone as described herein, in the manufacture of a medicament for use in a method of hormone replacement therapy. In any of the compositions for use, the methods, and the uses described above, the composition may be administered to the subject in a therapeutically effective amount.

[0195] As used herein, a subject, a subject in need thereof, or a patient may refer to a mammalian subject, such as a human subject. In some examples, the mammalian subject may be a female mammalian subject.

[0196] General Definitions

[0197] It should be noted that the terms “comprise”, “comprising” and / or “comprises” is / are used to denote that the various aspects, embodiments and examples of this disclosure “comprise” a particular feature or features. It should be understood that this / these terms may also encompass aspects, embodiments and / or examples which “consist essentially of” or “consist of” the relevant feature or features. Moreover, the entire contents of all references described or referred to herein are to be regarded as incorporated herein by reference.

[0198] As used herein, the term “about” when qualifying a number or value, may refer to values that lie within ± 5% of the value specified. For example, where the wetting agent is described as being present at a concentration of about 2% w / w in the dispersion, a range of 1 .9% w / w to 2.1 % w / w is included.

[0199] Additionally, in the present disclosure, the nomenclature used herein for defining compounds, in particular the compounds according to the disclosure, is in general based on the rules of the IUPAC organisation for chemical compounds, specifically the “IUPAC Compendium of Chemical Terminology (Gold Book)”, unless the context indicates otherwise.

[0200] DESCRIPTION OF FIGURES

[0201] The present disclosure will now be further described, by way of example only, with reference to the following Figures and examples.

[0202] Figure 1 shows the viscosity versus shear rate curve of a number of polymers tested as an aqueous dispersion at the described concentrations.

[0203] Figure 2 shows the viscosity at a shear rate of 10s-1of a number of polymers tested as an aqueous dispersion at the described concentrations.

[0204] Figure 3 shows: (a) the rupture strength (Rp); and (b) elongation to puncture (EP) of a number of exemplary polymeric films. Figure 4 shows the viscosity of the exemplary polymer dispersions PVF-001 , PVF- 002, PVF-003, PVF-004, and PVF-005 when measured at a shear rate of 10s-1.

[0205] Figure 5 shows a schematic representation of an exemplary method of manufacturing an exemplary polymeric film comprising progesterone as disclosed herein.

[0206] Figure 6 shows: (a) elongation to puncture (EP); and (b) rupture strength (Rp) of polymeric films obtained from exemplary dispersions PVF-001 , PVF-001 -P, PVF-001 -GR, PVF-001-GP, and PVF-001-G.

[0207] Figure 7 shows: (a) rupture strength (resistance to puncture); and (b) elongation to puncture (EP) of polymeric films obtained from exemplary dispersions formed from a placebo film, PVF-001.03 (applied at a wet thickness of 1200 pm), PVF-001.03 (applied at a wet thickness of 1500 pm) and PVF-001 (applied at a wet thickness of 1200 pm).

[0208] Figure 8 shows the release profile of progesterone from exemplary polymeric films PVF-001.03 (90mg) and PVF-001.03 (45 mg) in comparison to commercial products Crinone (90 mg) and Utrogestan (200 mg).

[0209] Figure 9 shows the pharmacokinetics profile of progesterone from exemplary polymeric films PVF-001.03 (90mg) and PVF-001.03 (45 mg) in comparison to commercial products Crinone (90 mg) and Utrogestan (200 mg).

[0210] Figure 10 shows (a) elongation to puncture (EP); and (b) rupture strength (RP) of exemplary polymeric films PVF-Poly Placebo, PVF-Poly (90mg) and PVF-Poly (45 mg).

[0211] Figure 11 shows the release profile of progesterone from exemplary polymeric films PVF-Poly (90mg), PVF-SA (90 mg) and PVF-poly (45 mg) in comparison to commercial products Crinone (90 mg) and Utrogestan (200 mg).

[0212] Figure 12 shows a pharmacokinetic profile of progesterone from exemplary polymeric films PVF-001 .03 (90 mg) and PVF-Poly (90 mg) in comparison to a commercial product, Crinone®.

[0213] Figure 13 shows a pharmacokinetic profile of progesterone from exemplary polymeric film PVF-Poly (45 mg) in comparison to a commercial product, Utrogestan (200 mg).

[0214] Measurement of parameters

[0215] In the following examples section, a number of mechanical properties are determined. Unless otherwise stated, these parameters are determined in accordance with the general methodologies outlined below. Elongation to puncture (EP) and Rupture Strength (Resistance to Puncture (Rp)

[0216] The elongation to puncture and rupture strength were determined in accordance with the mechanical strength test described in Preis et al, International Journal of Pharmaceutics, 461 (2014), 22-29, using probe C as described in that document (see, in particular, section 3.4 “Mechanical strength test”).

[0217] In particular, the method comprised using a Texture Analyser TA-Xtplus with a spherical head. The polymeric film was fixed between two plates with a cylindrical hole of 10mm diameter. The Texture Analyzer was moved forwards using a velocity of 1.0mm / s. Measurement was started when the probe contacted the sample film. The probe was moved on at a constant speed until the film broke apart. The applied force and displacement (penetration depth) were recorded.

[0218] As referred to herein, the term “elongation to puncture” (EP) may be used interchangeably with the term “flexibility”.

[0219] As referred to herein, the term “rupture strength” may be used interechangably with “resistance to puncture” (Rp) and “mechanical strength”.

[0220] Folding endurance

[0221] The folding endurance was determined in accordance with the following method. A sample of film was prepared having a size of 3 cm by 5 cm. The films typically had a thickness from 100 to 280 pm. A sample of film was repeatedly folded at 90° along the same axis. The number of folds until break was recorded.

[0222] Viscosity

[0223] The viscosities were determined using a rheometer (Modular Compact Rheometer MCR 102, Anton Paar), using cone plate setting (CP60-1 / TI, 60 mm, Anton Paar). The shear ramp was recorded from 0 to 100 s-1 , at 20°C and each sample analyzed in triplicate.

[0224] In particular the viscosities described above and herein may refer to a viscosity measured at a shear rate of 10 s-1and a temperature of 20 °C using a rheometer cone plate setting. By way of further example, the viscosities described herein may represent a dynamic viscosity.

[0225] Film Thickness: The thickness of the films was measured using a micrometer. Measurements at the middle and ends of the film were taken and an average thickness calculated.

[0226] Progesterone Content:

[0227] The progesterone content of the films was determined using a high performance liquid chromatography (HPLC) technique.

[0228] Water Content:

[0229] Water content was determined via volumetric titration by the Karl Fischer technique, using samples amounts around 30mg.

[0230] Water Activity:

[0231] Water activity was determined as per described in USP 43 chapter <922> Water Activity, which uses vapor pressure measurements in a headspace for quantification.

[0232] Uniformity of Dosage:

[0233] Uniformity of dosage was performed by analysing 10 individual films according to the “Progesterone Content” analytical method described above. The uniformity of dosage was calculated according to chapter 2.9.40 Uniformity of Dosage Units of the European Pharmacopoeia.

[0234] Disintegration Time:

[0235] The disintegration time of the polymeric films was measured using an orbital shaker at 37°C and 150 revolutions per minute (RPM). The films were immersed in acetate buffer and incubated in the shaker until complete disintegration was observed. The time taken for complete disintegration was recorded.

[0236] General Method of forming polymeric films

[0237] Films were prepared through the solvent casting technique. Initially, in 2 / 3 of the water mass containing plasticizers, the high-viscosity HPMC was dispersed, under mechanical stirring (shear blade, 500-800 RPM) at room temperature. After homogenization, filmforming polymers and / or polymers for release rate control were added, and this mixture was kept under stirring at a lower speed (-300 RPM) to prevent air entrapment in the formulation. In the remaining water (1 / 3 of the total mass), the wetting agent was added, followed by progesterone, maintaining magnetic stirring (500 RPM) for approximately 30 minutes. After the dispersion of progesterone was added to the polymers dispersion and kept under mechanical stirring (shear blade, 250 RPM) for another 2 hours or until complete homogenization. This mixture was then applied onto a substrate at specific thicknesses using an automatic film applicator (TKB instruments) and dried in an oven with air circulation. The drying process may vary, preferably involving 1 to 2 hours of drying at an approximate temperature of 70°C. Higher temperatures (up to 120°C) can be applied to reduce drying time. This method is also illustrated in Figure 5.

[0238] In the following examples, where progesterone was included in the exemplary films, progesterone microparticles were used (Progesterone USP micronized sourced from Pharmacia & Upjohn Company LLC (a wholly owned subsidiary of Pfizer)). Progesterone USP micronized comprises an average particle size of not more than 15 pm, D10 of not more than 6 pm, D50 of not more than 10 pm, and D90 of not more than 16 pm.

[0239] EXAMPLES

[0240] 1. Development of placebo film

[0241] 1.1 Evaluation of isolated polymers with potential to compose the vaginal film

[0242] The first step of the development involved the identification of polymers that showed good potential to compose the film matrix. Considering the high load of progesterone to be incorporated into the film, the inventors hypothesized that a matrix with a higher polymeric concentration would be necessary, to be able to retain the entire drug load in the polymeric matrix. However, polymeric dispersions of high concentration can present very high viscosity and high viscosities can cause difficulties during manufacturing. The inventors analyzed a number of different polymers to investigate viscosity, film formation capacity and appearance of the formed film.

[0243] 1.1.1 Preparation of polymeric dispersions

[0244] For polymers of low medium and high viscosity the concentrations of the dispersions tested were 8%, 4% and 2 % (w / w). The dispersions of each isolated polymer were prepared in water at the described concentrations (Table 1 ) and kept under magnetic stirring for 24 hours.

[0245] Table 1. Tested polymers and concentrations for polymeric film formation.

[0246] It was noted that the complete homogenization of the dispersion was difficult for the high viscosity polymers HPMC K4M, CMC 7MF and CMC 7HF, even at the lower concentration of 2% (w / w). All dispersions, except for CMC 7HF and CMC 7MF, had a clear or slightly turbid homogeneous appearance. For CMC 7HF and 7MF there was the formation of a granular gel.

[0247] 1.1.2 Viscosity assessment

[0248] The viscosity of aqueous dispersions of different polymers were measured in accordance with the “Viscosity” measurement method outlined above. To compare the samples, a shear rate of 10 s-1was selected, as a representative of the forces imposed on the material during the continuous film coating process in the industrial manufacturing method.

[0249] All polymers, except for Pharmacoat 603, showed non-Newtonian and pseudoplastic behavior (Figure 1 ), that is, the relationship between the strain rate and the shear stress was not constant, and the greater the force applied to the material, the lower its apparent viscosity.

[0250] As shown in Figure 2, among the polymers with the lowest theoretical viscosity, when tested at a concentration of 8% w / w in water, Pharmacoat 603 and HPC-SL showed a viscosity around 50-60 mPa. CMC 7LF presented a significantly higher viscosity, reaching values close to 7500 mPa.

[0251] Among the “medium viscosity” polymers, the alginates presented viscosity values between 1000 and 2700 mPa. CMC 7MF, presented the highest value of viscosity, greater than 10000 mPa. Among the higher viscosity polymers, HPMC 4KM presented a viscosity value around 2,500 mPa and CMC 7HF a higher viscosity value, around 10000 mPa, even at a low concentration of 2 % w / w.

[0252] 1.1.3 Wet and dry film forming ability

[0253] After the viscosity evaluation, the dispersions were applied as a layer (1000 pm) using an automatic film applicator. Immediately after application, the behaviour of the applied layer was observed and recorded.

[0254] For Pharmacoat 603 and HPC-SL at 2% (w / w), after application the dispersion spread over the substrate, not maintaining the apparent shape or thickness. Following application to the substrate, the dispersion spread significantly outside the applied area limits.

[0255] For the CMC 7LF, due to the higher viscosity, there was no spreading of the dispersion, however, there was a contraction of the polymeric dispersion. The dispersion did not maintain its shape and holes formed in the applied layer.

[0256] For the alginates, a similar behavior of shrink was observed after the layer application.

[0257] For CMC 7MF this behavior was not observed, probably due to the high viscosity, however, it was possible to observe the presence of granules in the coating layer.

[0258] Among the higher viscosity polymers, CMC 7HF showed such high viscosity that it was not possible to apply a film using the automatic film applicator. In contrast, the HPMC 4KM was easily applied, not leaking, or showing contraction.

[0259] All applied films were dried in an oven with air circulation and heated to 65°C. The drying time varied according to the dispersion composition and concentration, ranging between 50 to 90 minutes. The CMC polymers took the longest time to dry (about 2 h). After the drying step, the appearance of the films was recorded. The appearance of the formed films is shown in Table 2.

[0260] Table 2. Appearance of the films formed after drying.

[0261] 1.1.4 Evaluation of mechanical properties

[0262] The mechanical properties of films composed by isolated polymers were evaluated from the measure of rupture strength (Rp) and elongation to puncture (EP) in accordance with the elongation to puncture and rupture strength measurement method outlined above.

[0263] Sodium alginate films were not further evaluated, due to deformation and formation of a hard material after the drying process.

[0264] The results of this analysis are shown in Figures 3a and 3b.

[0265] Regarding the rupture strength, films obtained from dispersions of Pharmacoat 603 (8% w / w) and HPMC 4 KM (2% w / w) showed equivalent results (~20 N / mm2), even at different concentrations. The HPC-SL film showed the lowest rupture strength (~ 12 N / mm2) and those based on CMC the highest rupture strength values, between 55 and 60 N / mm2. Considering the elongation to puncture (EP), high elasticity was observed for the film obtained from a dispersion of HPC-SL (~12 %) and low for the film of Pharmacoat 603 (~5 %). The other films presented values around 9 to 13 %.

[0266] 1.1.5 Summary

[0267] The CMC polymers presented problems regarding the homogeneity in dispersion, in addition to resulting in heterogeneous and slightly deformed films. The alginates formed homogeneous dispersions of adequate viscosity, however both the wet gel layer and the one submitted to drying showed high deformation.

[0268] Among the lower viscosity polymers, it was identified that Pharmacoat 603 provided a good film forming capacity and rupture strength, but a lower elasticity. It was further identified that HPC-SL showed good elasticity but poor tear strength and greater peel strength. The HPMC 4KM presented good mechanical properties and resistance to deformation, however it was shown to form a thin and fragile film, due to the limitation in the working concentration (as it is a high viscosity polymer).

[0269] Following this initial stage of development, the present inventors concluded that none of the tested polymers showed appropriate film forming ability when used in isolation.

[0270] 1.2 Evaluation of polymeric blends to compose the vaginal film

[0271] The inventors then conducted further investigations to ascertain if a polymeric blend could be identified to provide a polymeric film suitable for vaginal administration.

[0272] 1.2.1 Preliminary study of blends

[0273] Following the results as outlined in section 1.1 , the polymers Pharmacoat 603, HPMC 4KM, HPC-SL and CMC 7HF were selected for further investigation. A preliminary screening of dispersions was carried out to investigate whether suitable polymeric blends and concentration ranges could be identified. The details of this screening are shown in Table 3.

[0274] Table 3. Composition and characteristics of polymeric dispersions and films.

[0275]

[0276] In the preliminary screening, Pharmacoat 603 proved to be an excellent film-forming polymer, but showed very low viscosity even at high concentrations. HPC-SL and CMC formed waxy and heterogeneous films that were not peelable. Excess plasticizers did not improve the mechanical properties of the films and appeared to be expelled from the matrix during drying. Based on tests 4a and 5b, the combination of Pharmacoat 603 and HPMC 4KM was selected for further investigation.

[0277] 1.2.2 Preparation of polymeric blends dispersions

[0278] A number of exemplary polymeric blends were prepared in accordance with the concentrations shown in Table 4.

[0279] Table 4. Exemplary polymeric blends and concentrations of components in dispersions used to form the polymeric films.

[0280]

[0281] For the preparation of examples PVF-001 , PVF-002, PVF-003, PVF-004, and PVF-005, the following method was used. Water was weighed together with the plasticizers and mixed under magnetic stirring at 300 RPM. The polymers were individually weighed and added to the water as follows: firstly the polymer with the highest viscosity (HPMC 4KM or CMC 7MF) was added under stirring at 1000 RPM, after the partial dispersion (30 minutes), the polymers of lower viscosity were added, keeping the stirring for approximately 4 hours. Afterwards, the dispersions were kept overnight (12 h) at room temperature to eliminate bubbles.

[0282] 1.2.3 Viscosity assessment

[0283] A shear rate of 10 s-1was selected to measure the viscosity value of the exemplary dispersions. The results of this analysis in presented in Figure 4.

[0284] It was identified that a viscosity value between 1500 and 5000 mPa.s-1for the dispersion was preferable, since viscosity lower than 1500 mPa.s-1result in leakage during coating process in the manufacturing. Furthermore, dispersions with a viscosity higher than 5000 mPa.s-1resulted in a high air entrapment into the mixture and provided a slower drying film.

[0285] Of the tested dispersions, PVF-001 and PVF-005 showed viscosity values in the preferred range. In addition, the PVF-002 dispersion presented a value very close to the established minimum of 1500 mPa.s-1. The viscosities of the PVF-003 and PVF-004 dispersions were measured as 578 and 1260 mPa.s-1, respectively. These results demonstrated the importance of including HPMC 4KM in the dispersion at a concentration higher than 0.5 % w / w, preferably close to 1 %, to provide the preferred viscosities for the dispersion.

[0286] 1.2.4 Wet and dry film forming ability

[0287] The exemplary dispersions were applied as a layer of 1000 pm, using the automatic film applicator (TKB- Erichsen Instruments). Immediately after application, the behavior of the applied layer was observed. For exemplary dispersions, PVF-001 , PVF- 002 and PVF-005, there were no spreading of the dispersion. For the PVF-003 and PVF- 004 dispersions, leakage occurred, especially when larger gap applicators were used (for coating thicker films).

[0288] Before drying, all applied films presented a homogeneous appearance, without the presence of bubbles. After drying, the PVF-002 dispersion resulted in a film that was brittle and difficult to detach from the substrate. The PVF-003, PVF-004 and PVF-005 dispersions formed peelable films, but which were not resistant to fold.

[0289] The PVF-001 mixture showed the most promising result, with a peelable and flexible film, slightly plastic in texture.

[0290] 1.2.5 Summary

[0291] Of the exemplary dispersions tested, PVF-001 presented adequate viscosity before drying and produced films with promising properties such as high apparent mechanical strength, flexibility and bending resistance. Thus, dispersions comprising Pharmacoat 603 and HPMC 4KM were selected for further investigation.

[0292] 1.3 Polymeric films comprising progesterone

[0293] The incorporation of progesterone into polymeric films was then evaluated, using dispersion PVF-001 as a starting point.

[0294] 1.3.1 Initial investigations

[0295] Progesterone was added to the PVF-001 dispersion at a concentration of 4.5% (w / w). This concentration was subtracted from the water percentage in the PVF-001 dispersion to avoid dilution of the other components. In this initial test, the inventors observed it was difficult to incorporate all of the progesterone into the dispersion. In particular, it seemed that air became trapped. After drying, the film presented a heterogeneous appearance, with progesterone clusters along its entire length. Furthermore, the formed film was also observed to be very brittle and fragile to handling.

[0296] Based on this result, it was hypothesized that a wetting agent could be used to facilitate the dispersion of hydrophobic progesterone throughout the polymeric matrix.

[0297] 1.3.2 Further investigations

[0298] A number of potential wetting agents were evaluated, including polysorbate 80, glycerol, poloxamer and sodium lauryl sulfate.

[0299] In particular, polysorbate 80 was tested at a concentration of 0.70% w / w in the dispersion. For efficient wettability, the polysorbate 80 was dissolved in part of the formulation water (1 / 4) followed by progesterone addition to the mixture. The polymers were dispersed in the rest (3 / 4) of the water with the plasticizers. The two phases were then each homogenized and then mixed together under magnetic stirring (200 RPM). This exemplary manufacturing method is represented in Figure 5.

[0300] Using this method, an improvement in the appearance of the film was observed. In particular, it showed greater homogeneity and the presence of clusters was not observed. However, the film remained rigid with the presence of bubbles. It was hypothesized that the presence of air bubbles and the rigid characteristic of the film was possibly the result of the high viscosity of the starting dispersion due to the subtraction of 4.5% of water from the formula and the incorporation of 4.5 % of progesterone. Thus, a further adjustment was made to reduce the low-viscosity polymer HPMC E3 concentration from 8.0% to 6.5% (w / w). The modified dispersion is presented in Table 5.

[0301] Table 5. Further exemplary dispersions comprising progesterone.

[0302] After this modification, the dispersion was applied at a thickness of 1200 pm and dried at 65°C for 50-60 minutes. The result of the modification was an apparently homogeneous film, with enough flexibility to roll. The prototype was coded as PVF-001 - PG.

[0303] 1.3.3 Analysis and adjustments of the prototype PVF-001 -PG

[0304] The PVF-001 -PG prototype was analyzed using a progesterone assay, according to the analytical protocol (HPLC method). The progesterone content in the film was found to vary from 74 to 85 % (equivalent of a dose around 67 to 76 mg, per film). For this concentration of progesterone, films showed good mechanical properties however, the prototypes were already with 25 cm2, the maximum acceptable area limit.

[0305] It was desirable to increase the concentration of progesterone in the starting dispersion from 4.5% to 6.0% (w / w) to allow delivery of higher dosages. Such an example is shown above as PVF-001 ,02-PG. Whilst a film was formed after the drying of this dispersion, it showed a slight increase in stiffness and lost resistance to folding, breaking after 4 bends on the same axis.

[0306] 1.3 Summary

[0307] The inclusion of a wetting agent and adaptation in the film production methodology resulted in improvements in the film’s appearance and flexibility. However, an increase in the concentration of progesterone in the starting dispersion resulted in an increase in film stiffness and brittleness upon bending. The present inventors then hypothesized that further components could be added to the film to allow an increase to the progesterone concentration, whilst maintaining the other desirable properties of the film (e.g. elasticity and malleability).

[0308] 1.4 Further investigations including the use of plasticizers

[0309] The incorporation of further components was then investigated, including the use of plasticizers.

[0310] 1.4.1 Influence of plasticizer in film mechanical properties To understand the influence of the plasticizer combination on the mechanical properties of the films, placebos were prepared, varying the combination of plasticizers (as shown in Table 6).

[0311] Table 6. Further exemplary dispersions to provide placebo films.

[0312] 1.4.2 Preparation of polymeric dispersions

[0313] The dispersions were prepared in accordance with the following method. The water was weighed with the plasticizers. The higher viscosity polymer was added first under mechanical stirring. After partial dispersion, the lower viscosity polymer was added, under mechanical stirring.

[0314] No significant differences were observed in the apparent viscosity and appearance of the dispersions.

[0315] 1.4.3 Film forming ability evaluation

[0316] The films were applied to a thickness of 1200 pm using the Automatic Film Applicator. All samples were found to be suitable for the application step, not dripping or showing the incorporation of excessive air bubbles. All films dried properly, were easy to peel off, and showed no deformation and / or defects.

[0317] 1.4.4 Evaluation of films mechanical properties

[0318] Rupture strength (RP) and elongation to puncture (EP) of the polymeric films were determined in accordance with the methods outlined above. The results of these tests are shown in Figures 6a and 6b. The placebo leading prototype (PVF-001 ) presented high mechanical strength (RP) and elongation to puncture (EP). However, it was observed to comprise a relatively plastic texture and was not soft.

[0319] The dispersion comprising only propylene glycol as the plasticizer (PVF-001-P) showed the lowest EP (-10%) and low breaking strength. Without being bound by theory, it was hypothesized that the relatively low boiling point of propylene glycol, may cause it to evaporate from the formula during the drying process.

[0320] The combined use of glycerol and PEG-400 (PVF-GP) as platicizers in the dispersion resulted in a significant increase in the EP value from 15% to 20% and in the formation of a soft film.

[0321] The combined use of glycerol and propylene glycol (PVF-001 -GR) in the dispersion resulted in fragile films with a greasy texture.

[0322] The dispersions comprising only glycerol as plasticizer (PVF-001 -G) showed an intermediate value of elasticity (EP) but a high breaking strength around 30 N / mm2. In addition, very smooth textured films were formed when glycerol was used as a plasticizer.

[0323] Based on these results, further investigations focused on dispersions comprising both glycerol and PEG400 as the plasticizer.

[0324] 1.4.5 Investigating addition of HPC-SL

[0325] Exemplary dispersions further comprising HPC-SL as film-forming polymer were prepared as shown in Table 7. These films were prepared in accordance with the methods disclosed herein, e.g. as outlined on Figure 5.

[0326] Table 7. Further exemplary dispersions used to provide polymeric films loaded with progesterone.

[0327] After drying, the PVF-001.01 film composed of 6.5% HPC-SL presented a waxy texture and it was difficult to detach it, remaining adhered to the substrate.

[0328] The PVF-001.02 film containing 3% HPC-SL (in addition to Pharmacoat 603) was peelable but fragile.

[0329] The PVF-001.03 film was detachable, presented excellent malleability and flexibility in addition to a smooth texture, promising results for the intended application.

[0330] 1.4 Summary

[0331] These investigations indicated that the addition of a mixture of glycerol and PEG-400 as plasticizers and also the inclusion of HPC-SL (as an additional film forming polymer) could be helpful in providing polymeric films suitable for vaginal administration. In particular, these additions to the dispersion were found to assist in the formation of more malleable and smoother films.

[0332] 1.5 Films containing progesterone

[0333] Films based on the PVF-001.03 formula were prepared and applied with wet thicknesses of 1200 pm and 1500 pm. Films applied with thicknesses of 1200 pm and 1500 pm presented a final thickness of 131-132 and 176-178 pm after drying respectively.

[0334] Due to the difference and thickness, when targeting a 90 mg dose of progesterone, the films presented different areas of 25 cm2and 15 cm2for the thinnest and thickest respectively. The placebo applied at a thickness of 1200 pm had a final thickness of 75 to 79 pm.

[0335] The films were analyzed for mechanical properties, for comparison, the placebo, the leading prototype and the non-optimized formula PVF-001 with 6% progesterone were analyzed. The results are illustrated in Figures 7a and 7b.

[0336] The inclusion of progesterone was observed to reduce the film's resistance to puncture and flexibility. Between thicknesses tested, no significant impact was observed on the mechanical properties. However, it was noted that the changes in the dispersion formulation from PVF-001 to PVF-001.03 significantly impacted the elasticity of the film (with PVF-001 .03 showing greater levels of elasticity). The disintegration time of the films was measured using an orbital shaker at 37°C and 150 RPM. The films were immersed in acetate buffer and incubated in the shaker until complete disintegration was observed. For placebo, disintegration occurs around 1 and a half hours after the start of the test. For films containing progesterone, the disintegration time was approximately 4 hours, without significant differences regarding the thickness.

[0337] Considering ease of handling and production yield, the smaller and thicker film was selected for the following tests.

[0338] As progesterone can be used for hormone replacement in smaller doses, PVF- 001 .03 film was produced also with 45 mg of PRO, that is, with 3.5% (w / w) of progesterone in the initial dispersion to prepare the film (Table 8).

[0339] Table 8. Further exemplary dispersions used to provide polymeric films loaded with progesterone.

[0340] These exemplary dispersions may be dried to provide polymeric films with a water content between 6% w / w and 10% w / w based on the total weight of the final polymeric film. Accordingly, these dispersions may be used to provide polymeric films comprising the components as shown in Table 9 below, with the %w / w given based on the total weight of the final polymeric film.

[0341] Table 9. Components in final polymeric film in % (w / w) based on total weight of polymeric film with a water content from 6% w / w to 10% w / w.

[0342]

[0343] The lead prototypes containing 45 or 90 mg of progesterone and 15 cm2were manufactured and characterized. The results are presented in Table 10.

[0344] Films presented with quality criteria within expectations. In particular, the exemplary films provided a progesterone content between 95 and 105%, showed good dose uniformity, adequate mechanical resistance and flexibility and a disintegration time greater than 60 minutes.

[0345] The water activity of the films with progesterone was observed to be less than 0.6, indicating that there is no risk of microbial growth in the material.

[0346] Table 10. Properties of progesterone-containing polymeric films and placebo polymeric films.

[0347] After characterization, in vitro release test was performed with the samples, in the Franz diffusion cell, at 200 rpm in 10 mL of acetate buffer with 3 % of sodium lauryl sulphate as the dissolution medium, at 37°C ± 0.5°C.

[0348] The release profiles of formulations against the commercial products Crinone (gel) and Utrogestan (soft gel capsule) are shown in Figure 8. The formulations exhibited a faster in vitro release of progesterone compared to Crinone (90 mg) and Utrogestan (200 mg).

[0349] It was observed that Crinone® released - 30% of the dose in 24h and Utrogestan showed a burst release in 24h (-40% of the dose). PVF-001 .0345 mg and 90 mg released 100% of the dose between 12 to 24h.

[0350] According to the results, the film was shown to have a relatively faster release rate compared to commercial products. This behavior was expected, since the film is composed of a thin matrix, with a large surface area that is in contact with the medium used for dissolution.

[0351] Pharmacokinetic (PK) studies in an ovariectomized female dog model were performed. The formulations were administered in a single-dose regimen, intravaginally and blood samples were collected at pre-determined times. The results are presented in Figure 9. At this stage n=4 animal was used for each product.

[0352] According to the profile, at a dosage of 90 mg there was similarity in the profile for up to 3.5 hours. From that time on, probably due to the greater availability of progesterone conveyed in the film for permeation, a significant difference in the profiles was observed. The pharmacokinetics parameters are presented in Table 11 below.

[0353] Table 11. Pharmacokinetics parameters based on the release of progesterone from exemplary polymeric films PVF-001.03 (90mg) and PVF-001.03 (45 mg) in comparison to commercial products Crinone (90 mg) and Utrogestan (200 mg).

[0354] With regard to the pharmacokinetic parameters, there was a similarity in Tmax and Cmax between PVF-001.03 (90 mg), Crinone and Utrogestan, but a difference was observed in the AUC 0-24h. With regard to bioavailability, the PVF-001.03 (90 mg) film presented a value close to that of Utrogestan.

[0355] 1.5.1 Preparation of further films comprising progesterone

[0356] Further exemplary dispersions were prepared which further comprise one or more additional components to assist in controlling the rate of release of progesterone. In particular, dispersions including sodium alginate and calcium chloride, or polycarbophil were further investigated.

[0357] It was observed that high concentrations of sodium alginate (>2%, w / w) or polycarbophil (>0.2%, w / w) formed films that were brittle or difficult to detach from the substrate. The alginate film showed low bending resistance, cracking after bending twice on the same axis. Films with polycarbophil presented good appearance and resistance to bending.

[0358] Two 90 mg polymeric films were made from the dispersions as shown in Table 12. Table 12. Further exemplary dispersions used to provide polymeric films loaded with progesterone.

[0359] These exemplary dispersions may be dried to provide polymeric films with a water content between 6% w / w and 10% w / w based on the total weight of the final polymeric film. Accordingly, these dispersions may be used to provide polymeric films comprising the components as shown in Table 13 below, with the %w / w given based on the total weight of the final polymeric film.

[0360] Table 13. Components in final polymeric film in % (w / w) based on total weight of polymeric film with a water content from 6% w / w to 10% w / w.

[0361] Polymeric films containing 90 mg and 45 mg PVF-001 ,03-Poly films were made and further analyzed. The results are presented in table 14 and in Figure 10. Table 14. Properties of further exemplary progesterone-loaded polymeric films and placebo modified films.

[0362] An in vitro release test was performed with the samples, in the Franz diffusion cell, at 200 rpm in 10 mL of acetate buffer with 3 % of sodium lauryl sulphate as the dissolution medium, at 37°C ± 0.5°C.

[0363] The release profiles of the exemplary polymeric films were investigated using the commercial products Crinone (gel) and Utrogestan (soft gel capsule) for comparison. The results are shown in Figure 11.

[0364] The formulations exhibited a faster in vitro release of progesterone compared to Crinone® (90 mg) and Utrogestan (200 mg) but showed a lower rate of release compared to PVF-001.03.

[0365] Crinone® released - 30% of the dose in 24h and Utrogestan showed a burst release in 24h (-40% of the dose). PVF-Poly (45 mg) and PVF-Poly (90 mg) released -80% of the dose in 24h but in a low rate compared to other polymeric films tested herein.

[0366] Pharmacokinetic (PK) studies in an ovariectomized female dog model were performed. The formulations were administered in a single-dose regimen, intravaginally and blood samples were collected at pre-determined times, using 12 animals per group. The results are shown in Figures 12 and 13.

[0367] Crinone vs PVF-001 .03 (90 mg) presented main profile differences after 8 hours of study, indicating a possible necessity of twice or 3 times daily administration. The extent of absorption for Crinone continued unlike the tested films, with similar Cmax and Tmax but different AUC.

[0368] Progesterone delivered by PVF-Poly (90 mg) was observed to be consistently slower in absorption, compared to PVF-001.03 and Crinone®. Comparing the exemplary film PVF-poly (45 mg) to the commercial product Utrogestan (200 mg), a 20% lower Cmax and 60% lower AUC was observed.

[0369] The pharmacokinetics parameters are presented in Table 15 below.

[0370] Table 15. Pharmacokinetics parameters based on the release of progesterone from exemplary polymeric films PVF-001.03 (90mg), PVF-Poly (45 mg), PVF-Poly (90 mg) and PVF-001.03 (45 mg) in comparison to commercial products Crinone® (90 mg) and Utrogestan (200 mg).

[0371] While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the invention in its broader aspects.

Claims

CLAIMS:1 . A polymeric film comprising:(a) a high viscosity hydroxypropylmethyl cellulose in an amount from about 0.01 % w / w to about 20% w / w based on a total weight of the polymeric film; and(b) a film former, wherein the film former comprises a low viscosity hydroxypropylmethyl cellulose in an amount from about 5% w / w to about 50% w / w based on a total weight of the polymeric film; wherein: the polymeric film further comprises a pharmaceutically active agent, which is a hormone; and the pharmaceutically active agent is present in an amount from about 15% w / w to about 35% w / w based on the total weight of the polymeric film.

2. The polymeric film according to claim 1 , wherein the hormone is selected from progesterone, estradiol and testosterone.

3. The polymeric film according to claim 1 or 2, wherein the hormone is progesterone.

4. A polymeric film according to any one of the preceding claims, wherein the high viscosity hydroxypropylmethyl cellulose comprises a viscosity from about 2000 to about 5500 mPa.s, or from about 2200 to about 5040 mPa.s, at 20°C at 2% w / w in water, optionally wherein the high viscosity hydroxypropylmethyl cellulose is HPMC K4M.

5. A polymeric film according to any one of the preceding claims, wherein: the high viscosity hydroxypropylmethyl cellulose is present in an amount from about 0.1% w / w to about 15% w / w, from about 0.5% w / w to about 12% w / w, or from about 3% w / w to about 10% w / w based on a total weight of the polymeric film; and / or the film former is present in an amount from about 5% w / w to about 75% w / w, from about 15% w / w to about 60%, from about 20% w / w to 50%w / w, or from about 30% w / w to about 40% w / w based on a total weight of the polymeric film.

6. A polymeric film according to any one of the preceding claims, wherein the low viscosity hydroxypropylmethyl cellulose comprises a viscosity from about 0.5 mPa.s to about 10 mPa.s, from about 1 mPa.s to about 7.5 mPa.s, from about 2 mPa.s to about5 mPa.s, from about 2 to about 4 mPa.s, or from about 3 to about 4 mPa.s when measured at 20°C at 2% w / w in water, optionally wherein the low viscosity hydroxypropylmethyl cellulose is HPMC E3.

7. The polymeric film according to any one of the preceding claims, wherein the film former further comprises hydroxypropyl cellulose (HPC), optionally a low viscosity hydroxypropyl cellulose, such as HPC-SL.

8. The polymer film according to any one of the preceding claims, wherein the film former comprises: the low viscosity hydroxypropylmethyl cellulose in an amount from about 5% w / w to about 50% w / w, from about 10% w / w to about 40% w / w, or from about 15% to about 30% based on the total weight of the polymeric film; and a low viscosity hydroxypropyl cellulose in an amount from about 1 % w / w to about 25% w / w, from about 5% w / w to about 20% w / w, from about 10% w / w to about 15% w / w based on the total weight of the polymeric film.

9. The polymeric film according to any one of the preceding claims, wherein the film further comprises a plasticizer, optionally wherein the plasticizer comprises one or more, or all, of:(i) low molecular weight polyethylene glycol (e.g. PEG400), optionally present in an amount from about 1 % w / w to about 25% w / w based on a total weight of the polymeric film;(ii) glycerol, optionally present in an amount from about 1 % w / w to 25% w / w based on a total weight of the polymeric film; and(iii) propylene glycol, optionally present in an amount from about 1% w / w to 25% w / w based on a total weight of the polymeric film.

10. The polymeric film according to any one of the preceding claims, wherein the polymeric film comprises one or more, or all, of the following:(i) water, optionally in an amount from about 0.1% w / w to about 20% w / w based on a total weight of the polymeric film; and(ii) one or more additional components to control a rate of release selected from carbomers, polycarbophil, sodium alginate and calcium chloride, optionally inan amount from about 0.05% w / w to about 20% w / w based on a total weight of the polymeric film.

11. The polymeric film according to any one of the preceding claims, wherein the polymeric film comprises a wetting agent, optionally in an amount from about 0.1% w / w to about 10% w / w based on a total weight of the polymeric film.

12. The polymeric film of any one of the preceding claims, which comprises one or more of the following properties:(i) a flexibility of at least about 10%, or at least about 15%;(ii) a rupture strength of at least about 2 N / mm2, or at least about 3 N / mm2;(iii) a folding endurance of greater than 30; wherein flexibility, rupture strength and folding endurance are determined using the methods as described in the description.

13. A polymeric film comprising:(a) a high viscosity hydroxypropylmethyl cellulose in an amount from about 0.01% w / w to about 20% w / w based on a total weight of the polymeric film; and(b) a film former, wherein the film former comprises a low viscosity hydroxypropylmethyl cellulose in an amount from about 5% w / w to about 50% w / w based on a total weight of the polymeric film and a low viscosity hydroxypropyl cellulose from about 1% w / w to about 25% w / w based on the total weight of the polymeric film.

14. The polymeric film according to claim 13, wherein the low viscosity hydroxypropyl cellulose comprises a viscosity from about 1 to about 10 mPa.s, from about 2 to about 8 mPa.s, from about 3 to about 6.5 mPa.s, or from about 6 to about 6.5 mPa.s at 20 °C at 2% w / w in water, optionally wherein the low viscosity hydroxypropyl cellulose is HPC- SL.

15. A polymeric film according to claim 13 or 14, wherein the high viscosity h yd roxypropyl methyl cellulose comprises a viscosity from about 2000 to about 5500 mPa.s, or from about 2200 to about 5040 mPa.s, at 20°C at 2% w / w in water, optionally wherein the high viscosity hydroxypropylmethyl cellulose is HPMC K4M.

16. A polymeric film according to any one of claims 13 to 15, wherein:the high viscosity hydroxypropylmethyl cellulose is present in an amount from about 0.1% w / w to about 15% w / w, from about 0.5% w / w to about 12% w / w, or from about 3% w / w to about 10% w / w based on a total weight of the polymeric film; and / or the film former is present in an amount from about 5% w / w to about 75% w / w, from about 15% w / w to about 60%, from about 20% w / w to 50%w / w, or from about 30% w / w to about 40% w / w based on a total weight of the polymeric film.

17. A polymeric film according to any one of claims 13 to 16, wherein the low viscosity h yd roxypropyl methyl cellulose comprises a viscosity from about 0.5 mPa.s to about 10 mPa.s, from about 1 mPa.s to about 7.5 mPa.s, from about 2 mPa.s to about 5 mPa.s, from about 2 to about 4 mPa.s, or from about 3 to about 4 mPa.s when measured at 20°C at 2% w / w in water, optionally wherein the low viscosity hydroxypropylmethyl cellulose is HPMC E3.

18. The polymer film according to any one of claims 13 to 17, wherein the film former comprises: the low viscosity hydroxypropylmethyl cellulose in an amount from about 5% w / w to about 50% w / w, from about 10% w / w to about 40% w / w, or from about 15% to about 30% based on the total weight of the polymeric film; and the low viscosity hydroxypropyl cellulose in an amount from about 1% w / w to about 25% w / w, from about 5% w / w to about 20% w / w, from about 10% w / w to about 15% w / w based on the total weight of the polymeric film.

19. The polymeric film according to any one of claims 13 to 18, wherein the film further comprises a plasticizer, optionally wherein the plasticizer comprises one or more, or all, of:(i) low molecular weight polyethylene glycol (e.g. PEG400), optionally present in an amount from about 1 % w / w to about 25% w / w based on a total weight of the polymeric film;(ii) glycerol, optionally present in an amount from about 1% w / w to 25% w / w based on a total weight of the polymeric film; and(iii) propylene glycol, optionally present in an amount from about 1% w / w to 25% w / w based on a total weight of the polymeric film.

20. The polymeric film according to any one of the claims 13 to 19, wherein the polymeric film comprises one or more, or all, of the following:(i) water, optionally in an amount from about 0.1% w / w to about 20% w / w based on a total weight of the polymeric film;(ii) one or more additional components to control a rate of release selected from carbomers, polycarbophil, sodium alginate and calcium chloride, optionally in an amount from about 0.05% w / w to about 20% w / w based on a total weight of the polymeric film; and(iii) a wetting agent, optionally in an amount from about 0.1 % w / w to about 10% w / w based on a total weight of the polymeric film.21 . The polymeric film according to any one of claims 13 to 20, further comprising a pharmaceutically active agent, optionally wherein the pharmaceutically active agent is a hormone, and further optionally wherein the hormone is selected from progesterone, estradiol and testosterone.

22. The polymeric film according to claim 21 , wherein the pharmaceutically active agent is present in amount from about 5% w / w to about 50% w / w, from about 10% w / w to about 40% w / w, or from about 15% w / w to about 35% w / w based on a total weight of the polymeric film.

23. A method of making a polymeric film, the method comprising:(i) providing a dispersion comprising:(a) a high viscosity hydroxypropylmethyl cellulose in a concentration range from about 0.01 % w / w to about 2.0% w / w of the dispersion; and(b) a film former, wherein the film former comprises a low viscosity hydroxypropylmethyl cellulose in a concentration range from about 2% w / w to about 10% w / w of the dispersion;(ii) casting the dispersion onto a surface; and(iii) drying the dispersion to provide the polymeric film; optionally wherein the polymeric film is as defined in any one of the preceding claims.

24. The method of claim 23, wherein the dispersion further comprises a pharmaceutically active agent at a concentration from about 0.01% w / w to about 10%w / w, from about 0.1% w / w to about 7.5% w / w, or from about 0.5% w / w to about 6% w / w of the dispersion, optionally wherein the pharmaceutically active agent is a hormone.

25. The method of claim 23 or 24, wherein the film former further comprises a low viscosity hydroxypropyl cellulose at a concentration from about 0.5% w / w to about 7% w / w of the dispersion.

26. The method of any one of claims 23 to 25, wherein the dispersion comprises:(i) a solvent, optionally wherein the solvent is an aqueous solvent; and / or(ii) a viscosity from about 1000 mPa.s to about 7500 mPa.s, such as from about 1500 mPa.s to about 5000 mPa.s when measured at a shear rate of 10 s'1at 20°C.

27. A polymeric film obtained or obtainable by the method of any one of claims 23 to 26.

28. The polymeric film of any one of claims 1 to 22, or 27, for intravaginal administration.

29. The polymeric film of any one of claims 1 to 22, or 27, for use in therapy.

30. The polymeric film of any one of claims 1 to 22, or 27, wherein the polymeric film comprises progesterone, and the film is for use in:(i) the treatment or prevention of a condition associated with reduced levels of progesterone or a progesterone deficiency;(ii) supplementing progesterone levels in a subject undergoing an assisted reproductive technology (ART) procedure, such as in vitro fertilization (IVF);(iii) the treatment or prevention of a condition selected from infertility, miscarriage, pre-term labour, endometriosis, adenomyosis, irregular menstruation, dysfunctional uterine bleeding, endometrial hyperplasia and amenorrhea;(iv) reducing the risk of miscarriage or pre-term labour; or(v) the treatment or prevention of symptoms associated with the menopause; or(vi) a method of hormone replacement therapy.

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