BACKGROUND

Orodispersible films (ODFs) are pharmaceutical dosage forms that are designed as a thin film having a large surface area that leads to rapid disintegration within seconds on a wet surface, such as the oral cavity. See e.g., Thakir S., Orodispersible films and their patent technology's as a novel drug delivery systems. Int. J Pharm Sci Rev Res [Internet]. 2019 September [cited 2019 Dec. 13]; 58 (1): 52-60. Advantages of this type of formulation include that the drug or other deliverable is absorbed directly into the systemic circulation, thus avoiding the hepatic 1stpass effect. Additionally, ODFs are seen to be more convenient for patients due to their relative ease of administration. As such, this type of delivery system can lend itself to better patient compliance. If the drug is absorbed in the oral cavity then drug degradation in the gastrointestinal tract is also avoided. This type of formulation is extremely favourable for paediatric and geriatric patients that have difficulty swallowing tablets or who have a fear of choking, patients who are unconscious, patients wherein parenteral administration brings sufficient risks (e.g., HIV patients) and/or patients suffering from dysphagia (e.g., post-stroke). Typically, the aforementioned patient groups would conventionally be given liquid or nasal spray formulations of medicines, which often have their own drawbacks (e.g. risk of microbial contamination, self-instability either over a period of months or once opened, the requirement of specialized designated devices for administration etc.).

For example, Itraconazole (ITZ) is a triazole antifungal drug that prevents the synthesis of ergosterol, the main component of fungal cell wall. ITZ is primarily used to treat candidiasis and tinea infections (See, e.g., Trey et al., (2008) ‘Delivery of Itraconazole from Extruded HPC Films’,Drug Dev. Ind. Pharm.,33(7), pp. 727-735). ITZ has a dose dependent effect for different indication, it is typically 100-200 mg; for the treatment of recurrent vulvovaginal candidiasis, but doses as low as 50 mg can be effective (See, JOINT FORMULARY COMMITTEE, 2017. Itraconazole. In: JOINT FORMULARY COMMITTEE. British National Formulary. [online]. London: BMJ Group and Pharmaceutical Press). Physiochemically, ITZ is a Biopharmaceutical Classification System (BCS) Class II drug; exhibiting poor solubility but high permeability. Importantly due to presence the piperazine ring, the pKa of ITZ is 3.7. The drug is highly hydrophobic (log P reported to be 5.7-6.2) with no hydrogen bond donors, and very poorly water-soluble (See, Bagavatula et al., (2014) ‘Comparative Studies on Solubility and Dissolution Enhancement of Different Itraconazole Salts and Their Complexes’,Adv. Pharmacol. Pharm.,2(6), pp. 85-95). Its aqueous solubility is highly pH dependent, varying from 1 ng/mL at pH 7 to 4 μg/mL at pH 1. ITZ is therefore practically insoluble at physiological pH; it is very slightly soluble in alcohol (See Savjani, et al., (2017) ‘Design and Optimization of Itraconazole Tablet Employing Solid Dispersion Approach’,Asian J. Pharm.,11(1), pp. 192-207). However, the highly lipophilic nature of ITZ means that it readily permeates through the intestinal mucosa and the drug's absolute oral bioavailability is reported to be 55% (Saviani, supra). ITZ undergoes hepatic first pass effect. It is recommended that ITZ be taken with food (increasing oral bioavailability by 33-37%) (See, Prentice et al., (2005) ‘Making sense of itraconazole pharmacokinetics’,J. Antimicrob. Chemother.,56(1), pp. 17-22). ITZ is metabolised primarily by the cytochrome P450 3A4 isoenzyme system into hydroxy-itraconazole, keto-itraconazole and N-desalkyl-itraconazole; all of which are competitive inhibitors of the CYP3A4 metabolizing enzyme.

ITZ is licensed for the treatment of oral candidiasis in both HIV/other immunosuppressed patients and in non-immunosuppressed patients. ITZ is available as a capsule, oral solution, suspension and intravenous (IV) formulation. As all these require swallowing or breaking of the skin, they can complicate matters in immunosuppressed patients and patients with severe symptoms. Thus, the need for a dosage form that has none of these drawbacks can be very advantageous to patients. Considering ITZ's physiochemical properties such as limited solubility and its subjection to hepatic 1st pass metabolism, an ODF comprising itraconazole would be highly desirable.

As another example, naloxone is an inverse opioid agonist which binds with high affinity to the μ-opioid receptor and to a lesser extent to the kappa and delta opioid receptors. When the drug binds, it replaces the offending opioid at the active site and elicits the opposite pharmaceutical effects. (See, Koyyalagunta D. chapter 113—Opioid Analgesics. In: Waldman S D, Bloch C drawings by Joseph I, editors. Pain Management [Internet]. Philadelphia: W.B. Saunders; 2007 [cited 2017 Dec. 15]. p. 939-64.) If given in time, naloxone reverses respiratory depression caused by an opioid overdose and can be lifesaving. In the United States 64000 people died from drug overdoses in 2016, around 53000 of which were opioid related, making opioids the leading cause of death in people under the age of 50. Furthermore, the death toll in 2016 was 22% higher than the previous year. The increase was in part due the potent opioid fentanyl becoming more widely available. Deaths from fentanyl have increased by 540% in the past 3 years. (See, e.g., Drug Overdose Death Data|Drug Overdose|CDC Injury Center [Internet]. 2017 [cited 2017 Dec. 13]. Available from: https://www.cdc.gov/drugoverdose/data/statedeaths.html) Public health campaigns have focused on getting naloxone into the hands of as many members of the public as possible, with focus on the family and friends of users. (See, Davis et al., Engaging Law Enforcement in Overdose Reversal Initiatives: Authorization and Liability for Naloxone Administration. American Journal of Public Health. 2015 August; 105:1530-7.) Accordingly, the need for an easy to use and inexpensive naloxone delivery system such as that disclosed herein, is more important than ever.

Currently naloxone is licensed as IV, S/C and IM formulation in both the EU and US. It is also approved as a nasal spray in the US. (See, Naloxone: Uses, Dose & Side Effects [Internet]. Drugs.com. [cited 2017 Dec. 15]. Available from: https://www.drugs.com/naloxone.html) All the current delivery methods require a device for administration. This complicates their use for the everyday user. Coupled to this naloxone's half-life is short, at around 30 minutes. (See, Narcan (Naloxone Hydrochloride Injection): Side Effects, Interactions, Warning, Dosage & Uses [Internet]. RxList. [cited 2017 Dec. 15]. Available from: https://www.rxlist.com/narcan-side-effects-drug-center.htm) As a result, re-dosing is often required. naloxone's viability can only be ensured if it is carried by first responders and members of the public. As such, a delivery method, such as that disclosed herein, which is compact and easy to carry presents a huge advantage.

The current most prominent method used in the formulation and manufacture of orodispersible thin films is solvent casting. This generally involves creating a casting solution of an aqueous based polymer with a uniformly dispersed active pharmaceutical ingredient (API). The solvent casting solution generally de-gassed, is applied to a casting surface, before drying and cutting to the appropriate size before packaging. See, e.g., Morales J, McConville J. Manufacture and characterisation of mucoadhesive buccal films. Eur J Pharm Biopharm [internet]. 2011 February [cited 2019 Nov. 3]; 77(2): 187-99.

However, the solvent casting method for thin film production has limitations, including: difficulty and expense related to scaling up for industrial manufacture, long drying times, lack of drug uniformity which could lead to unsafe dosing, and variable storage conditions for the finished product. (See, e.g., U.S. Pat. No. 7,425,292 issued Sep. 16, 2008.) For example, the problems associated with long drying times at room temperature (RT) have led to the use of ovens for drying; in some cases, a hot forced-air oven. This subjects the film to stress, and can cause a rippling effect which can lead to clumping and non-uniform drug distribution. The use of ovens can also result in degradation of the API. Moreover, the hygroscopic nature of films can cause issues for storage and stability. See e.g., Karki, S. et al., Thin films as an emerging platform for drug delivery. Asian J. Pharm. Sci. [Internet]. 2016 June [cited 2019 Dec. 13]; 11(5):559-74.

Furthermore, many APIs and or desirable additives are hydrophobic. However, the incorporation of a uniform distribution of a hydrophobic agent into ODFs has proven to be extremely difficult.

Accordingly, novel ODFs and methods for forming the same that overcome these limitations are greatly desired.

SUMMARY

The present disclosure provides orodispersible films (ODFs) and methods for making the same. According to an embodiment, the ODFs are formed using a solvent casting technique wherein a mixture comprising a thermoresponsive polymer, an active pharmaceutical ingredient (API) and any optional excipients or other ingredients are cast at a temperature at or above the thermal gelation point of the mixture to form a stable gel, the solvent in the gel is then evaporated to produce a thin film.

