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US-12616653-B2 - Solid orodispersible pharmaceutical composition in film containing lorazepam

US12616653B2US 12616653 B2US12616653 B2US 12616653B2US-12616653-B2

Abstract

Disclosed are solid orodispersible pharmaceutical compositions in film form for oral administration of lorazepam, characterised by high stability throughout the shelf life of the product. The compositions disclosed are suitable for administration even to unconscious or dysphagic patients.

Inventors

  • Eleonora Dellera
  • Andrea Giori
  • Roberta Lollini
  • Fabio Marra

Assignees

  • ALTERGON S.A.

Dates

Publication Date
20260505
Application Date
20220301
Priority Date
20210302

Claims (12)

  1. 1 . Solid orodispersible pharmaceutical composition in fast-disintegrating film form comprising lorazepam, one or more film-forming polymers selected from maltodextrins, copovidone, sodium alginate or mixtures thereof, and one or more plasticizers, wherein the plasticizers are exclusively plasticizers in solid form at room temperature and the composition comprises water and a pharmaceutical-grade non-essential oil.
  2. 2 . Composition according to claim 1 , wherein the plasticizers are selected from polyalcohols and betaine.
  3. 3 . Composition according to claim 2 , wherein the polyalcohol is selected from sorbitol, mannitol, maltitol and xylitol.
  4. 4 . Composition according to claim 1 , wherein the solid plasticizers are present in percentages ranging from 5 to 50% by weight.
  5. 5 . Composition according to claim 1 , wherein the film-forming polymer is a mixture of maltodextrins with copovidone or sodium alginate.
  6. 6 . Composition according to claim 1 , wherein the film-forming polymer is present in percentages ranging from 40 to 80% by weight.
  7. 7 . Composition according to claim 1 , wherein water is present in percentages ranging from 5 to 30% by weight.
  8. 8 . Composition according to claim 1 , wherein the non-essential oil is of vegetable or animal origin or a medium-chain triglyceride.
  9. 9 . Composition according to claim 1 , wherein the non-essential oil is selected from olive, sesame, sunflower, soybean, peanut, corn, safflower and fish oil.
  10. 10 . Composition according to claim 8 , wherein the non-essential oil is present in percentages ranging from 1 to 15% by weight.
  11. 11 . Composition according to claim 1 , wherein lorazepam is present in percentages ranging from 0.25 to 10% by weight.
  12. 12 . Composition according to claim 1 , wherein the solid plasticizers are present in percentages ranging from 10 to 30%.

Description

This application is a U.S. national stage of PCT/IB2022/051793 filed on 1 March 2022, which claims priority to and the benefit of Italian Patent Application No. 102021000004880 filed on 2 Mar. 2021, the contents of which are incorporated herein by reference in their entireties. The present invention relates to a solid orodispersible pharmaceutical composition in film form for the oral administration of lorazepam. In particular, the invention describes an orodispersible film containing lorazepam, a ready-to-use pharmaceutical form, usable without water, suitable for the administration of the active ingredient even to unconscious or dysphagic patients, which can be prepared not only in the various dosages already approved, but also in dosages adaptable to the patient's therapeutic requirements and which remains stable throughout the entire shelf life of the product. PRIOR ART Lorazepam (7-chloro-5 -(2′-chlorophenyl-)1,3-dihydro-3-hydroxy-2H-1,4-benzo-diazepin-2-one, formula I) belongs to the benzodiazepine family, a class of medicaments which has been used for decades for the treatment of anxiety caused by depression or neurosis, insomnia and sleep disorders of various origins, treatment of psychosomatic disorders and as adjuvant in the treatment of epilepsy and neuropathic pain. The nature of the substituent groups on the 1,4-benzodiazepine ring has an impact on the pharmacological potency. The presence of the chlorine atom in the 2′ position makes lorazepam pharmacologically highly active, but the presence of the electron-acceptor atom destabilizes lorazepam, making it one of the least chemically stable benzodiazepines. The hydroxyl group present on the 7-atom ring causes a tensioning on the molecular structure, that brings to the rearrangement towards a 6-atom ring, which is much more stable and less strained, with the elimination of a water molecule (Scheme 1). This lorazepam rearrangement/dehydration process is promoted by temperature increase and is responsible for the formation of quinazoline aldehyde, identified in the USP monograph as Impurity C (M. S. Siddegowda et al. “Facile Thermal Rearrangement of Lorazepam and Oxazepam”, Indian Journal of Chemistry Section B 51(11):1628-1632, 2012). There are no ready-to-use oral solutions of lorazepam on the market, only solutions designed to be reconstituted prior to use, by solubilizing lorazepam in the mixture of solvents immediately before administration. The reconstituted solution has a shelf life limited to one month, preferably at low temperature. WO2004004783 discloses a ready-to-use liquid oral formulation of lorazepam, which does not need to be reconstituted. The formulation overcomes the problem of the stability of lorazepam by eliminating water from the formulation and using triacetin (triacetyl glycerin), a colourless, odourless solvent described in the pharmacopoeias, combined with diethylene glycol monoethylether (commercially known as Transcutol®). WO2004004783 does not use polyalcohols, which, like all solvents containing hydroxyl groups, are considered to be responsible for the instability of lorazepam. WO2008/019109 has already described the problems of formulating lorazepam in orodispersible pharmaceutical forms, such as orodispersible tablets (ODT). WO2008/019109 specifies that the use of common excipients for this type of pharmaceutical form, such as mannitol or polyvinylpyrrolidone (PVP), reduces the stability of the lorazepam in the finished product. The stability of the active ingredient is guaranteed in this case by protecting lorazepam with a granulation process or coating it with a polymer having a glass transition temperature (Tg) exceeding 65° C., preferably cellulose derivatives or PVP. US2016/0000803 discloses a liquid formulation for nasal administration of benzodiazepines, including lorazepam. It makes no reference to the poor chemical stability of lorazepam, but aims to overcome the poor solubility of lorazepam which causes its precipitation in water and in hydrophobic solvents. Therefore, it is impossible to obtain concentrated solutions which can be administered in small volumes suitable for the small size of the nasal cavities. US2016/0000803 overcomes the problem by including in the emulsions substances which form eutectic mixtures with benzodiazepines (menthol, thymol). Ready-to-use oral solutions and ODTs are very convenient pharmaceutical forms which are useful in specific clinical applications of benzodiazepines, in particular lorazepam, such as the treatment of patients suffering from epileptic fits, for whom the fastest possible administration is required. Among the fast-dissolving oral forms, orodispersible films (ODFs) have recently attracted increasing interest. Said films are thin sheets designed to be introduced into the oral cavity, contain the active ingredient, either dispersed or dissolved, and consist of film-forming polymers and other excipients used to obtain a dosage form suitable for oral administratio