Pharmaceutical composition for nasal delivery

Abstract

According to the invention, there is provided a solid pharmaceutical composition formulation for nasal delivery of an opioid antagonist, comprising a pharmacologically-effective amount of an opioid antagonist and a pharmaceutically-acceptable carrier. Said compositions are preferably in the form of a powder produced by spray-drying, which are subsequently loaded into single use nasal applicators. Preferred pharmaceutically-acceptable carriers in this regard include disaccharides (e.g. lactose or trehalose) and dextrins (e.g. cyclodextrins or maltodextrins), preferably spray-dried together in combination. Compositions may further comprise an alkyl saccharide, preferably a sucrose ester, such as sucrose monolaurate. Said compositions and applicators may be employed in the treatment of opioid overdose in subjects.

Description

[0001] This application is a Continuation of U.S. patent application Ser. No. 16 / 876,468, filed May 18, 2020, which is a Continuation-in-Part of U.S. patent application Ser. No. 16 / 506,023, filed on Jul. 9, 2019, now U.S. Pat. No. 10,653,690, which are hereby incorporated by reference in their entirety.

[0002] This invention relates to new pharmaceutical compositions containing opioid antagonists that are useful in the treatment of inter alia opioid / opiate overdose. The invention also relates to methods of manufacturing such compositions and formulating them into dosage forms, as well as their use in the treatment of opioid / opiate overdose.PRIOR ART AND BACKGROUND

[0003] The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or common general knowledge.

[0004] Drug addiction is a worldwide problem, of which opioid dependence is a major component. Opioid...

Examples

example 2

Physical Stability of Spray-Dried Powders

[0231]In order to assess the physical stability and mitigate the risk for crystallization during storage, glass transition temperatures (Tg) were determined using differential scanning calorimetry (DSC) and are presented in Table 3 below.

[0232]Compositions were prepared generally in accordance with the procedure described in Example 1 above, using mannitol, trehalose and lactose as carrier materials.

[0233]For lactose, the true Tg, as well as that of the formulation subjected to equilibration at four different RH conditions at 25° C. (10%, 20%, 30% and 40% RH), were measured (although 30% was not logged). For mannitol and trehalose, Tg was measured as received (‘Ambient’) and after drying (‘Dried’).

[0234]For the dried samples, the DSC ampoule lid was punched automatically immediately before start of the DSC run, introducing a hole of about 0.3 mm diameter. The purpose of this was to allow any remaining moisture to evaporate before the glass tr...

example 3

Ex-vivo Evaluation of Nasal Mucosal Absorption of Naloxone and Nalmefene

[0236]A standard static diffusion (Franz) cell set up was employed to set up an ex vivo model for nasal mucosa absorption, using an excised porcine nasal tissue.

[0237]Solutions containing naloxone HCl dihydrate, nalmefene HCl, benzalkonium chloride (Sigma-Aldrich Sweden AB), sucrose monolaurate (IMCD Nordic AB) and / or polysorbate 80 (Croda Nordica AB) were prepared by standard techniques, to provide formulations according to Table 4 below. Potassium phosphate buffer (Sigma-Aldrich Sweden AB) was added to give the pH stated in Table 4 below.

TABLE 4Formulation12345678naloxone (mg / mL)5555555nalmefene (mg / mL)5555555benzalkonium chloride (mg / mL)0.10.10.1sucrose monolaurate (mg / mL)0.42polysorbate 80 (mg / mL)2pH4.54.54.54.54.54.54.56.5

Diffusion through the tissue was measured after 7 hours and permeation is shown as mean (three repeats) cumulative transport (μg / cm2; with SD) in FIGS. 8 and 9 for naloxone and nalmefene, ...

example 4

Naloxone-Containing Composition B

[0239]The general procedure described in Example 1 was employed to make a spray-dried composition from naloxone HCl dihydrate (1.199 g), along with α-D-lactose monohydrate (5.026 g; DFE Pharma Germany), sucrose monolaurate D-1216 (0.062 g; Mitsubishi-Kagaku Foods Corporation, Japan).

[0240]Composition B comprised a single dose of naloxone of 4 mg (calculated as the HCl salt).

[0241]Devices were placed in heat-sealed aluminum pouches (Protective Packaging, UK) before use.

[0242]The geometric particle size distribution (PSD) was measured using a Malvern Mastersizer 2000 (Malvern Panalytical Ltd, UK) and aerodynamic particle size distribution (aPSD) using a fast screening impactor (FSI, Copley Scientific, UK). PSD: d10=15 μm and d90=55 μm; aPSD <5 μm=0%.

[0243]General method for PSD measurements: 80 to 100 mg of sample was dispersed in 5 mL of silicone oil and mixed well before sonication for 20 to 30 seconds. Three measurements were made on the solution us...

[0001] This application is a Continuation of U.S. patent application Ser. No. 16 / 876,468, filed May 18, 2020, which is a Continuation-in-Part of U.S. patent application Ser. No. 16 / 506,023, filed on Jul. 9, 2019, now U.S. Pat. No. 10,653,690, which are hereby incorporated by reference in their entirety.

[0002] This invention relates to new pharmaceutical compositions containing opioid antagonists that are useful in the treatment of inter alia opioid / opiate overdose. The invention also relates to methods of manufacturing such compositions and formulating them into dosage forms, as well as their use in the treatment of opioid / opiate overdose.PRIOR ART AND BACKGROUND

[0003] The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or common general knowledge.

[0004] Drug addiction is a worldwide problem, of which opioid dependence is a major component. Opioid...

Examples

example 2

Physical Stability of Spray-Dried Powders

[0231]In order to assess the physical stability and mitigate the risk for crystallization during storage, glass transition temperatures (Tg) were determined using differential scanning calorimetry (DSC) and are presented in Table 3 below.

[0232]Compositions were prepared generally in accordance with the procedure described in Example 1 above, using mannitol, trehalose and lactose as carrier materials.

[0233]For lactose, the true Tg, as well as that of the formulation subjected to equilibration at four different RH conditions at 25° C. (10%, 20%, 30% and 40% RH), were measured (although 30% was not logged). For mannitol and trehalose, Tg was measured as received (‘Ambient’) and after drying (‘Dried’).

[0234]For the dried samples, the DSC ampoule lid was punched automatically immediately before start of the DSC run, introducing a hole of about 0.3 mm diameter. The purpose of this was to allow any remaining moisture to evaporate before the glass tr...

example 3

Ex-vivo Evaluation of Nasal Mucosal Absorption of Naloxone and Nalmefene

[0236]A standard static diffusion (Franz) cell set up was employed to set up an ex vivo model for nasal mucosa absorption, using an excised porcine nasal tissue.

[0237]Solutions containing naloxone HCl dihydrate, nalmefene HCl, benzalkonium chloride (Sigma-Aldrich Sweden AB), sucrose monolaurate (IMCD Nordic AB) and / or polysorbate 80 (Croda Nordica AB) were prepared by standard techniques, to provide formulations according to Table 4 below. Potassium phosphate buffer (Sigma-Aldrich Sweden AB) was added to give the pH stated in Table 4 below.

TABLE 4Formulation12345678naloxone (mg / mL)5555555nalmefene (mg / mL)5555555benzalkonium chloride (mg / mL)0.10.10.1sucrose monolaurate (mg / mL)0.42polysorbate 80 (mg / mL)2pH4.54.54.54.54.54.54.56.5

Diffusion through the tissue was measured after 7 hours and permeation is shown as mean (three repeats) cumulative transport (μg / cm2; with SD) in FIGS. 8 and 9 for naloxone and nalmefene, ...

example 4

Naloxone-Containing Composition B

[0239]The general procedure described in Example 1 was employed to make a spray-dried composition from naloxone HCl dihydrate (1.199 g), along with α-D-lactose monohydrate (5.026 g; DFE Pharma Germany), sucrose monolaurate D-1216 (0.062 g; Mitsubishi-Kagaku Foods Corporation, Japan).

[0240]Composition B comprised a single dose of naloxone of 4 mg (calculated as the HCl salt).

[0241]Devices were placed in heat-sealed aluminum pouches (Protective Packaging, UK) before use.

[0242]The geometric particle size distribution (PSD) was measured using a Malvern Mastersizer 2000 (Malvern Panalytical Ltd, UK) and aerodynamic particle size distribution (aPSD) using a fast screening impactor (FSI, Copley Scientific, UK). PSD: d10=15 μm and d90=55 μm; aPSD <5 μm=0%.

[0243]General method for PSD measurements: 80 to 100 mg of sample was dispersed in 5 mL of silicone oil and mixed well before sonication for 20 to 30 seconds. Three measurements were made on the solution us...

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