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Pharmaceutical formulations comprising opioid receptor agonist as active ingredients, methods of manufacture and therapeutic uses thereof

a technology of opioid receptor and active ingredient, which is applied in the field of pharmaceutical formulations comprising opioid receptor agonist as active ingredient, can solve the problems of increased muscle tone, poor sucking reflex, autonomic instability, etc., and achieves adequate viscosity, safe and effective formulation, and avoids swallowing and absorption

Inactive Publication Date: 2020-07-30
CHIESI FARM SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides new pharmaceutical formulations that contain an opioid receptor agonist for safe and effective treatment of neonates through sublingual administration. These formulations have a good shelf-life and are easy to use. They have a suitable viscosity to stay in place on the tongue and are absorbed through the mucus membrane, avoiding swallowing and the gastrointestinal tract.

Problems solved by technology

The main manifestations include increased muscle tone, autonomic instability, irritability, poor sucking reflex, and impaired weight increase.
The optimal treatment of NAS has not been established yet.
However, there has been little experience with the use of buprenorphine in neonatal or pediatric populations and limited information about the use of sublingual formulation in the newborns.
Therefore, fixed-dose film formulations for sublingual and buccal administration such as those commercially available or disclosed in EP 2 461 795, which is incorporated herein by reference in its entirety, could not be suitable as it will not be possible of promptly adjusting the needed amount of drug.
Due to the presence of ethanol, said formulation might not be suitable for repeated administration in human neonates.
Furthermore, if devoid of the proper viscosity, sublingual / buccal dosage forms in form of solution may deliver variable amounts of drug, as they will have poor retention at the site of application.
In particular, given the volumes likely to be administered the recumbent position of the neonate after dosing, and use of a pacifier, the drug risks to be swallowed and absorbed through the gastrointestinal tract instead of through the sublingual route.

Method used

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  • Pharmaceutical formulations comprising opioid receptor agonist as active ingredients, methods of manufacture and therapeutic uses thereof
  • Pharmaceutical formulations comprising opioid receptor agonist as active ingredients, methods of manufacture and therapeutic uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0113]A first set of experiments was aimed at assessing the possibility of preparing buprenorphine aqueous solution formulations of adequate viscosity and pH in such a way as that they would turn out to be physically and chemical stable while maintaining a good profile of absorption.

The following formulations were prepared:

Formulation 1 pH = 6.0Quantity per mL (mg)FunctionBuprenorphine HCl0.075*Active PrincipleIngredientAnhydrous Citric Acid1.22Buffering AgentSodium Citrate Anhydrous11.3Buffering AgentHydroxyethylcellulose15.0Thickening AgentWater for Injection100 mlSolvent

Formulation 2 pH = 6.0Quantity per mL (mg)FunctionBuprenorphine HCl0.075*Active PrincipleIngredientAnhydrous Citric Acid1.22Buffering AgentSodium Citrate Anhydrous11.3Buffering AgentSodium Carboxymethylcellulose60.0Thickening AgentWater for Injection100 mlSolvent

Formulation 3 pH = 7.2Quantity per mL (mg)FunctionBuprenorphine HCl0.075*Active IngredientPotassium phosphate bibasic2.28Buffering AgentPotassium phosphat...

example 2

[0119]The Formulations 1, 2, 3, and 4 of Example 1 at a buprenorphine concentration of 0.01% w / v were stored for one month under long term conditions, i.e. 25±2° C. and 60% relative humidity, and under accelerated conditions, i.e. at 50±2° C., in order to evaluate their physical and chemical stability.

[0120]Stability was also tested under refrigerated conditions

[0121]The assay of buprenorphine and its impurities were performed by HPLC. The following parameters were also tested: pH, viscosity, and appearance. The results under long-term conditions are shown in Table 1. The results at 50°±2 C are shown in Table 2.

TABLE 1Stability of Formulations 1, 2, 3, and 4 according to Example 1 under long-term conditions.pHViscosity (mPas)Total degradation products (%)Assay % vs INITIALAppearanceFormulation 1Initial (t = 0)6.020670.63100Clear, colorless solutiont = 2 weeks6.118491.3991.4Clear, colorless solutiont = 1 month6.016070.8992.6Clear, colorless solutionFormulation 2Initial (t = 0)5.81035...

example 3

[0124]Formulations 1 and 2 at a buprenorphine concentration of 0.075 mg / ml expressed as a base, and the reference one were administered to dogs by sublingual administration. Three male Beagle dogs were used and received all the treatments with one-week washout period. The formulations were administered by dispensing the dose (max. 2.5 mL) under the tongue to the sublingual region and then holding the mouth closed for ca 45 s. This procedure was repeated until the full dose volume (0.4 mL / kg) was administered.

[0125]Buprenorphine concentrations in dog plasma were determined by a validated HPLC-MS / MS bioanalytical method and used for comparing systemic exposure obtained by the three different formulations.

[0126]As shown in FIG. 1, Formulation 1 and the Reference Formulation showed the maximum concentration at the same time and after dose normalization had almost equal maximum concentration and AUC.

[0127]Formulation 2 and the Reference Formulation are compared in FIG. 2: the time of the...

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Abstract

Formulation comprising buprenorphine or a pharmaceutically acceptable salt thereof as the sole active ingredient, a viscosity enhancer, and a buffering agent in an amount to provide a pH of from 5.0 to 7.0 are useful for treating opioid withdrawal syndrome.

Description

CROSS REFERENCES TO RELATED APPLICATIONS[0001]This application claims priority to European Patent Application No 17197466.0 filed on Oct. 20, 2017, which is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTIONField of the Invention[0002]The present invention relates to pharmaceutical formulations comprising an opioid receptor agonist as active ingredient, methods of manufacture such a formulation, and therapeutic uses of such a formulation. The present invention more particularly relates to a buprenorphine formulation for buccal / sublingual administration providing a therapeutically effective dosage for the treatment of neonatal abstinence syndrome.DISCUSSION OF THE BACKGROUND[0003]Neonatal abstinence syndrome (NAS) is a complex of signs and symptoms in the postnatal period associated with the sudden withdrawal of maternally transferred opioids. The main manifestations include increased muscle tone, autonomic instability, irritability, poor sucking reflex, and...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/00A61K9/08A61K47/38A61K31/485A61K47/12A61K31/00
CPCA61K47/12A61K9/006A61K31/485A61K47/38A61K31/00A61K9/08A61P25/30
Inventor CAIVANO, GRAZIASILVA BORGES, ANA FILIPA
Owner CHIESI FARM SPA
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