Nalbuphine Ester Prodrug Formulation for Sustained Release

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Solution Overview

Problem

Current extended release opioid formulations, such as those for nalbuphine ester prodrugs, face challenges in achieving a well-controlled release period, suitable for low injection volumes, and cost-effective industrial-scale manufacturing, due to complexity in sterilization and limited solubility in oily substances.

Innovation Solution

Pharmaceutical formulations comprising nalbuphine ester prodrugs dissolved in a release-controlling solution with a high weight ratio of oil-miscible retaining solvent to pharmaceutically acceptable oil, such as benzyl benzoate to sesame oil, which extends the release period and allows for higher concentrations of the prodrug, enabling administration by injection with improved stability and solubility.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Duration of action of moving object

If nalbuphine ester prodrugs are dissolved in oily substances for extended release formulations, then the release period is extended, but the solubility of the prodrug in the oily substance is limited

Engineering Contradiction:

Improverelease periodVSAvoidsolubility of prodrug

Core Design Contradiction:

Duration of action of moving objectVSQuantity of substance

Solution Approach 1:

The patent uses a composite solvent system combining oil-miscible retaining solvent (benzyl benzoate) with pharmaceutically acceptable oil (sesame oil, castor oil, or cottonseed oil). This composite approach allows the prodrug to achieve high solubility in the retaining solvent component while the oil component provides extended release properties, resolving the contradiction between solubility and release duration.

Inventive Principle:

Principle #40Composite materials

2Reliability

If complex sterilization procedures are used for emulsion formulations, then the formulations can be administered by injection, but the manufacturing process becomes time-consuming and not cost-effective for large scale production

Engineering Contradiction:

Improvesuitability for injectionVSAvoidmanufacturing process complexity

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent extracts the problematic emulsion system and replaces it with a homogeneous solution system using oil-miscible retaining solvent combined with pharmaceutically acceptable oil. This eliminates the need for complex emulsion preparation and sterilization procedures while maintaining injectability, thus resolving the contradiction between reliability and ease of manufacture.

Inventive Principle:

Principle #2Taking out (Extraction)

3Duration of action of moving object

If large injection volumes (3 mL or greater) are administered to achieve extended release, then the release period is extended, but serious injection site irritation occurs

Engineering Contradiction:

Improverelease periodVSAvoidinjection site irritation

Core Design Contradiction:

Duration of action of moving objectVSObject-affected harmful factors

Solution Approach 1:

The patent changes the concentration parameter of the prodrug in the formulation by using oil-miscible retaining solvent which provides high solubility. This allows achieving extended release duration with smaller injection volumes (below 3 mL), thereby resolving the contradiction between release period and injection site irritation.

Inventive Principle:

Principle #35Parameter changes

4Loss of time

If oral formulations are used for nalbuphine administration, then the dosing frequency can be reduced, but the apparent half-life is only about 24 hours requiring dosing every 8 to 12 hours

Engineering Contradiction:

Improvedosing frequencyVSAvoidapparent half-life

Core Design Contradiction:

Loss of timeVSDuration of action of moving object

Solution Approach 1:

The patent changes the physical form parameter from oral solid formulation to parenteral liquid formulation using oil-miscible retaining solvent. This enables achieving prolonged duration of action (greater than 24 hours) through intramuscular or subcutaneous injection, resolving the contradiction between dosing frequency and half-life.

Inventive Principle:

Principle #35Parameter changes

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The formulations provide an extended release period of up to 14 days or more, with higher solubility and stability, allowing for effective pain management with reduced dosing frequency and improved manufacturing efficiency.

Implementation Method 1

nalbuphine ester prodrugs dissolved in a release-controlling solution with a high weight ratio of oil-miscible retaining solvent to pharmaceutically acceptable oil

Methodology Applied

Scientific EffectSolubility: Solvation

Implementation Method 2

release the nalbuphine ester prodrug in an extended manner

Methodology Applied

Scientific EffectDiffusion: Diffusion

Data Source

PatentUS10183018B2Pharmaceutical formulations for sustained release of sebacoyl dinalbuphine ester

Publication Date: 2019.01.22 SHANGHAI LUMOSA THERAPEUTICS

AI summary

The present invention relates to injectable, extended-release, pharmaceutical formulations comprising a nalbuphine ester prodrug homogenously dissolved in a solution comprising a pharmaceutically acceptable oil and an oil-miscible retaining solvent, as well as manufacturing processes and medical uses of the formulations. The invention further provides methods for adjusting the duration of action of the formulations by varying the ratio of the pharmaceutically acceptable oil and the oil-miscible retaining solvent.