Acid Gelatin Soft Capsule for Dutasteride Stability
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Solution Overview
Problem
The existing formulations of 17-beta-N-[2,5-bis(trifluoromethyl)phenylcarbamoyl-4-aza-5-alpha-androst-1-en-3-one, such as dutasteride, face challenges with stability, bioavailability, and manufacturing complexity in soft gelatin capsules, particularly due to cross-linking of gelatin, solubility issues, and sensitivity to temperature and humidity, leading to reduced efficacy and short shelf life.
Innovation Solution
The development of an immediate release soft gelatin capsule using acid gelatin with less than 150 g Bloom of gel strength, combined with glycerol monocaprylocaprate and an antioxidant like butylhydroxytoluene, which ensures stable dissolution profiles and bioavailability, and can be stored up to 40 °C, with a reproducible filling process to maintain consistent drug content.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If conventional gelatin is used in soft gelatin capsules, then the capsule can be manufactured, but the gelatin cross-links during storage leading to reduced dissolution and bioavailability
Solution Approach 1:
The patent changes the chemical parameter of gelatin by using acid gelatin with a specific Bloom strength range (less than 150 g Bloom, preferably 75-145 g Bloom). This parameter change prevents cross-linking during storage while maintaining capsule integrity and dissolution profile.
2Reliability
If the capsule fill is designed to form an emulsion in the stomach, then absorption is facilitated, but the active substance may precipitate out reducing bioavailability
Solution Approach 1:
The patent uses a composite carrier medium comprising glycerol monocaprylocaprate (a mixed glyceride) combined with antioxidants. This composite formulation maintains solubility and prevents precipitation of the active substance while enabling emulsion formation for facilitated absorption.
3Reliability
If components are included in the capsule fill to improve solubility, then bioavailability is enhanced, but components migrate into the capsule shell during manufacture changing the composition
Solution Approach 1:
The patent controls the temperature parameter during manufacturing (maintaining gelatin ribbon temperature between 35-50°C) and uses acid gelatin with specific properties to minimize migration of carrier medium components into the capsule shell during the encapsulation and drying processes.
4Strength
If the capsule is made with high gel strength gelatin, then the capsule structure is stronger, but the dissolution profile is reduced due to cross-linking
Solution Approach 1:
The patent specifies using acid gelatin with Bloom strength in the range of 75-145 g Bloom (less than 150 g Bloom), which provides adequate capsule strength while preventing the cross-linking that occurs with higher Bloom strength gelatins, thereby maintaining reliable dissolution profiles.
5Duration of action of stationary object
If the capsule is stored at elevated temperatures, then shelf life is extended, but the dissolution profile deteriorates due to cross-linking and instability
Solution Approach 1:
The patent performs preliminary stabilization by incorporating antioxidants (such as butylhydroxytoluene) into the capsule formulation before storage. This preliminary protective action prevents oxidative cross-linking and degradation during elevated temperature storage, maintaining dissolution profile and extending shelf life.
Solution Approach 2:
The patent changes the chemical composition parameter by using acid gelatin with specific Bloom strength and incorporating antioxidants, which alters the stability characteristics of the capsule to allow storage at elevated temperatures without deterioration of the dissolution profile.
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 solution provides a stable and bioavailable immediate release dosage form with enhanced stability and bioavailability, maintaining dissolution profiles even after storage at elevated temperatures and humidity, and simplifies the manufacturing process, addressing the limitations of previous formulations.
Implementation Method 1
it avoids the dissolution problems of the soft gelatin shell that become apparent upon aging and which are attributed to the cross-linking of gelatin
Implementation Method 2
The carrier medium may be designed to form an emulsion/solution in the stomach thereby facilitating absorption of the pharmacologically active substance
Implementation Method 3
the capsule shell is formed from wet gelatin bands and the resultant wet capsules are dried
Data Source
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AI summary
The present invention relates to immediate release soft gelatin capsules comprising 17-beta-N-[2,5- bis(trifluoromethyl)]phenylcarbamoyl-4-aza-5-alpha-androst-1-en-3-one. The invention further relates to processes for preparing such soft gelatin capsules.