Lyophilized Spherical Pellets for Biological Materials

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Solution Overview

Problem

Existing methods for preparing lyophilized biological materials, such as proteins, often result in cakes rather than spherical pellets, which have slower reconstitution times and are cumbersome to produce, especially when using glass containers or complex assembly designs.

Innovation Solution

A method involving dispensing liquid droplets onto a cold, flat metal or hydrophobic surface to freeze and lyophilize them into spherical pellets, allowing for faster reconstitution and high-throughput production without the need for cryogenic substances or complex machinery.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Loss of time

If liquid composition is frozen and lyophilized in glass containers to produce cakes, then the biological material is preserved, but the reconstitution time is slow

Engineering Contradiction:
Improvereconstitution timeVSAvoidmanufacturing process simplicity
Core Design Contradiction:
Loss of timeVSEase of manufacture

Solution Approach 1:

The invention divides the lyophilized biological material into multiple small spherical pellets instead of producing a single large cake. Each pellet is formed by dispensing individual liquid droplets onto a cold surface, freezing them, and lyophilizing. This segmentation dramatically increases the surface area to volume ratio, enabling faster reconstitution times while maintaining simplicity in the manufacturing process through automated droplet dispensing.

Inventive Principle:
Principle #1Segmentation

Solution Approach 2:

The invention uses spherical droplets as the basic unit for lyophilization. By dispensing liquid composition as spherical droplets onto a cold surface, the resulting pellets maintain a spherical shape. This spherical geometry provides optimal surface area to volume ratio for rapid reconstitution, solving the contradiction between fast reconstitution and manufacturing simplicity.

Inventive Principle:
Principle #14Spheroidality (Curvature)

2Loss of time

If individual droplets are frozen and lyophilized to produce spherical pellets, then reconstitution time is fast, but the manufacturing process becomes more complex

Engineering Contradiction:
Improvereconstitution timeVSAvoidmanufacturing device complexity
Core Design Contradiction:
Loss of timeVSDevice complexity

Solution Approach 1:

The cold surface used in this invention serves multiple functions: it acts as a freezing surface, a support during lyophilization, and a release surface for the finished pellets. This multi-functionality eliminates the need for complex assembly disassembly and pellet detachment mechanisms, reducing device complexity while maintaining fast reconstitution times through spherical pellet formation.

Inventive Principle:
Principle #6Universality (Multi-functionality)

Solution Approach 2:

The invention uses a simple, disposable cold surface that is discarded after use, eliminating the need for complex, expensive, and reusable equipment with multiple moving parts. This approach reduces device complexity significantly while still achieving the goal of fast reconstitution through spherical pellet production.

Inventive Principle:
Principle #27Cheap short-living objects (Disposable)

3Temperature

If cryogenic substances are used to freeze droplets, then freezing is effective, but the process becomes more complex and requires special handling

Engineering Contradiction:
Improvefreezing temperatureVSAvoidfreezing system complexity
Core Design Contradiction:
TemperatureVSDevice complexity

Solution Approach 1:

The invention replaces the mechanical system of cryogenic substance handling with a thermal conduction system. Instead of using liquid nitrogen or other cryogens that require special handling, storage, and safety protocols, the invention uses a cold surface maintained at freezing temperature through conventional refrigeration. This substitution eliminates the complexity associated with cryogenic substances while achieving effective freezing for spherical pellet production.

Inventive Principle:
Principle #28Mechanics substitution (Replace mechanical system)

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

This method produces dried spherical pellets with significantly faster reconstitution times compared to traditional lyophilized cakes, enabling efficient and stable storage and administration of biological materials like proteins and vaccines.

Implementation Method 1

freezing the droplet on the surface without contacting the droplet with a cryogenic substance

Methodology Applied
Scientific EffectFreezing: Freezing

Implementation Method 2

a bottom surface that is in physical contact with a heat sink adapted to maintain the top surface of the metal plate at a temperature of -90°C or below

Methodology Applied
Scientific EffectHeat sink: Heat Sink

Implementation Method 3

lyophilizing the frozen droplet to produce a dried pellet

Methodology Applied
Scientific EffectLyophilization: Freeze Drying

Implementation Method 4

The lyophilization process involves freezing a liquid sample which is then subjected to a vacuum so that the ice in the frozen sample directly changes to water vapour or sublimes

Methodology Applied
Scientific EffectSublimation: Sublimation

Data Source

PatentEP3812468A1Methods of preparing lyophilized spherical-shaped pellets of biological materials
Publication Date: 2021.04.28 MERCK SHARP & DOHME LLC
  • EP3812468A1 patent drawingFigure 1
  • EP3812468A1 patent drawingFigure 2
  • EP3812468A1 patent drawingFigure 3

AI summary

Methods for preparing lyophilized pellets of biological materials are described. The pellets have a substantially spherical shape and are prepared by freezing droplets of a liquid composition of a desired biological material on a flat, solid surface, in particular, a surface that does not have any cavities, followed by lyophilizing the frozen droplets. These methods are useful for preparing lyophilized pellets having a high concentration of a desired biological material, in particular a therapeutic protein or vaccine, and which have a faster reconstitution time than lyophilized powder cakes prepared in vials.