WO2013117169A1

WO2013117169A1 - Apparatus and method for the encapsulation of materials

Info

Publication number: WO2013117169A1
Application number: PCT/CN2013/071553
Authority: WO
Inventors: Zhidao Xia
Original assignee: Wuhan Fl Medical Technology Company Ltd.
Priority date: 2012-02-09
Filing date: 2013-02-08
Publication date: 2013-08-15
Also published as: EP2811965A4; CN104135987A; GB201202265D0; EP2811965A1

Abstract

Apparatus for the encapsulation of materials comprises a container (1) which is pre-coated with lipids (2) on an inside surface of the container (1) and has an opening into which a drug (3) in solution can be introduced. The container (1) is then placed in a sonication bath and the lipid (2) which is in solution with the drug (3) forms vesicles under sonication which entrap the drug (3). The encapsulated drug (3) is removed from the container (1) and delivered to the patient shortly after encapsulation.

Description

APPARATUS AND METHOD FOR THE ENCAPSULATION OF MATERIALS

Field of the Invention

The invention relates to the encapsulation of materials and in particular but not exclusively to the encapsulation of materials in lipids, said materials for example being pharmaceuticals.

Backgrou nd of the Invention

The encapsulation of pharmaceuticals is known but these methods involve the encapsulation of materials that are then stored before being used. The preparations typically are stored and then transported to locations where the drug is prescribed and administered. This means that there may be a relatively long period between manufacture of the compositions and delivery to a patient. This occurs in a wide range of areas where materials are administered to an individual, including the treatment of humans, veterinary applications and during drug delivery with specialised medical devices which are used to control the administration of drugs, for example in the administering of a chemotherapy agent. Often when delivering drugs to an individual there is the need to reduce the diffusion rate of the drugs into tissue and capillaries where the drug is not required as the drug ideally enters the arterial system for delivery around the body. Also delivery should be such that it is possible to extend the effect of the drug locally over a period of time and this is often done by way of an injectable solution contain liposome encapsulated drugs.

Typical methods for the slow release of drugs is by using slow release particles or drugs that have been encapsulated by ultrasonicators and filtration devices and these can control the encapsulation ratio, the size and electric charges of liposomes. However these processes are for large scale drug production and the drug encapsulation rate is relatively low and inconsistent from batch to batch. Furthermore due to the low rate of drug encapsulation there is a waste of resource and energy to separate un-capsulated drugs from liposomes and this makes it difficult to control the quality and to ensure stability of drug encapsulated liposomes over a period of shelf life. For these reasons, only a handful of liposomal encapsulated drugs have been approved for marketing. The present invention seeks to overcome the problems of the prior art by providing a method of encapsulating material where the process is performed at the point of delivery so avoiding the need to use a stored drug. Furthermore, discrete amounts of drugs can be prepared and as they are delivered directly to an individual at the point of delivery there is little wastage of the drugs used.

Su mmary of the Invention

Throughout this document, unless otherwise indicated to the contrary, the terms "comprising", "consisting of", and the like, are to be construed as non-exhaustive, or in other words, as meaning "including, but not limited to".

According to a first aspect of the present invention there is provided an apparatus to encapsulate a drug in a lipid, said apparatus comprising a container having at least one surface having a pre-coated, dried lipid film thereon, and an opening into which a solution may be introduced that includes a material to be encapsulated, characterised in that said container is portable to the point of delivery of the drug to a patient and that on introduction of the solution into the container said dried lipid film can be released from the least one surface to form a solution and lipid mix and when the container is subjected to ultrasonication the lipid forms vesicles capable of encapsulation of at least a portion of the material following which the container can be opened to deliver the encapsulated drug directly to the individual.

Preferably the container is a medical grade-neutral glass bottle.

In a preferred arrangement the container includes a covering for the opening formed from a pierceable membrane.

It is envisaged that the lipids are in an organic solvent prior to being dried onto a wall of the container.

Preferably the lipid film is formed from a mixture of lipids.

It is envisaged that the lipids are phospholipids.

Preferably the phospholipids are derived from plant material.

The encapsulation ratio is controlled within a range of 50±10% of the drug available. It is envisaged that the vesicles produced by the lipid and sonication may range in size so that the drug may be delivered over a period of time, for example initially smaller vesicles can release a drug and as time progresses larger vesicles which dissolve more slowly than the larger vesicles allow for release of the drug after the smaller vesicles so there is a drug delivery over a period of time. After preparation, the drugs containing liposomes are injected within 1 -3 hours.

It is preferred that the lipid film is heated to a temperature between 25 and 60°C. The heating of the lipid film allows it to become dried onto the container wall.

It is envisaged that the heating is for a period of between 10 - 30 minutes.

It is preferred that ultrasonication is at a temperature between 25 and 60°C and more particularly between 30 and 50°C and even more particularly between 35 and 40°C for 5-10 minutes.

Preferably the temperature of the sonication bath is adjusted to 37°C before delivery to an individual. The temperature can be adjusted to that of the temperature of the individual receiving the drug.

Preferably the drug is delivered by injection.

According to a second aspect of the invention there is provided a method of preparing a drug at the point of delivery to an individual wherein the method comprises providing apparatus comprising a container having at least one surface having a pre-coated, dried lipid film thereon, introducing a solution into an opening in the container that includes a material to be encapsulated, allowing the solution to come into contact with the dried lipid film so that the lipid film is released from the at least one surface and subjecting the container to sonication so the material is encapsulated in lipid vesicles formed from the film that has been released from the at least one surface of the container following which the encapsulated drug is delivered directly from the container to the individual.

Brief Description of the Drawi ngs

An embodiment of the invention will now be described by way of example only with reference to and as illustrated in the accompanying figures, in which: Figure 1 shows: a device according to an embodiment of the invention where a drug for encapsulation is being delivered to said device; and

Figure 2 shows: sonication of a drug loaded in a device according to Figure 1 .

Detailed Description of the Preferred Embodi ments

As shown in Figu re 1 , a glass bottle 1 is provided which is pre-coated with lipids 2 which are allowed to dry on the surface of the bottle to form a thin film. Typically the bottle is a pharmaceutical neutral glass bottle with a volume of between 5 and 100 ml as this is a volume that is suitable for the delivery of individual doses at the patient bedside. The film extends to approximately half way up the container. Glass is the preferred material to be used for the container but high grade plastics or ceramics may be used as long as the material of the container can allow for the transmission of ultrasonic waves to a material in the container.

The lipid may be a simple carrier for a pharmaceutical material or the lipid may act as a supplement which enhances the activity or delivery of the drug to an individual. Alternatively the lipid is a non-active drug supplement, and will not interfere with the effect of active drug except for slowing down the release of the active drug in local tissue.

It is preferred that the drug 3 is an injectable drug that is delivered to the container via a delivery device such as a syringe 30. The drug is delivered through opening 10 of the container and the opening can be a hole in the container or the hole may be sealed by a pierceable membrane 32 through which a needle 31 of the syringe 30 can be inserted to introduce a solution of the drug into the container and then withdraw the encapsulated drug from the container after sonication.

The pre-coated thin film of dried lipid are formed by adding individual phospholipids, or a mixture of them, produced from plant, animal or biotechnological materials with water or an organic solvent (ethanol, chloroform, methanol etc), without any other biologically active substances. The lipid solution can be dried via rotating the bottle in an oven, or via freezing dry, and stored at -20°C for long-term storage within the shelf life of the lipid film, or 4°C to room temperature for delivery or short term storage. The actual ingredients of lipids or a mixture of them will dependent on the desired injectable drug for patients, such as pH, dissolvent, charge of the molecules. The drug use will be a commercially available, well-approved, clinically applied medicine for desired treatment, without any additional modification before the encapsulation process.

Once the solution is introduced in to the container, the container can be sealed and placed in a sonication bath as shown in Figu re 2. The sonication bath includes an ultrasound generator 4, a temperature control 5 to control the temperature of the fluid in the sonication bath, which typically is water, and a timer 6 to control on and off of the ultrasound generator. The temperature of the water bath in the ultrasonication device is pre-warmed to the highest phase transition temperature ( 7_C) of the lipids, but without causing change in the molecular structure of the drug added. Examples of the types of drugs that can be encapsulated are as follows:

EXAMPLE 1

To partially encapsulate bupivacaine hydrochloride for local anaesthesia and pain relief after major joint replacement, 430 mg/ml 1 ,2-Dioleoyl-sn-glycero-3- phosphocholine (DOPC, Sigma-Aldrich) and 330 mg/ml cholesterol (CH, Sigma- Aldrich) are dissolved in 100% ethanol at 60°C, and dried at 60°C in a rotating system with nitrogen protection to avoid lipid oxidation. The dried lipid film in glass bottles are frozen and stored at -20°C. The glass bottle contains dried lipid thin film is thawed and heated to 60°C in an ultrasonicator water bath, before 0.5% Bupivacaine hydrochloride is added to the bottle. The drug/lipid mixture is left at 60°C for 20 minutes then ultrasonicated for 10 minutes, and used within 2 hours.

EXAMPLE 2

To partially encapsulate BMP-2 and incorporate the mixture with calcium phosphate scaffold as implants for bone tissue regeneration, 1 mg/ml of dimiristoylphosphatidylcholine (DMPC), or dilaurylphosphatidylcholine (DLPC) was dissolved in organic dissolvent (chloroform or ethanol) and dried in a rotating system with nitrogen protection to form a lipid thin film on the wall of glass bottles. Alternatively, DMPC or DLPC may be mixed with water, frozen dried to form lipid cakes within the bottle. 100 μg BMP is dissolved in 1 ml water and added into the bottle containing lipids thin film or cake, and ultrasonicate in water bath at 45°C from 10 minutes, add calcium phosphate scaffold and further sonicated for 5 minutes at room temperature, use immediately, or freezing dry and store at 4°C for late use.

It should be noted that the above mentioned embodiments illustrate rather than limits the invention and that alterations or modifications are possible without departing from the scope of the invention as described. It is also to be noted that the invention covers not only individual embodiments but also combinations of any of the embodiments as described.

Claims

Clai ms

1 . Apparatus to encapsulate a drug in a lipid, said apparatus comprising a container having at least one surface having a pre-coated, dried lipid film thereon, and an opening into which a solution may be introduced that includes a material to be encapsulated, characterised in that said container is portable to the point of delivery of the drug to a patient and that on introduction of the solution into the container said dried lipid film can be released from the least one surface to form a solution and lipid mix and when the container is subjected to ultrasonication the lipid forms vesicles capable of encapsulation of at least a portion of the material following which the container can be opened to deliver the encapsulated drug directly to the individual.

2. Apparatus according to claim 1 wherein the container is a medical grade- neutral glass bottle.

3. Apparatus according to claim 1 or claim 2 wherein the container includes a covering for the opening formed from a pierceable membrane.

4. Apparatus according to any preceding claim wherein the lipids are in an organic solvent prior to being dried onto a wall of the container.

5. Apparatus according to any preceding claim wherein the lipid film is formed from a mixture of lipids.

6. Apparatus according to any preceding claim wherein the lipids are phospholipids.

7. Apparatus according to claim 6 wherein the phospholipids are derived from plant material.

8. Apparatus according to any preceding claim wherein the lipid film is heat dried onto the at least one wall of the container by heating at a temperature of between 25 and 60°C. Alternatively, lipids may be mixed with water and freezing dried to form the lipid film or cake.

9. A method of preparing a drug at the point of delivery to an individual wherein the method comprises providing apparatus comprising a container having at least one surface having a pre-coated, dried lipid film thereon, introducing a solution into an opening in the container that includes a material to be encapsulated, allowing the solution to come into contact with the dried lipid film so that the lipid film is released from the at least one surface and subjecting the container to sonication so the material is encapsulated in lipid vesicles formed from the film that has been released from the at least one surface of the container following which the encapsulated drug is delivered directly from the container to the individual.

10. A method according to claim 10, wherein ultrasonication is at a temperature between 25 and 60°C and more particularly between 30 and 50°C and even more particularly between 35 and 40°C for 5-10 minutes.

1 1 . A method according to claim 9 or claim 10, wherein the temperature of the sonication bath is adjusted to 37°C before delivery to an individual.

12. A method according to any of claims 9 to 11 , wherein the drug is delivered by injection.

13. A method according to any of claims 9 to 12 wherein the encapsulation ratio is within a range of 50±10% of the drug available.

14. A method according to any of claims 9 to 13 wherein the vesicles produced from the lipid by sonication range in size to allow for the drug to be delivered over a period of time.

15. Apparatus for the delivery of a drug as substantially described herein with reference to and as illustrated in the accompanying figures.