Injections

Abstract

A syringe containing a compressible porous matrix, which compressible porous matrix has in it a pharmaceutical in a soluble glass, Methods of producing and using the syringe, and compressible porous matrix inserts for insertion into a syringe barrel are also provided.

Claims

1. A pharmaceutical syringe comprising a syringe barrel comprising an interior syringe barrel wall, a proximal opening configured to receive a plunger in contact with the interior syringe barrel wall, and an integrally formed outlet connectable to a needle, the syringe barrel containing a compressible porous matrix, wherein the compressible porous matrix contains a pharmaceutical suitable for administration into a human patient and wherein the pharmaceutical is in a soluble glass in the compressible porous matrix.

2. The pharmaceutical syringe according to claim 1, wherein the compressible porous matrix in a non-compressed state occupies at least about 10% of a volume of the syringe barrel.

3. The pharmaceutical syringe according to claim 1, wherein the compressible porous matrix has a compressibility of about 2:1 or more.

4. The pharmaceutical syringe according to claim 1, wherein a gap for a passage of air during venting of the syringe is present between the compressible porous matrix and the interior syringe barrel wall.

5. The pharmaceutical syringe according to claim 1, wherein the compressible porous matrix is in the form of an elongate block.

6. The pharmaceutical syringe according to claim 1, wherein the compressible porous matrix is in a form of a block having a non-circular cross section.

7. The pharmaceutical syringe according to claim 6 wherein the block has a rectangular cross section.

8. The pharmaceutical syringe according to claim 1, wherein the compressible porous matrix is a foam, a sponge, or a fibrous body.

9. The pharmaceutical syringe according to claim 8, wherein the compressible porous matrix is cellulose foam, polyurethane foam, or melamine foam.

10. The pharmaceutical syringe according to claim 1, wherein the compressible porous matrix has a functional pore size of between: a) 1 micron and 2 mm; b) 10 micron and 1 mm; or c) 10 micron and 100 micron.

11. The pharmaceutical syringe according claim 1, wherein the compressible porous matrix is hydrophilic for an application of water soluble glassy substances.

12. The pharmaceutical syringe according to claim 1, wherein the compressible porous matrix is hydrophobic for an application of oil soluble glassy substances.

13. The pharmaceutical syringe according to claim 1, wherein the pharmaceutical is stabilized in the soluble glass on the compressible porous matrix.

14. The pharmaceutical syringe according to claim 1, wherein the soluble glass is an amino acid glass, a sugar glass, a hydrophobically modified sugar glass, a carbohydrate glass, or a mixture thereof.

15. The pharmaceutical syringe according to claim 14 wherein the soluable glass is a trehalose glass.

16. The pharmaceutical syringe according to claim 1, wherein the compressible porous matrix is fixed to a seal of a syringe plunger.

17. The pharmaceutical syringe according to claim 1 wherein the outlet is directly connectable to the needle.

18. The pharmaceutical syringe according to claim 1 further comprising the plunger slideably housed within the barrel, wherein the compressible porous matrix is located between the plunger and the outlet such that partial withdrawal of the plunger to aspirate a carrier liquid into the barrel rehydrates the compressible porous matrix such that the soluble glass containing the pharmaceutical dissolves.

19. The pharmaceutical syringe according to claim 18 wherein movement of the plunger to discharge the carrier liquid in the barrel results in compression of the compressible porous matrix.

20. The pharmaceutical syringe according to claim 19 wherein, when the plunger is fully depressed towards the outlet, the compressible porous matrix is compressed and the carrier liquid in the compressible porous matrix is expelled therefrom and exits the syringe via the outlet.

21. A method of producing a compressible porous matrix insert comprising contacting a compressible porous matrix with a solution of a glass-forming material, which solution contains a pharmaceutical for delivery into a patient, and drying the solution to form a glass in the compressible porous matrix, which glass comprises the pharmaceutical, wherein the compressible porous matrix is capable of being placed into a barrel of a pharmaceutical syringe comprising a syringe barrel comprising an interior syringe barrel wall, a proximal opening configured to receive a plunger in contact with the interior syringe barrel wall, and an integrally formed outlet at a distal end of the syringe barrel connectable to a needle.

22. The method according to claim 21, comprising treating the compressible porous matrix with a blocking agent before contacting the compressible porous matrix with the solution of glass-forming material containing the pharmaceutical.

23. The method according to claim 21 comprising treating the compressible porous matrix with a surfactant.

Description

(1) An example of the invention, and experimental results underlying the present invention, will now be described by referring to the accompanying drawings:

(2) FIG. 1 Shows the improved syringe as supplied with the dry pharmaceutical in a porous matrix in the barrel

(3) FIG. 2 is a transverse cross section showing the rehydrated porous matrix and its relationship with the walls of the barrel

(4) FIG. 3 shows the filling of the syringe with sterile water or saline and rehydration of the vaccine for injection

(5) FIG. 4 shows the injection of the solubilised pharmaceutical and it's expulsion from the porous matrix by compression

(6) FIG. 5 shows the results of experimental example 3.

(7) FIGS. 6A and 6B show the results of experimental example 5.

(8) FIGS. 7A and 7B show the results of experimental example 6.

DETAILED DESCRIPTION OF THE FIGURES

(9) FIG. 1a: Axial cross-section through a syringe containing the pre-loaded porous matrix. The syringe is illustrated in the configuration as it is in storage. The syringe barrel 1 has an open end 2 through which is inserted a plunger 3 with an attached sealing member 4 making a water-tight seal with the interior syringe barrel wall 18 of the barrel which houses the dried porous matrix 5 containing the glass-stabilised product. In certain embodiments, the porous matrix 5 may be fixed to the seal by, for example, a glue or a fastening 17. The porous matrix is located inside the barrel between the sealing member and the needle end with its attached hypodermic needle 6. The dashed line 7 is the location of the transverse cross section in FIG. 1b

(10) FIG. 1b: Transverse cross section of one configuration of the porous matrix, after it has been rehydrated to its original dimensions, showing the circular barrel of the syringe 8 containing a porous sponge of rectangular cross section 9 which makes contact with the barrel inner surface only at the corners leaving a circle-segment shaped space on each of the sides which allows the free passage of any trapped air during purging of the syringe. The axial cross sections of FIGS. 1a, 2, 3 and 4 are made at the location of the dashed line 10.

(11) FIG. 2: Axial cross-section through a syringe containing the porous matrix 9 rehydrated after the needle 6 is inserted into a vial of sterile water for injection 11, by withdrawal of the plunger 12 which rehydrates the porous matrix 9 with the aspirated water 13 and dissolves the glass stabilised vaccine.

(12) FIG. 3: Axial cross-section through a syringe containing the porous matrix in the inverted position, after the air has been expelled through the needle, ready for injection.

(13) FIG. 4: Axial cross-section through a syringe containing the porous matrix at the point of injection when the needle is inserted into the subcutaneous, intramuscular or intravenous location 14. By depressing the plunger completely to the needle end, the porous matrix is compressed 15 to expel the full dose into the injection site 16.

(14) FIG. 5: Aluminium hydroxide was dried in 7.5% w/v, 15% w/v and 30% w/v trehalose buffer and recovered up to 30 days after storage at 55 C. Recovery was measured by column sedimentation. At 15% w/v trehalose concentration and above this adjuvant is recovered fully intact.

(15) FIG. 6A: Recovered dried HepB shows long term stability after storage at various temperatures for six months. The majority of the vaccine is recovered in intact form except at 70 C. Control is fresh (non-stored) vaccine.

(16) FIG. 6B: Antibody response of groups of 5 mice given three different doses of Hepatitis B vaccine either fresh or stabilised in trehalose with storage at 55 C. for two months. All responses are equivalent to fresh vaccine within the variability of the assay.

(17) FIG. 7A: Recovery of adjuvanted tetanus vaccine after drying in trehalose buffer and storage for more than eight months. While non-stabilised vaccine lost some activity on drying and all activity on storage, stabilised vaccine was recovered intact. Recovery of intact vaccine was determined by immunoassay.

(18) FIG. 7B: Antibody levels measured in three groups of 10 mice at 4, 8 or 12 weeks after injection with either fresh (non-stored) vaccine or two different dried formulations of trehalose buffer (treh 1 and treh 2) stored at 37 prior to injection The immune response of the mice to both dried preparations was equivalent to fresh vaccine within the variability of the assay.

(19) Obviously, variations can be made to the described format without departing from the substance of the invention. For example, the product could be a vaccine drug or any biological material that would normally be subject to degradation if stored in liquid solution or suspension. This includes products such as hormones, protein and viral vaccines and genetic material. The glass forming material could be any non reactive glass-forming sugars such as trehalose, raffinose or sucrose or mixtures of sugars or any other carbohydrate glass-former; also glass-forming amino acids such as monosodium glutamate (MSG), monosodium aspartate (MSA) or a MSG/MSA mixture or other soluble stabilising glasses or mixtures of the above could be used; and the syringe could be either a standard syringe or an auto-disable syringe or other liquid delivery device or a device for mass inoculations. In an alternative embodiment, the carrier liquid could be an emulsion of the oil-in-water or water-in-oii type and as such the active product could become associated with the aqueous phase of the emulsion as the aqueous phase dissolves the glass. In a further alternative, an oil solvent could be used in conjunction with a hydrophobic pharmaceutical stabilised in an oil soluble glass.

DETAILED DESCRIPTION

(20) The present invention is an improvement on the syringes typically used to give parenteral injections of pharmaceutical agents. It incorporates the pharmaceutical material stabilised by drying it in a solution of a stabilising excipient, for example trehalose, to form a glass in a three dimensional and compressible porous matrix which is then located within the barrel of a conventional plastic syringe between the plunger and the needle fitting. This syringe can then be stored for prolonged periods at ambient temperatures and is ready for instant use. Upon drawing up the water for injection, capillary action draws the solvent liquid into the porous matrix and the soluble glass therein rapidly dissolves to release the pharmaceutical into the liquid for injection. A significant advantage of the present invention is that it uses no additional housings and is designed to be made with minimal change to existing manufacturing processes. In use it also requires no changes from standard injection technique and requires no training. It is therefore of minimal cost.

(21) In a preferred realisation of the present invention the pharmaceutical material is dried in a compressible porous matrix in a wide range of possible sizes and is then introduced into the barrel of an appropriately sized syringe, which syringe typically has an internal volume larger than the matrix. Thus even a large volume of porous matrix can be accommodated in the syringe and a consequently large volume of active product dried therein.

(22) For example a compressible porous matrix in the form of a rectangular block measuring 6 mm6 mm10 mm in its non-compressed state, and having a glass comprising a pharmaceutical in it, may be introduced into the barrel of a 2 ml syringe (a syringe having a maximum dispensing volume of 2 ml). In this example the compressible porous matrix in its non-compressed state occupies 18% of the volume of the syringe barrel (the nominal internal volume of the syringe). The compressible porous matrix in its non-compressed state may occupy at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, about 10-90%, about 20-90%, about 30-90%, about 40-90%, about 50-90%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90% of the volume of the syringe barrel into which it is to be inserted for use. Typical syringes for use in the present invention will have volumes of between about 1-10 ml, and therefore typical compressible porous matrix blocks for use in the present invention may have volumes of between about 0.1-9 ml (100-9000 mm.sup.3) depending on which size of syringe they are to be inserted into for use. The volume of a syringe refers to the volume of the barrel of the syringe, that is the internal volume of the cylindrical compartment in the syringe which holds the liquid for injection (so, for example, a 2 ml syringe has a barrel volume of 2 ml), The compressible porous matrix may be biased towards its non-compressed (expanded) state, which means that during use depression of the syringe plunger is needed in order to force the porous matrix into its compressed form.

(23) In addition to the standard disposable plastic syringes a variety of other injectors maybe used. These include without restriction, glass syringes, auto-disable syringes, retractable needle syringes and other injection devices. Such devices may have a compartment for holding a liquid for injection comprising a compressible porous matrix insert of the invention. The compressible porous matrix of the invention may be suitable for inserting into the liquid-holding compartment of such a device. Thus the present invention provides a method of storing and or transporting a pharmaceutical stabilized in a glass that is soluble in a carrier liquid, wherein the pharmaceutical is stored in a compressible porous supporting structure in a passage for the flow of the said liquid so that the agent can be administered by aspirating the carrier liquid into the spaces or pores of the supporting structure and then causing the liquid to be expelled through the passage and thence to the patient as the porous supporting structure is compressed.

(24) Many drugs and highly multivalent vaccines can easily be stabilised in the syringe with a minimal requirement for prior concentration. A normal injection procedure is used in which the practitioner inserts the needle into a vial of sterile water or saline and withdraws the required volume of liquid into the syringe and then injects the active product into the patient. This is the procedure currently used and is familiar to health care workers, thereby reducing the need for additional training and the chances of error. Indeed, because the appropriate dose is already in the syringe as supplied, any error in the volume of liquid aspirated (providing it is sufficient to dissolve the pharmaceutical) does not alter the dose delivered to the patient

(25) In another novel realisation of the present invention the porous matrix containing the pharmaceutical product is easily compressed after rehydration. The aspiration of the water starts the dissolution of soluble glass containing the pharmaceutical as the liquid permeates the porous matrix by capillarity. For injection, the plunger of the syringe is depressed, preferably fully depressed, causing the compression of the porous matrix thus expelling the liquid contained therein, preferably all, or essentially all of the liquid contained therein, and the full dose of the pharmaceutical is delivered into the patient. The injection process can also be made to activate the disabling step of an auto-disable syringe rendering it incapable of reuse.

(26) A compressible porous matrix comprising a pharmaceutical is a compressible porous matrix insert, suitable for inserting into the barrel of a syringe for use in delivery of the pharmaceutical. In use, the compressible porous matrix is compressed by the action of depressing the syringe plunger, that is, the action of urging the syringe plunger towards the needle end of the syringe barrel. In use, the syringe plunger draws a volume of solvent, or carrier liquid, (e.g. sterile water, saline) into the barrel of the syringe by the action of raising the plunger, that is the action of urging the syringe plunger towards the open end of the syringe barrel (away from the needle end of the syringe barrel). The solvent rehydrates the porous matrix. The solvent is drawn into the porous matrix and dissolves the glass in which the pharmaceutical is comprised, such that the pharmaceutical becomes dissolved or suspended in the carrier liquid. The plunger is then depressed to deliver the pharmaceutical to a subject. This depression of the plunger compresses the porous matrix into its compressed state.

(27) The compressibility of the porous matrix is advantageous because the action of compressing the porous matrix forces pharmaceutical out of the porous matrix, where it would otherwise tend to be held in the carrier liquid by the capillarity of the porous matrix. The action of compressing the porous matrix forces the pharmaceutical out of the syringe for delivery to a subject. Preferably in use the action of depressing the syringe plunger is capable of forcing out of the syringe (i.e. discharging or expelling from the syringe barrel) at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99% or substantially 100% of the pharmaceutical, that is the pharmaceutical that was in the glass.

(28) We have found that some porous matrices although hydrophilic, absorb water slowly. This problem can be overcome and water uptake greatly accelerated by the addition of small quantities of an inert biocompatible surfactant to the glass-forming solution prior to loading the matrix with the pharmaceutical in the stabilising solution and drying. When such a syringe eventually comes to be used, the surfactant dried in the matrix facilitates the uptake of solvent and the rapid rehydration of the glassified product. The use of surfactant in the same way can even render certain hydrophobic foams suitable as matrices for water-soluble products. Examples of suitable surfactants include without limitation polyoxyl castor oils, polysorbates and other injectable surfactants approved by regulatory authorities.

(29) In some cases however, the recovery of the product may be reduced by physicochemical binding of the substance to the surfaces of the porous matrix. This can be overcome by prior treatment of the porous matrix with a blocking agent optionally followed by washing to remove surplus blocking agent and re-drying. Examples of blocking agents include, without limitation, proteins like caseins or serum albumins, surfactants such as the polysorbate detergents Tween 20 or Tween 80 or polymers such as polyvinyl pyrrolidone or polyvinyl alcohols.

(30) In manufacture of the present invention, the pharmaceutical product is mixed, either dissolved or in suspension, with preservative solution. It is absorbed by capillarity into the porous matrix and then dried by any simple process such as air drying, vacuum drying, freeze drying etc. Preferably it is dried outside the syringe. Preferably, the preservative solution (glass-farming solution) is dried by air drying to form a glass (i.e. a noncrystalline solid). Air drying is convenient, inexpensive, and may be done at any ambient temperature (e.g. room temperature), at about 15 C. or higher, about 20 C. or higher, about 25 C. or higher, about 30 C. or higher, at about 40 C. or higher, at about 50 C. or higher, at about 60 C. or higher, at about 70 C. or higher, at about 10 C. to about 70 C., at about 10 C. to about 60 C., at about 10 C. to about 50 C., at about 20 C. to about 70 C., at about 20 C. to about 60 C., at about 20 C. to about 50 C., at about 20 C. to about 40 C., at about 15 C. to about 45 C., at about 20 C. to about 40 C. or at about 18 C. to 25 C. Air drying may be done at atmospheric pressure (approximately 100 kPa). The preservative solution may be dried by air drying overnight, or over a period of about 1, 2, 4, 8, 16 or 24 hours or more. A low relative humidity may be used during drying, for example of between about 0-20% or 2-10%. Glass formation may optionally be facilitated by using a solution purged of any less soluble solids by filtration and/or by boiling. Drying a preservative solution on a porous matrix outside the syringe is convenient and low cost, compared with methods of drying a preservative solution while it is inside the barrel of the syringe. This is at least partly because drying a preservative solution on a porous matrix outside the barrel of the syringe may be done by air drying, rather than vacuum drying or freeze drying.

(31) In the present invention a pharmaceutical is included in the glass-forming solution before drying and is stabilised in the resultant glass. Methods for stabilising products such as pharmaceuticals (including biological therapeutics) are known and are described for example in U.S. Pat. No. 4,892,319, GB2187191, U.S. Pat. No. 5,955,448, WO96/40077 and WO2011/098837. In the present invention, the glass containing the stabilised pharmaceutical may form a layer on the surfaces of the voids or cells in the compressible porous matrix. The relative thinness of this layer means that the pharmaceutical-containing glass dries very rapidly and thoroughly and then subsequently dissolves relatively quickly upon contact with a solvent that may be drawn into the barrel of a syringe for injection (e.g. sterile water or saline).

(32) Examples of preservatives include, without limitation, trehalose, raffinose or sucrose and structural isomers thereof or mixtures of these or any other carbohydrate glass former, glass-forming amino acids such as monosodium glutamate (MSG), monosodium aspartate (MSA) or a MSG/MSA mixture or other soluble stabilising glasses may also be used. The manufacturing process requires minimal additional equipment to that currently used. Because the volume of each of the porous matrices used with any particular product at the same they can be loaded with the correct dose of product by precise delivery to each dry matrix insert when the dose is uniformly distributed by capillary action.

(33) Alternatively because the capillarity of each porous matrix insert precisely made from the same batch is essentially the same, each insert will naturally aspirate the same volume of drug from bulk solution. For pharmaceuticals where the dose is not excessively critical, this can provide a simple and inexpensive method for dosing the syringes with standard doses of pharmaceutical. The improvement is made by simply inserting the dried porous matrix into a standard syringe, such as a disposable plastic one, so that costs are little affected, making these improved stable products competitively priced with existing ones.

(34) The nature of the porous matrix insert used in the syringe is not restricted and alternatives maybe obvious to those skilled in the art. A porous, open-cell foam or sponge has been found to be ideal but flexible woven or felted fabric on which the active product is glass-dried and which is then folded or crumpled into the syringe barrel can also work, in fact, any compressible porous matrix whether made by foaming or by woven or felted fibres is suitable. The porous matrix should be of high grade, sterilisable, suitable for housing parenterally injectable substances and that it is not particle or fibre-shedding nor contains toxic extractable chemicals. The porous matrix should be insoluble. The matrix, which is compressed against the aperture to the needle by the plunger, should not obstruct the aperture. In practice, appropriate matrices with good open cell structure are still fully porous when compressed and do not suffer from this problem. For the usual water soluble pharmaceuticals a preferred feature is that the porous matrix be of a hydrophilic nature in order to readily absorb the solution of pharmaceutical by capillarity and to redissolve it for injection. Example materials in the manufacture of the porous matrix include, without limitation, open cell foamed materials such as cellulose or melamine foams; felted material such as polyester fibre locked needlefelt or woven fabrics such as silk, cotton or synthetic hydrophilic fabrics that are sufficiently soft to be folded, crumpled or compressed for insertion into the syringe barrel. Preferred matrices are cellulose foam, polyurethane foam and melamine foam.

(35) In a preferred embodiment of the invention, simple refinements of the porous matrix render the syringe easier to use. After the aspiration of the water there remains a volume of air in the syringe that was present before aspiration and it must be removed by venting before injection. It is also important to avoid forcing the air through the porous matrix insert thereby displacing the liquid when venting the air before injection. To preserve the simplicity and familiarity of use, the air should be vented by the usual manoeuvre, of expelling the air by holding the syringe vertically with needle uppermost and driving the air out through the needle by depressing the plunger until the syringe contains liquid only. Preferably, therefore, the compressible porous matrix is shaped and/or sized to provide a gap for passage of air through or around the matrix when the matrix is inserted in the syringe barrel, for allowing passage of air through the gap on venting of the syringe.

(36) The syringe of the invention may have a gap for the passage of air during venting of the syringe, which gap is present between the matrix and the inner wall of the syringe barrel. When the syringe contains a carrier liquid and the needle end of the syringe is held uppermost, the gap allows air bubbles to move to the outlet at the needle end of the syringe and to be expelled from the syringe before injection. Such a gap can be provided in a syringe barrel of circular cross section by providing a compressible porous insert which is a block, cylinder or prism having a non-circular cross section, for example a cuboidal or rectangular block or a cylinder having an oval cross section. Venting of the syringe can also be facilitated by various modifications including making the porous matrix insert non-circular, for example square, in cross section and located inside the circular barrel without lateral compression. For example, when the porous matrix insert is square in cross section any air trapped between the porous matrix insert and the plunger is easily vented around the insert via the circle-segment shaped gaps between the flat sides of the insert and the circular inner surface of the barrel. Capillary forces in the matrix ensure the liquid remains in the insert during this venting. A similar refinement can also be achieved by fabricating the porous matrix as a cylindrical shape with an external diameter smaller than the internal diameter of the barrel or as a hollow cylinder fitting snugly in the barrel. Other formats of the porous matrix to achieve easy air venting are obviously possible and are evident to the skilled practitioner. In a further realisation the porous matrix insert containing the stabilised pharmaceutical material is fixed to the seal at the end of the syringe plunger so that entrained air is naturally located above the insert during the venting manoeuvre. The porous matrix insert may be fixed to the seal by, for example, a glue or a fastening. The geometry of the insert may then vary from a centrally located cylinder, a cylinder that occupies the full diameter of the syringe barrel, or alternative shapes and sizes that facilitate rapid release of the contained stabilised pharmaceutical. The cross-sectional diameter, or cross-sectional maximum width (width at the widest point of the transverse cross section; transverse to the longitudinal axis of the syringe when inserted), of the porous matrix insert may be smaller, around the same as, or larger than the internal diameter of the syringe barrel. If the cross-sectional diameter, or maximum width, of the porous matrix insert is larger than the internal diameter of the syringe barrel, then the insert may be inserted into the barrel with lateral compression. A further refinement can be the addition of an inert, non toxic, injectable, coloured substance to the active product, thus altering the observed colour of the porous matrix insert when it is absorbed and dried. The colour can be made specific to the particular pharmaceutical thus identifying which product is present in the syringe and ensuring the injection of the correct one. After use, the colour flushes from the porous matrix along with the active product thus uncovering the native colour of the matrix. Completeness of colour change can demonstrate injection of the full dose of active product. Also, the loss of colour in the porous matrix shows that the syringe has been used and reduces the possibility of accidental reuse. Suitable coloured substances include fluorescein.

(37) Of course the quantity of pharmaceutical material stored and delivered in this method described herein can vary over a very wide range by tailoring the size of the porous matrix insert to fit any size of syringe. Since the porous matrix is chosen to have a very high capacity to absorb water (of the order of 50 millilitres per gram), there is needed little or no additional increase in the size or the bulkiness of the syringe to accommodate the porous matrix insert. Theoretically, there is no physical limit to the size of the syringe or the contained insert.

(38) The present invention is further illustrated by the following 7 Examples that are illustrative and are not intended to be limiting in their scope.

EXAMPLES

(39) In these studies of the glass-forming solutions used contained dissolved trehalose at a concentration of 10-20% My or 10-30% w/v. The solutions were either dried by air drying at about 50 C., or spray drying at about 45 C.

Example 1

Materials Suitable as the Porous Matrix

(40) A programme of selection for the properties of the optimal porous matrix screened 36 foams, sponges and fibrous felts some of which were rejected because they were non absorbent closed-cell foams or of inappropriate pore sizes. Analysis of the remaining open cell matrices identified as foamed materials possessing most of the properties required, cellulose foam, melamine foam and hydrophilic reticulated polyether foam. A comparison of these showed that cellulose foam (FT-SPX Foam Techniques, Northants, NN8 6GR, UK) was superior to the others in that it was very absorbent, easy to wash clean and sterilise, free of plasticisers and other toxic additives, dried rapidly and evenly and was inexpensive. Commercial Melamine foam (FT-11 M Basotect, density 11 kg/m.sup.3, Foam Techniques, Northants, NN8 6GR, UK) also hydrated instantly on re-wetting without entrapped air bubbles and was soft and very compressible on injection releasing nearly all of the absorbed liquid.

Example 2

Testing Release of Model Product

(41) A model system was used to examine the behaviour of a porous matrix in the syringe. Rectangular blocks of cellulose foam measuring 6 mm6 mm10 mm were saturated with 10% w/v sugar glass forming solution containing a red Carmoisine dye and placed in an oven at 40 C. It was fully dried within 2 hours with slight but obvious shrinkage. It was loaded into a 2 ml plastic syringe. 0.8 ml of water was then aspirated into the syringe. The dry porous matrix immediately filled with water by capillary action, regained its previous volume when wet and the dye began to dissolve into the water. The air bubble was readily expelled from the syringe in the usual way. The liquid was then injected dropwise into a glass vessel by depressing the plunger to fully compress the porous matrix insert. All or nearly all of the dye appeared in the receiving vessel. On withdrawing the plunger after injection the porous matrix insert partially re-expanded to reveal that the Carmoisine had been expelled so that the porous matrix had nearly reverted to its native colour with only a pale residual pink colour.

Example 3

Recovery of Particulate Aluminium Hydroxide Adjuvant

(42) The possible entrapment of colloidal particles or aggregates within the pores of the matrix was tested by using the approved vaccine adjuvant Aluminium hydroxide. Recovery of this material is essential for the use of vaccines in the syringe since a major proportion of the vaccine antigens are physicochemically bound to the adjuvant and would be lost if significant entrapment occurred. This colloidal substance in aqueous suspension was mixed with trehalose solution and dried Measurement of the quantity of adjuvant loaded and the amount recovered indicated recovery of about 90% of the adjuvant. The results of this experiment are shown in FIG. 5. In embodiments of the invention, the colloidal substance in aqueous suspension may be mixed with trehalose and dried in a porous cellulose porous matrix block. The block could be inserted into the barrel of a 2 ml syringe and 0.6 ml of water aspirated to measure the recovery of aluminium hydroxide adjuvant. Air may be expelled and the contents of the syringe injected into a vial. Based on the results shown in FIG. 5, measurement of the quantity of adjuvant loaded into the porous matrix would be expected to indicate recovery of about 90% of the adjuvant.

Example 4

Recovery of Model Protein Pharmaceutical

(43) Alkaline phosphatase enzyme was used as a model protein for stability and recovery studies. It was loaded and dried in a porous matrix. Some matrices were placed into stability studies. The recovery of protein from the matrix was then measured. Substantially all the protein as measured by enzymatic activity was recovered even after storage at 37 C. or 45 C. for three months. Variation of the numerical result is the result of variability in the assay. These results indicate approximately 100% recovery of active protein. The results of this experiment are shown in Table 1, below. In embodiments of the invention a protein of interest may be loaded and dried in a porous matrix block (e.g. a cellulose porous matrix block). The block could then be placed in a syringe. Some syringes could then be placed in stability studies to measure recovery of protein from the matrix. Based on the results shown in Table 1, below, substantially all the protein as measured by enzymatic activity would be expected to be recovered after storage at 45 C. for three months.

(44) TABLE-US-00001 TABLE 1 % Alkaline phosphatase recovered Experiment Matrix stored at 37 C. Matrix stored at 45 C. 1 100.4 111.3 2 85.5 92.7 3 99.8 82.4

Example 5

Recovery of Adjuvanted Hepatitis B Vaccine

(45) The adjuvanted vaccine Hepatitis B was dried in a trehalose buffer. Some were set up for stability studies (results shown in FIG. 6A), others used for recovery experiments and a third set were put into stability studies and after a period were tested for their immunogenicity in mice (results shown in FIG. 6B), The results showed that immediate recovery, recovery after stability studies and immunogenicity of this vaccine were all equivalent to fresh vaccine.

Example 6

Recovery of Adjuvanted Tetanus Toxoid Vaccine

(46) To confirm the generality of the findings adjuvanted tetanus toxoid vaccine was dried as above on a porous matrix. Some were set up for stability studies, others used for recovery experiments (results shown in FIG. 7A) and a third set were put into stability study conditions and after a period were tested for their immunogenicity in mice by measuring serum antibodies (results shown in FIG. 7B). The results showed that immediate recovery and, recovery after stability studies and immunogenicity of this vaccine were all equivalent to fresh vaccine.

Example 7

Potency of Recovered Stabilised Vaccine

(47) To ensure that the protective clinical effect of vaccination is retained when using this technology, syringes loaded with stabilised tetanus vaccine as in example 6 are used to vaccinate mice which are then challenged with a lethal dose of active tetanus toxin. It is shown that the stabilised vaccine and syringe provide the normal levels of protection by a result in which control mice are killed, whereas mice immunised with either fresh vaccine or the stabilised vaccine survive the challenge.

STATEMENTS OF INVENTION

(48) The following numbered statements set out aspects of the invention and form part of the description. 1. A pharmaceutical syringe comprising a pharmaceutical material stabilised in a soluble dry glass coating the surfaces of the voids in a compressible porous matrix which is located within the barrel of the syringe between the plunger and the needle fitting. 2. A pharmaceutical syringe according to statement 1 characterised in that the porous matrix is compressible. 3. A pharmaceutical syringe according to state en or 2 characterised in that the porous matrix is a sponge. 4. A pharmaceutical syringe according to statement 1 or 2 characterised in that the porous matrix is a fibrous body. 5. A pharmaceutical syringe according to statement 2, 3, or 4 characterised in that the porous body is formed from a natural material 6. A pharmaceutical syringe according to statement 2, 3 and/or 4 characterised in that the porous matrix is formed from a synthetic plastics material. 7. A pharmaceutical syringe according to statement 5 characterised in that the porous body is formed from a natural sponge. 8. A pharmaceutical syringe according to statement 2, 3 and/or 4 characterised in that the porous matrix is formed from cellulose, polyethylene, polypropylene, polyester, polyether polyurethane, polyvinyl acetate or melamine formaldehyde resin. 9. A pharmaceutical syringe according to statements 2, 3, 4, 5, 6, 7 or 8 characterised in that the porous matrix has a functional pore size of between 1 micron and 2 mm. 10. A pharmaceutical syringe according to statements 2, 3, 4, 5, 6, 7 or 8 characterised in that the porous matrix has a functional pore size of between 10 microns and 1 mm. 11. A pharmaceutical syringe according to statements 2, 3, 4, 5, 6, 7 or 8 characterised in that the porous matrix has a functional pore size of between 10 microns and 100 microns. 12. A pharmaceutical syringe according to statement 4 characterised in that the glassy substances forms a coating on the surface of the fibres or pores thus defining spaces allowing the liquid to pass through. 13. A pharmaceutical syringe according to statement 1 characterised in that the carrier liquid is aqueous. 14. A pharmaceutical syringe according to statement 1 characterised in that the carrier liquid is an organic solvent. 15. A pharmaceutical syringe according to any previous statement characterised in that the porous matrix is treated with a blocking agent. 16. A pharmaceutical syringe according to any previous statement characterised in that the porous matrix is treated with a surfactant. 17. A pharmaceutical syringe according to statement 1 characterised in that the porous matrix is hydrophilic for the application of water soluble glassy substances and hydrophobic for the application of oil soluble glassy substances. 18. A pharmaceutical syringe according to any previous statement characterised in that the glass is an amino acid glass, a sugar glass, a hydrophobically modified sugar glass, a carbohydrate glass, or mixtures thereof the syringe being for the administration of a liquid-carried pharmaceutical to a patient characterised by an active pharmaceutical material stabilized in a glassy material that is soluble in the liquid and that forms a coating on supporting means located in the passage so that the glassy material will dissolve in the liquid thereby releasing the pharmaceutical into the liquid. 19. A method of storing and or transporting a biological agent stabilized in a glassy substance soluble in a carrier liquid characterised in that the biological agent is stored in a compressible porous supporting structure in a passage for the flow of the said liquid so that, the agent can be administered by aspirating the carrier liquid into the spaces or pores of the supporting structure and then causing the liquid to be expelled through the passage and thence to the patient as the porous supporting structure is compressed. 20. A method of preparing a pharmaceutical prior to administration to a patient in which a carrier liquid is caused to flow along a passage containing an active ingredient stabilised by a glassy substance so that the agent becomes dissolved or dispersed in the liquid prior to delivery to the patient. 21. A pharmaceutical syringe defining a spongy or fibrous body and glassy material stabilising an active ingredient deposited on the pores of the porous matrix or the fibres of the fibrous body, the coated pores or fibres defining spaces between them whereby a solvent can pass through the matrix dissolving the glassy substance.