GB2417900A

GB2417900A - Composition for oral drug delivery

Info

Publication number: GB2417900A
Application number: GB0420250A
Authority: GB
Inventors: John Mitchell; Martin Snowden; Victoria Cornelius
Original assignee: MEDWAY SCIENCE TECHNOLOGIES LT
Current assignee: MEDWAY SCIENCE TECHNOLOGIES LT
Priority date: 2004-09-11
Filing date: 2004-09-11
Publication date: 2006-03-15
Also published as: GB0420250D0

Abstract

A method of blending naturally occurring polymers with taste masking agents in a supercritical fluid, comprising the steps of forming a mixture of the supercritical fluid, the polymer, the taste masking agent and an active substance, allowing the polymer, taste masking agent, and active substance to interact to form a complex, and separating the particles from the supercritical fluid. The method for combining the polymers within the supercritical fluid may form a supramolecular complex. A method whereby any step incorporating a supercritical fluid is achieved in the supercritical state is also disclosed.

Description

241 7900

Description

Technical Field

This invention relates to a method for the formation of a supramolecular complex.

The complex is formed following the mixing of polymer(s) A; one or a combination of naturally occurring polymers and/or hydrophobically modified naturally occurring polymers, with agent(s) B. one or a combination of taste-masking agents and/or solubilisation enhancers, and agent C; pharmaceutical or cosmetic active ingredients or other molecule or complex that provides a therapeutic or otherwise beneficial effect with a supercritical fluid. The invention also relates to the modification of the physicochemical and theological properties of the supramolecular complex and the products formed when prepared by this method.

It is possible and sometimes desirable to take pre-supercritically blended A <a B and as a subsequent step blend agent C to form a different supramolecular complex which may be subsequently formulated into a final film dosage form. This may be achieved in either a supercritical fluid or alternative solvent such as water or a low boiling alcohol. Therefore the invention also relates to the modification of the physico chemical and theological properties of polymer(s) A and agent(s) B blended with a supercritical fluid in the absence of agent C and the products formed when prepared by this method.

A supercritical fluid is defined as a material which can be either liquid or gas, used in a state above the critical temperature and critical pressure where gases and liquids can coexist. Showing unique properties that are different from those of either gases or liquids, this method of invention considers that a fluid that may be defined as supercritical however may also be used in it non-supercritical, i.e. gas or liquid, state.

Description of prior art

Naturally occurring polymers and hydrophobically modified naturally occurring polymers are established excipients in pharmaceutical formulations. The application of these polymers to thin film technologies is limited as a result of their inability to taste mask and their limitations of loading for pharmaceutical actives (API) and cosmetic products. ABA triblock polymers (pluronics), carbohydrates or starches, amylose, amylopectin, cyclodextrin and modified versions of these are examples of molecules known to contain hydrophobic domains that could be used for both taste masking and increasing active loading. Mixing a combination of the following, naturally occurring polymers, hydrophobically modified polymers, taste-masking agents and solubility enhancers, dissolved in a supercritical fluid, produces a novel product.

The interaction of the bulk polymer with the taste-masking agent with or without the load-enhancing agent mixed in supercritical fluid will result in a complex possessing different physicochemical properties than if the individual components were combined in an aqueous solution, followed by freeze drying. The advantages of the former over the latter include enhanced loading of an API and enhanced taste masking capabilities. The formation of a polymer blend under supercritical fluid conditions will also result in different theological properties when re-dispersed in a solvent as a result of the difference in the synergistic interactions between polymer chains.

The rheology of polymer blends is not an additive effect as a result of synergistic interactions arising from inter and intra polymer bonding such as hydrogen bonding.

Typically the result is that of an increase in the viscosity, over the combination of the individual monomeric polymer dispersions at the same concentration.

Polymeric materials that contain hydrophobic domains may be manipulated under supercritical conditions to expose those domains thereby increasing the loading potential for poorly soluble active ingredients. The chemical modification of a naturally occurring polymer to increase the hydrophobic domains present is advantageous for thin film technologies as the theological properties and drug loading capability may be enhanced such that properties of the final film are improved with regard to casting, mouth feel and speed of dissolution.

Summary of the invention

The present invention provides an effective technique for the manufacture of a dry mixture that may be re-dispersed in a solvent to be cast as a polymeric thin film for the oral delivery of an active ingredient. Preparations, according to the invention, are prepared by charging a reactor with polymer A, agent B in the presence or absence of agent C and then adding a process medium to the reactor. The process medium, typically carbon dioxide, may be supplied to the reactor in a supercritical state or is heated and pressurised in the reactor to attain the supercritical state. The components are mixed in the heated and pressurised state for sufficient time as to form a homogeneous liquidlgas saturated suspension, or supercritical slurry. Once the process medium has been removed the final product will be finely divided particles with a low impurity level. The same process may be achieved by using supercritical fluids that are not in their supercritical state, such as liquid CO2.

Particles prepared in the absence of agent C may have the active incorporated by dispersing finely divided particles in a solvent, supercritical or otherwise with an active ingredient. In the case of redispersing in a supercritical fluid, the finely divided particles are left in the reactor, the active ingredient added and the process medium supplied to the reactor in a supercritical state or is heated and pressurised in the reactor to attain the critical state. The components are then mixed in the heated and pressurised state for sufficient time as to form a homogeneous liquid/gas saturated suspension. The removal of the process medium provides finely divided particles containing an active ingredient that may be dispersed in a solvent for the casting of a polymeric thin film. The same process may be achieved by using supercritical fluids that are not in their supercritical state, such as liquid CO2 such that the reactor is charged with the supercritical fluid but not under supercritical conditions.

Agent C may also be incorporated by dispersing the finely divided particles in a solvent such as low boiling alcohols or water with the active ingredient. The hydrophobic domains exposed in the first step, as a result of the complex formed, will still be accessible to active material, particularly hydrophobic molecules or complexes. If the solvent used to re-disperse the finely divided particles is water, this may be pH modified to further enhance the active loading. The resultant product may then be cast as a polymeric thin film.

It is also suggested that incorporation of agent D at any time throughout the process may provide enhancement of the film properties where agent D is one or more of the following; softeners, plastisisers, stabilisers, sweeteners and flavour modifiers which are complimentary to the tastemasking agent (B) present.

The active ingredient incorporated into the finely divided engineered particles containing a combination of the aforementioned reagents may be a pharmaceutical active (API), a cosmetic active, vitamins, minerals or another complex or molecule that provides a therapeutic or cosmetic or otherwise beneficial effect. This may be done under batch or continuous flow conditions.

Possible ingredients or conditions The polymers considered for this method are naturally occurring polymers or hydrophobically modified naturally occurring polymers that include but are not limited to carboxymethyl cellulose, gum xanthan, gum Arabic, guar gum, carageenan, amylose, amylopectin, dextrin, dextran, xylan, mannan, araban, cyclodextrin, pectin, chitin, chitosan, levan, elsinan, collagen, inulin, gelatin, Rein, gluten, soy protein isolate, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, pullulan, carboxymethyl pullulan, sodium alginate, tragaeanth Burn, polyacrylic acid and other polysaccharides, celluloses and starches and their derivatives. The modification of any naturally occurring polymer may include but is not limited to attaching hexadecyl residues to the polymeric backbone directly or via linkers (e.g. POE), addition of hydrocarbons to the polymer backbone or more bulky phenol groups, crosslinking polymer chains or alkyl substitutions.

The actives that may be incorporated include but are not limited to anti viral drugs, antibacterial drugs, antiarthritic drugs, analgesic, NSAID, antacid, anticholinergic, anti-parkinsonic, anti malarial, opiates, dietry supplements, iron supplements, oestrogen, anti-oestrogen, anti- cancer, maligno-toxic drugs, antifimgal drugs, anthelmintics, antibacterial drugs, antacids, anti-diarrheals drugs, diuretics, laxatives, anti depressants appetite suppressants, anti-epileptics, immune response modulators, sex hormones, antihistamines, immunological products, vaccines, vitamins and any further molecule or complex that provides a therapeutic or beneficial effect. s

Specifically, lopermaide hydrochloride, nitro-glycerine and ibuprofen.

The taste-masking agents may include but are not limited to A-B diblock copolymers, A-B-A triblock copolymers (e.g. pluronics), (a, ,B, or y) cyclodextrins, modified cyclodextrins, amylose, amylopectin, carbohydrates and starches.

Softeners and plastisisers may include but are not limited to glycerol, polyethylene glycol, monoethylene glycol, acetins (acetates of glycerol), and alpha hydroxyl acids and salts of those acids, such as 2 hydroxypropanoic acid, hydroxysuccinic acid, hydroxyethanoic acid and 2,3 dihydroxybutanedioc acid Solubility enhancers include but are not limited to cyclic carbohydrates, A-B diblock copolymers, A-B-A triblock copolymers (e.g. pluronics), (a, 0, or By) cyclodextrins, modified cyclodextrins, amylose, amylopectin, polyvinylpyrrolidones, carbohydrates and starches.

Sweeteners and flavour modifiers that may be incorporated include but are not limited to, thymol, menthol, methyl salicyl ate, eucalypto l, carvacro l, camphor, anethole, carvone, eugenol, isoeugenol, limonene, osimen, n-decyl alcohol, citronel, a salpineol, methyl acetate, citronellyl acetate, methyl eugenol, cineol, linalool, ethyl linalool, safrola vanillin, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil, pimento oil, laurel oil, cedar leaf oil, gerianol, verbenone, anise oil, bay oil, benzaldehyde, bergamot oil, bitter almond, chlorothymol, cinnamic aldehyde, citronella oil, clove oil, coal tar, eucalyptus oil, uaiacol, lavender oil, mustard oil, phenol, phenylsalicylate, pine oil, pine needle oil, sassafras oil, spike lavender oil, storax, thyme oil, tofu balsam, serpentine oil, clove oil and combinations thereof.

The super critical fluids that may be used as a process medium include CO2 ard N2O under liquid or supercritical conditions. For CO2 the supercritical conditions are observed at 31.3 C and 1071.34psi, and for N2O at 36.5 C and 1053.7psi.

Examples

Example 1

As an example of a naturally occurring polymer that can be hydrophobically modified carboxymethyl pullulan (CMP) was subjected to hydrophobic modification before the supercritical experiment was carried out. Alkylamine derivatised pullulan (2.5g) and alkyldiamine crosslinked pullulan (2.5g) were weighed and blended with lg of amylopectin and 0.5g of loperamide hydrochloride. The powder blend obtained was then placed in the reactor and sealed. The reactor was then flushed with carbon dioxide for 2 minutes.

The reactor was then pressurised with carbon dioxide from atmospheric up to 200 bar and the temperature was raised from ambient to 35 C to create the desired supercritical conditions for the reactor.

The blend was stirred at 100 rpm for 2 hours to allow the polymeric components, the taste masking agent and the active ingredient to interact fully. The pressure was then removed to atmospheric and the temperature lowered to ambient so the reaction product may be removed from the reactor. The resultant product, finely divided particles, consists of a polymer matrix that encapsulates the loperamide hydrochloride within the hydrophobic domains that were exposed while under supercritical conditions. The encapsulation of the loperamide hydrochloride by the amylopectin component of the matrix particularly, offers a degree of taste masking as the loperamide hydrochloride is shielded from taste buds during oral administration.

When the finely divided particles are dispersed in a small quantity of water containing 10% by volume of methanol so that they may be cast into thin films for the oral administration of the incorporated active, the theological properties are modified. The increase in the amount of interaction between the reagents because of the intial blending taking place in supercritical CO2 as opposed to water results in a greater synergistic effect with respect to the inter and intra polymeric interactions. Further there is an increase in the amount of loperamide hydrochloride that is incorporated into the polymer matrix over that observed in water. This is also as a result of the greater exposure of hydrophobic domains under supercritical conditions.

Example 2

In this example, complementary polymers in the form of 2g carboxymethyl cellulose and 3g of Dextran (high fraction) and the taste-masking agent, , B cyclodextrin, Ig, were weighed and physically blended with lg of ibuprofen. The powder blend obtained was placed in the reactor and sealed. The reactor was then flushed with carbon dioxide for 2 minutes.

The reactor was then pressurised with carbon dioxide from atmospheric up to 250 bar and the temperature was raised from ambient to 35 C to create the desired supercritical conditions for the reactor.

The blend was stirred at 100 rpm for 2 hours to allow the polymeric components and the active ingredient to interact fully. The pressure was then removed to atmospheric and the temperature lowered to ambient so the reaction product may be removed from the reactor. The resultant product, finely divided particles, consists of a polymer matrix that encapsulates the ibuprofen present within the hydrophobic domains that were exposed while under supercritical conditions. The encapsulation of the ibuprofen by the cyclodextrin component of the matrix particularly, offers a degree of taste masking during oral administration.

When the finely divided particles are dispersed in a small quantity of water so that they may be cast into thin films for the oral administering of the incorporated active, the theological properties are modified. In some cases, when forming a polymer blend under aqueous conditions, the effect on the viscosity is more than an additive effect, as a synergistic interaction occurs. Under supercritical conditions, this increase is seen to be even greater as the level of interaction between the polymers is greater than when the same experiment is repeated in water. Further there is an increase in the amount of ibuprofen that is incorporated into the polymer matrix over that observed in water. This is also as a result of the greater exposure of hydrophobic domains under supercritical conditions.

Example 3

In the final example, the naturally occurring polymer gum Arabic (5g) and the taste masking agent amylose (la) were weighed and placed in the reactor and sealed. The reactor was then flushed with carbon dioxide for 2 minutes. The reactor was then pressurized with carbon dioxide from atmospheric up to 300 bar and the temperature was raised from ambient to 35 C to create the desired supercritical conditions for the reactor.

The blend was stirred at lOOrpm for 1 hour to allow the polymer and the taste- masking agent to interact and form a complex. The pressure was removed to atmospheric and the temperature lowered to ambient so that the active, nitro-glycerine (1.5g) could be added to the finely divided particles obtained from the first supercritical step. The reactor was again flushed with carbon dioxide for 2 minutes when the reactor was pressurized with carbon dioxide from atmospheric up to 300 bar and the temperature raised from ambient to 35 C to create the desired supercritical conditions for the reactor.

The blend was stirred at 100 rpm for 2 hours to allow the active to fully integrate into the polymer taste-masking complex. The pressure was then removed to atmospheric and the temperature lowered to ambient so the reaction product may be removed from the reactor.

The finely divided particles that are produced which contain more nitroglycerine than would be if prepared in an aqueous environment are suitable for dissolution in a solvent such as a low boiling alcohol or water so that they may be cast as thin film oral dosage forms containing higher levels of nitro-glycerine than previously obtained using aqueous conditions.

Claims

Claims 1. A method of blending naturally occurring polymers with taste

masking agents in a supercritical fluid, the method being characterised in that it comprises the steps of (a) forming a mixture of a supercritical fluid, a naturally occurring polymer and a taste masking agent and an active substance (b) causing or allowing the polymer, the taste masking agent and the active substance to interact and form a complex (c) separating the finely divided particles from the supercritical fluid
2. A method as claimed in Claim 1 wherein the finely divided particles obtained are re-dispersed in a solvent for the purpose of oral drug delivery utilising thin film technologies.

IS
3. A method as claimed in Claim 1, wherein there is more than one naturally occurring polymer such as carboxymethyl cellulose, gum xanthan, gum Arabic, guar gum, carageenan, amylose, amylopectin, dextrin, dextran, xylan, mannan, araban, cyclodextrin, pectin, chitin, chitosan, levan, elsinan, collagen, inulin, gelatin, zein, gluten, soy protein isolate, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, pullulan, carboxymethyl pullulan, sodium alginate, tragacanth gum, polyacrylic acid and other polysaccharides, celluloses and starches and their derivatives.
4. A method as claimed in Claim 1 and Claim 3, wherein one or more of the naturally occurring polymer(s) has been hydrophobically modified, this may be achieved by but is not limited to the following methods: bonding of alkyl chains to the polymeric backbone or sidechains via ester functions, bonding of hexadecyl residues to the polymeric backbone directly or via linkers (e.g. POE), addition of hydrocarbons to the polymer backbone or more bulky phenol groups or alkyl substitutions, crosslinking neighbouring polymer chains using crosslinking agents, specifically with alkyl amines, alkyldiames or amine-terminated polyoxypropylene diols.
5. A method as claimed in Claim 1, characterised in that the tastemasking agent also acts as a solubility enhancer lo
6. A method as claimed in Claim 5, characterised in that a solubility enhancer is incorporated instead of or in addition to the taste masking agent and the remaining components.
7. A method as claimed in any one of the preceding Claims characterised in that the active is not incorporated at the start of the interaction.
8. A method as claimed in any of the preceding Claims wherein the reaction mixture in the supercritical reactor is agitated or otherwise stirred at a speed within the range 1-250rpm.
9. A method as claimed in Claim 7, characterised in that the active is incorporated in a separate supercritical fluid step.
10. A method as claimed in Claim 7, characterised in that the active is incorporated in a separate aqueous step.
11. A method as claimed in Claim 7, characterised in that the active substance is incorporated in a low boiling alcohol, such as methanol or ethanol or a solution containing a low boiling alcohol.
12. A method as claimed in Claim 10, characterised in that the pH of the aqueous addition of the active is adjusted to facilitate enhanced loading.
13. A method as claimed in any of Claims 7-12, characterised in that the dispersion is cast as a thin film.
14. A method as claimed in any of Claims 8-11, characterised in that the finely divided particles are collected and re-dispersed in an appropriate solvent for the casting of thin films.
15. A method as claimed in any of the preceding claims wherein the active incorporated is one of the following, anti viral drugs, antibacterial drugs, antiarthritic i, drugs, analgesic, NSAID, antacid, anticholinergic, anti-parkinsonic, anti malarial, opiates, dietry supplements, iron supplements, oestrogen, anti-oestrogen, anti-cancer, maligno-toxic drugs, antifungal drugs, anthelmintics, antibacterial drugs, antacids, antidiarrheals drugs, diuretics, laxatives, anti depressants appetite suppressants, anti epileptics, immune response modulators, sex hormones, antihistamines, immunological products, vaccines, vitamins and any further molecule or complex that provides a therapeutic or beneficial effect.
16. A method as claimed in Claim 14, wherein the active incorporated is loperarnide hydrochloride, nitro-glycerine, or ibuprofen.
17 A method as claimed in Claims 1-14, wherein the taste masking agent is A-B diblock copolymers, A-B-A triblock copolymers (e.g. pluronics), (a, 0, or y) cyclodextrins, modified cyclodexins, amylose, amylopectin, polyvinylpyrrolidones, carbohydrates or starch or other molecule containing hydrophobic domains that may be exploited by use of supercritical fluids.
18. A method as claimed in any of the preceding claims where a solubility enhancer, softener, viscosity modifier, plastisiser or sweetener is incorporated at any stage to facilitate enhanced film properties such as brittleness, mouth feel, flavour enhancing or other beneficial effect.
19. A method as claimed in Claim 18 wherein the softener or plastisiser is glycerol, polyethylene glycol, monoethylene glycol, acetins (acetates of glycerol), or an alpha hydroxyl acids and salts of those acids, such as 2 hydroxypropanoic acid, hydroxysuccinic acid, hydroxyethanoic acid and 2,3 dihydroxybutanedioc acid.
20. A method as claimed in Claim 18 wherein the sweetner or flavour modifier is thymol, menthol, methyl salicylate, eucalyptol, carvacrol, camphor, anethole, carvone, eugenol, isoeugenol, limonene, osimen, ndecyl alcohol, citronel, a-salpineol, methyl acetate, citronellyl acetate, methyl eugenol, cineol, linalool, ethyl linalool, safiola vanillin, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil, pimento oil, laurel oil, cedar leaf oil, gerianol, verbenone, anise oil, bay oil, benzaldehyde, bergamot oil, bitter almond, chlorothyrnol, cinnamic aldehyde, la citronella oil, clove oil, coal tar, eucalyptus oil, uaiacol, lavender oil, mustard oil, phenol, phenylsalicylate, pine oil, pine needle oil, sassafras oil, spike lavender oil, storax, thyme oil, tofu balsam, serpentine oil, clove oil and combinations thereof.
21. A method as claimed in Claim 18 wherein the solubility enhancer is is A-B diblock copolymers, A-B-A triblock copolymers (e.g. pluronics), (a, 0, or y) cyclodextrins, modified cyclodextrins, amylose, amylopectin, polyvinylpyrrolidones, carbohydrates or starch or other molecule containing hydrophobic domains that may be exploited by use of supercritical fluids.
22. A method whereby any step incorporating a supercritical fluid is achieved in the supercritical state whereby the temperature and pressure are above or inline with the critical pressure and critical temperature of the specific supercritical fluid.
23. A method as claimed in Claim 22 wherein any step incorporating a supercritical fluid is achieved in the gas or liquid state whereby either or both the temperature and pressure are below the critical pressure and critical temperature of the specific supercritical fluid.
24. A method as claimed in Claim 23, wherein the use of a supercritical fluid not in it's supercritical state is not carried out within a supercritical reactor but in a suitable mung vessel.
25. A method as claimed in Claim 22 and 23, wherein the supercritical fluid and components as mentioned in Claim 1 is agitated or otherwise stirred at a speed within the range 1-250rpm.
26. A method as claimed in Claim 22 and 23 whereby the supercritical fluid, which may be one of the following, CO2, N2O, CHF3, CHCIF2, CH3OCH3, CH3OH, C2HsOH, C2H4, C2H6, CsH2, C7He, He, Xe, SF6, CCIF3, H2O or NH3, is used above or below their respective supercritical conditions.
27. A method as claimed in Claim 22 and 23 whereby a co-solvent is used.
28. A method as claimed in Claim 27 wherein the co-solvent used is also a supercritical fluid
29. A method as claimed in Claim 27 wherein the co-solvent used is one of the following chlorofluorocarbon, perflourochlorocarbon, arson, butane, acetone, dichloromethane DMSO, methanol, ethanol or other alcohol or polar solvent.
30. A method as claimed in Claim 26 whereby the fluid is CO2 above the critical temperature (
31.3 C) and above the critical pressure (1071.34 psi) 31. A method as claimed in Claim 30 whereby the carbon dioxide is heated to a temperature in the range 0-127 C and is pressurized to a pressure within the range 250-14,500psi.
32. A method for combining naturally occurring polymers within a supercritical fluid creating a supramolecular complex.
33. A method as claimed in Claim 32, wherein the supramolecular complex has different physico-chemical properties, such as viscosity, hydrophobicity or particle size, than that of the supramolecular complex formed in an aqueous solvent at any pH.
34. A method as claimed in Claim 32, wherein the supramolecular complex has different physico-chemical properties, such as viscosity, hydrophobicity or particle size, than that of the supramolecular complex formed in a low boiling alcohol or solution containing in part a low boiling alcohol.
35. A method as claimed in any of the preceding claims whereby a product such as a film is produced that has a therapeutic, cosmetic, or otherwise beneficial effect.