WO2017089804A1

WO2017089804A1 - Novel pharmaceutical compositions

Info

Publication number: WO2017089804A1
Application number: PCT/GB2016/053687
Authority: WO
Inventors: Dermot O'hare; Henry Fisher
Original assignee: Oxford University Innovation Limited
Priority date: 2015-11-24
Filing date: 2016-11-24
Publication date: 2017-06-01
Also published as: GB201520762D0

Abstract

The present invention relates to a pharmaceutical composition comprising a plurality of layered double hydroxide nanoparticles and one or more pharmaceutically acceptable excipients, wherein the at least one aqueously unstable anionic drug compound is intercalated between the layers. The present invention also relates to a process for the preparation of such pharmaceutical compositions, the corresponding layered double hydroxides, as well as methods for their use in stablising unstable anionic drug compounds.

Description

NOVEL PHARMACEUTICAL COMPOSITIONS

INTRODUCTION

[0001] The present invention relates to novel pharmaceutical compositions suitable for the delivery of aqueously unstable anionic drug compounds. The present invention also relates to a process for the preparation of these pharmaceutical compositions and to their use for the stabilization of aqueously unstable anionic drug compounds.

BACKGROUND OF THE INVENTION

[0002] Gabapentin (l -(aminomethyl)cyclohexylacetic acid) and pregabalin ((S)-3- (aminomethyl)-5-methylhexanoic acid) are γ-aminobutyric acid (GABA) analogues and anticonvulsant drugs used in the treatment of epilepsy and neuropathic pain such as postherpetic neuralgia, as well as many off-label indications such as restless leg syndrome.^1-

5

[0003] These drugs have high potential for use in treating paediatric patients, but their suitability is currently limited by their poor aqueous stability and extremely bitter taste, which have prevented stable and palatable liquid dosage forms from being created ^6-8 This has also limited their suitability for use by patients who have difficulty swallowing tablets, such as geriatric patients and those with limited muscle control.⁹

[0004] Gabapentin (GBP), pregabalin (PGB) and analogues thereof undergo degradation in aqueous solution via intramolecular cyclisation to form lactam analogues, namely 2-aza- spiro[4,5]decan-3-one and (S)-4- isobutyl-2-pyrrolidinone respectively, or similar lactams in the case of related drug analogues. Attempts to stabilize GBP through complexation with certain species, such as cyclodextrin compounds, have proved unsuccessful, with complexation reported as actually increasing the rate of lactamisation through restricting the drug in more reactive conformers.^10-12

[0005] Furthermore, the gabapentin lactam decomposition product has been shown to exhibit a sufficiently high toxicity, such that its presence in pharmaceutical preparations of GBP must be kept to a minimum.¹³' ¹⁴

[0006] Thus, there remains a need for ways in which to solubilise and stabilise GBP and PGB in aqueous solutions such that they may be more readily used in the treatment of conditions, such as epilepsy and neuropathic pain. [0007] More generally, there is a need for pharmaceutical compositions that are capable of stabilising any aqueously unstable anionic compound.

[0008] The present invention was devised with the foregoing in mind.

SUMMARY OF THE INVENTION

[0009] According to a first aspect of the present invention, there is provided a pharmaceutical composition comprising a plurality of layered double hydroxide nanoparticles and one or more pharmaceutically acceptable excipients, wherein the layered double hydroxide nanoparticles comprise layers of metal hydroxide and at least one anionic drug compound intercalated between the layers of metal hydroxide; and wherein the at least one anionic drug compound is an aqueously unstable anionic drug compound.

[0010] According to another aspect of the present invention, there is provided layered double hydroxide nanoparticles comprising layers of metal hydroxide and at least one anionic drug compound intercalated between the layers of metal hydroxide; and wherein the at least one anionic drug compound is an aqueously unstable anionic drug compound.

[0011] According to another aspect of the present invention, there is provided a process for the preparation of layered hydroxide nanoparticles as defined herein, the process comprising: a) delaminating particles of layered double hydroxide to form a dispersion of metal hydroxide layers;

b) mixing the dispersion of metal hydroxide layers formed in step a) with a solution of an aqueously unstable anionic drug compound in a pharmaceutically acceptable solvent to form nanoparticles comprising layers of metal hydroxide and the anionic drug compound intercalated between the layers of metal hydroxide; and

c) collecting the nanoparticles formed in step b).

[0012] According to another aspect of the present invention, there is provided a process for the preparation of a pharmaceutical composition as defined herein, wherein the process comprises mixing layered double hydroxide nanoparticles as defined herein, with one or more pharmaceutically acceptable excipients.

[0013] According to another aspect of the present invention, there is provided layered double hydroxide nanoparticles prepared by / obtainable by / obtained by / directly obtained by any process defined herein. [0014] According to another aspect of the present invention, there is provided a pharmaceutical composition prepared by / obtainable by / obtained by / directly obtained by the process as defined herein.

[0015] According to another aspect of the present invention, there is provided a method of stabilising an aqueously unstable anionic drug compound, the method comprising forming layered double hydroxide nanoparticles comprising the aqueously unstable anionic drug compounds as defined herein, optionally by a process as defined herein.

[0016] According to another aspect of the present invention, there is provided a method of stabilising an aqueously unstable anionic drug compound, the method comprising forming a pharmaceutical composition comprising the compound as defined herein, optionally by a process as defined herein.

DETAILED DESCRIPTION OF THE INVENTION

[0017] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of them mean "including but not limited to", and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0018] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0019] Unless otherwise specified, the terms "intercalating", "intercalate" and "intercalation" will be understood as referring to the reversible inclusion or insertion of a compound (or ion) into another compound(s) with a layered structure. [0020] Unless otherwise specified, the term "delaminating" will be understood as referring to a process of splitting or separating a bulk material into individual or multiple nanometer or sub- nanometre layers.

[0021] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

Pharmaceutical formulations of the present invention

[0022] The present invention provides a pharmaceutical composition comprising a plurality of layered double hydroxide nanoparticles and one or more pharmaceutically acceptable excipients, wherein the layered double hydroxide nanoparticles comprise layers of metal hydroxide and at least one anionic drug compound intercalated between the layers of metal hydroxide; and wherein the at least one anionic drug compound is an aqueously unstable anionic drug compound.

[0023] The pharmaceutical compositions of the present invention advantageously increase the dispersibility and, more importantly, the stability of the aqueously unstable anionic drug compounds.

[0024] It will be appreciated that the pharmaceutical composition may be in any suitable form. For example, the pharmaceutical compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0025] In an embodiment, the pharmaceutical composition is a solid dosage form, a dispersion, an emulsion or a cream. Suitably, the pharmaceutical composition is a solid dosage form or a dispersion of the nanoparticles in a pharmaceutically acceptable diluent. Most suitably, the pharmaceutical composition is a solid dosage form.

[0026] The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients that are well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.

[0027] Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal track, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.

[0028] Compositions for oral use may be in the form of hard gelatin capsules in which the layered double hydroxide nanoparticles defined herein is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, soya bean oil, coconut oil, or preferably olive oil, or any other acceptable vehicle

[0029] Aqueous suspensions generally contain the layered double hydroxide nanoparticles defined herein in the form of a fine powder together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).

[0030] Oily suspensions may be formulated by suspending the layered double hydroxide nanoparticles defined herein in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

[0031] Dispersible or lyophilised powders and granules suitable for preparation of an aqueous suspension or solution by the addition of water generally contain the layered double hydroxide nanoparticles defined herein together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.

[0032] Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.

[0033] The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, solutions, emulsions or particular systems, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable suspension in a non-toxic parenterally acceptable diluent or solvent, for example a solution in polyethylene glycol.

[0034] Suppository formulations may be prepared by mixing the active ingredient with a suitable non irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.

[0035] Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating the layered double hydroxide nanoparticles defined herein with a conventional, topically acceptable, vehicle or diluent using conventional procedure well known in the art.

[0036] Compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30μηι or much less preferably 5μηι or less and more preferably between 5μηι and 1 μηι, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose. The powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50mg of active ingredient for use with a turbo inhaler device. [0037] Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.

Layered double hydroxides nanoparticles

[0038] Layered double hydroxides (LDHs) are a class of compounds which comprise two metal cations and have a layered structure. A brief review of LDHs is provided in Chemistry in Britain, September 1997, pages 59 to 62.

[0039] Layered double hydroxides have previously been reported as intercalating certain organic species into their layers,³⁵ but also for their use in drug delivery (see European Patent No. 1341556). However, the organic species previously intercalated into the LDH layers were both soluble and stable in aqueous environments. Thus, there have been no reports of using LDH nanoparticles to increase the stability of aqueously unstable anionic compounds.

[0040] Somewhat surprisingly, the inventors have found that, despite previously reported difficulties in complexing aqueously unstable anionic drug compounds, such as, for example gabapentin, ^{10 12} the intercalation of aqueously unstable anionic drug compounds into layered double hydroxides resulted in a dramatic and unexpected enhancement in the stability of these drug compounds in aqueous environments. This enhancement in stability has enabled these aqueously unstable drug compounds to be formulated into a wider variety of formulations, including aqueous suspensions.

[0041] Accordingly, in one aspect of the present invention, there are provided layered double hydroxide nanoparticles comprising layers of metal hydroxide and at least one anionic drug compound intercalated between the layers of metal hydroxide; and wherein the at least one anionic drug compound is an aqueously unstable anionic drug compound.

[0042] In another aspect of the present invention, there is provided a pharmaceutical composition comprising a plurality of layered double hydroxide nanoparticles and one or more pharmaceutically acceptable excipients, wherein the layered double hydroxide nanoparticles comprise layers of metal hydroxide and at least one anionic drug compound intercalated between the layers of metal hydroxide; and wherein the at least one anionic drug compound is an aqueously unstable anionic drug compound. [0043] It will be appreciated by a person skilled in the art that any suitable layered double hydroxide nanoparticles may be used in the present invention. Suitable layered double hydroxide nanoparticles are described in EP1341556, the entire contents of which are incorporated herein by reference.

[0044] In an embodiment, the layered double hydroxide nanoparticles of the present invention contain positively charged mixed-metal hydroxide layers whose composition are selected from one of the two formulae shown below:

wherein:

Μ', M" and M'" are mono-, di- and trivalent metal cations respectively;

x is a number less than 1 ; and

n is equal to 2x-1 .

[0045] In another embodiment of the present invention, the layered double hydroxide nanoparticles contain positively charged mixed-metal hydroxide layers whose composition are given by formula (I) shown below:

wherein

M" is a divalent cation;

M^III is a trivalent cation; and

x is a number less than 1 .

[0046] It will be appreciated by a person skilled in the art that when the layered double hydroxide nanoparticles are of formula (I) shown above, M" and M^III may comprise any suitable divalent and trivalent cation respectively.

[0047] In an embodiment, the layered double hydroxide nanoparticles have the formula (I), shown above, wherein M" is selected from Mg²⁺, Ca²⁺, Mn²⁺, Fe²⁺, Co²⁺, Ni²⁺, Cu²⁺ or Zn²⁺. Suitably, the layered double hydroxide nanoparticles have the formula (I) shown above, wherein M" is selected from Mg²⁺, Ca²⁺, Ni²⁺, Cu²⁺ or Zn²⁺. More suitably, the layered double hydroxide nanoparticles have the formula (I) shown above, wherein M" is selected from Mg²⁺ or Ca²⁺. Most suitably, the layered double hydroxide nanoparticles have the formula (I) shown above, wherein M" is Mg²⁺.

[0048] In an embodiment, the layered double hydroxide nanoparticles have the formula (I) shown above, wherein M¹" is selected from Al³⁺ or Fe³⁺. Suitably, the layered double hydroxide nanoparticles have the formula (I) shown above, wherein M¹" is Al³⁺.

[0049] In another embodiment of the present invention, the layered double hydroxide nanoparticles contain positively charged mixed-metal hydroxide layers whose composition is given by the formula (II) shown below:

wherein

M^III is a trivalent cation; and

x is a number less than 1 .

[0050] In an embodiment, the layered double hydroxide nanoparticles have the formula (II) shown above, wherein M^III is selected from Al³⁺ or Fe³⁺. In another embodiment, the layered double hydroxide nanoparticles have the formula (II), shown above, wherein M^III is Al³⁺.

[0051] In another embodiment of the present invention, the layered double hydroxide nanoparticles contain positively charged mixed-metal hydroxide layers whose composition are by the formula (III), shown below:

wherein

M" is a divalent cation; and

x is a number less than 1 .

[0052] In an embodiment, the layered double hydroxide nanoparticles contain positively charged mixed-metal hydroxide layers whose composition have the formula (III), shown above, wherein M" is selected from Mg²⁺, Ca²⁺, Mn²⁺, Fe²⁺, Co²⁺, Ni²⁺, Cu²⁺ or Zn²⁺. Suitably, the layered double hydroxide nanoparticles have the formula (III), shown above, wherein M" is selected from Mg²⁺, Ca²⁺, Ni²⁺, Cu²⁺ or Zn²⁺. Most suitably, the layered double hydroxide nanoparticles have the formula (III), shown above, wherein M" is selected from Mg²⁺ or Ca²⁺.

[0053] The layered double hydroxide nanoparticles may have any suitable ratio of M" : M^III. Suitably, the ratio of M" : M'" is between 1 .5 : 1 and 5 : 1 . More suitably, the ratio of M" : M'" is between 1 .5 : 1 and 4 : 1 . Yet more suitably, the ratio M" : M^III is between 1 .5 : 1 and 2.5 : 1 . Most suitably, the ratio of M" : M'" is 2 : 1 .

[0054] In an embodiment, the mean particle size (platelet diameter) of the layered double hydroxide nanoparticles is within the range of 20 nm to 1000 nm. Suitably, the mean particle size of the layered double hydroxide nanoparticles is within the range of 200 nm to 1000 nm. More suitably, the mean particle size of the layered double hydroxide nanoparticles is within the range of 500 nm to 1000 nm. Yet more suitably, the mean particle size of the layered double hydroxide nanoparticles is within the range of 600 nm to 1000 nm. Most suitably, the mean particle size of the layered double hydroxide nanoparticles is within the range of 600 nm to 800 nm.

[0055] The layered double hydroxide nanoparticles may be suspended in any suitable medium.

Agueously unstable anionic drug compound

[0056] The term aqueously unstable anionic drug compound will be understood to refer to any anionic (negatively charged) drug compound that is unstable in a medium comprising water. Accordingly, the term aqueously unstable anionic drug compound will be understood to comprise any drug molecule that is capable of carrying a negative charge and displays some level of instability to water. A non-limiting example of an aqueously unstable anionic drug molecule is Gabapentin, which substantially decomposes in water over the course of approximately 3 days to yield a toxic decomposition product.^{36 37}

[0057] It will be appreciated that the aqueous instability demonstrated by the aqueously unstable anionic drug compound may be as a result of any chemical or physical change to the drug compound. Typically, the instability displayed by the aqueously unstable anionic drug compound will be the result of a chemical reaction. In some cases, the aqueously unstable anionic drug compound may undergo an intermolecular cyclisation reaction in water, for example by the reaction between carbonyl and amino moieties present on the drug compound. An example of this is the intramolecular cyclisation of Gabapentin (a) in the presence of water to form the lactam analogue 2-aza-spiro[4,5]decan-3-one (c), as shown below.

[0058] In an embodiment of the present invention, the aqueously unstable anionic drug compound comprises at least one carboxy group. Suitably, the aqueously unstable anionic drug compound comprises at least one carboxy group and at least one amino group. More suitably, the aqueously unstable anionic drug compound comprises at least one carboxy group and at least one amino group, wherein the at least one carboxy group and the at least one amino group are capable of reacting together in an aqueous environment to form a cyclic amide (e.g. a lactam).

[0059] In another embodiment of the present invention, the aqueously unstable anionic drug has a molecular weight of less than 1000. Suitably, the aqueously unstable anionic drug has a molecular weight of less than 800. More suitably, the aqueously unstable anionic drug has a molecular weight of less than 500. Most suitably, the aqueously unstable anionic drug has a molecular weight of less than 300.

[0060] In another embodiment of the present invention, the aqueously unstable anionic drug is selected from Gabapentin, Pregabalin, L-Dopa, Carbidopa, Methyldopa, Baclofen, Lesogaberan, Phenibut, GABOB, Phaclofen, Saclofen or Vigabatrin. Suitably, the aqueously unstable anionic drug is selected from Gabapentin, Pregabalin, L-Dopa. Most suitably, the aqueously unstable anionic drug is selected from Gabapentin or Pregabalin.

Process of the present invention

[0061] It will be appreciated that the layered double hydroxides described herein, may be prepared by any suitable method known in the art. Thus, the person skilled in the art will be able to select suitable conditions in which to prepare the layered double hydroxides described herein, such as, for example, selecting appropriate reaction concentrations, temperatures, durations and pressures.

[0062] Particular processes for the preparation of layered double hydroxides are described further in the accompanying examples hereinbelow.

[0063] According to one aspect of the present invention, there is provided a process for the preparation of layered hydroxide nanoparticles, as defined herein, the process comprising: a) delaminating particles of layered double hydroxide to form a dispersion of metal hydroxide layers;

c) collecting the nanoparticles formed in step b).

[0064] In an embodiment, the layered double hydroxide of step a) of the process of the present invention is of the formula (IV), shown below:

wherein

M" is a divalent cation;

M^III is a trivalent cation;

x is a number less than 1 ;

A is a displaceable anion;

n is an integer;

and wherein the compound is optionally hydrated with a stoichiometric or non-stoichiometric amount of water.

[0065] In another embodiment, the process of the present invention comprises mixing layered double hydroxide nanoparticles, as defined herein, with one or more pharmaceutically acceptable excipients.

[0066] In another embodiment, the process of the present invention comprises mixing layered double hydroxide nanoparticles prepared according the any process defined herein, with one or more pharmaceutically acceptable excipients

Step a)

[0067] The layered double hydroxide (LDH) of step a) of the process of the present invention may be delaminated by any suitable means known in the art. Suitably, the layered double hydroxide (LDH) of step a) of the process of the present invention is delaminated by agitating (e.g. mixing and/or sonicating) the LDH in an organic solvent. More suitably, the layered double hydroxide (LDH) of step a) of the process of the present invention is delaminated by agitating (e.g. mixing and/or sonicating) the LDH in formamide.

[0068] In another embodiment, the layered double hydroxide of step a) of the process of the present invention is of the formula (IV), shown above, wherein M" is selected from Mg²⁺, Ca²⁺, Mn²⁺, Fe²⁺, Co²⁺, Ni²⁺, Cu²⁺ or Zn²⁺. Suitably, the layered double hydroxide of step a) of the process is of the formula (IV), shown above, wherein M" is selected from Mg²⁺, Ca²⁺, Ni²⁺, Cu²⁺ or Zn²⁺. More suitably, the layered double hydroxide of step a) of the process is of the formula (IV), shown above, wherein M" is selected from Mg²⁺ or Ca²⁺. Most suitably, the layered double hydroxide of step a) of the process is of the formula (IV), shown above, wherein M" is Mg²⁺.

[0069] In another embodiment, the layered double hydroxide of step a) of the process of the present invention is of the formula (IV), shown above, wherein M'" is selected from Al³⁺ or Fe³⁺. Suitably, the layered double hydroxide of step a) of the process is of the formula (IV), shown above, wherein M'" is Al³⁺.

[0070] The layered double hydroxide of formula (IV) may have any suitable ratio of M" : M'". Suitably, the ratio of M" : M'" is between 1 .5 : 1 and 5 : 1 . More suitably, the ratio of M" : M'" is between 1 .5 : 1 and 4 : 1 . Yet more suitably, the ratio M" : M^III is between 1 .5 : 1 and 2.5 : 1 . Most suitably, the ratio of M" : M'" is 2 : 1 .

[0071] It will also be appreciated by a person skilled in the art that A may be any anion capable of being replaced. Suitably, A is an anion selected from OH-, F, CI-, Br, I-, S0₄ ^2-, C0₃ ^2- or N0₃-. More suitably, A is an anion selected from, CI-, Br, CO3^2- or N0₃-. Most suitably, A is NO3-.

[0072] In another embodiment, layered double hydroxide of step a) of the process of the present invention is [Mg₀.66Alo.33(OH)2](N03)o.33.xH₂0 termed (MgAI-N0₃).

Step b)

[0073] Step b) of the process may be carried out in any suitable pharmaceutically acceptable solvent. In an embodiment, the pharmaceutically acceptable solvent of step b) of the process is selected from water, (1 -4C)alcohol, acetone, ethyl acetate, acetonitrile or ethylene glycol (or a mixture thereof). Suitably, the pharmaceutically acceptable solvent of step b) of the process is selected from water, ethanol, methanol, isopropanol or acetone. More suitably, the pharmaceutically acceptable solvent of step b) of the process is selected from water or ethanol. Most suitably, the pharmaceutically acceptable solvent of step b) of the process is ethanol. [0074] In an embodiment of the present invention, the aqueously unstable anionic drug compound introduced in step b) of the process is as defined in any one of aqueously insoluble drugs defined hereinbefore.

[0075] In another embodiment of the present invention, the aqueously unstable anionic drug compound introduced in step b) of the process may be mixed with a suitable base. Suitably, the aqueously unstable anionic drug compound introduced in step b) of the process is mixed with an equimolar amount of a suitable base. More suitably, the aqueously unstable anionic drug compound introduced in step b) of the process is mixed with an equimolar amount of NaOH or NaOEt.

Step c)

[0076] It will be understood by a person skilled in the art that any suitable collection means may be used in step c) of the process. Suitably, the nanoparticles formed in step b) of the process are collected by centrifugation or filtration. More suitably, the nanoparticles formed in step b) are collect by centrifugation. Yet more suitably, the nanoparticles formed in step b) are collect by centrifugation at a speed of between 1000 rpm and 15000 rpm. Even more suitably, the nanoparticles formed in step b) are collect by centrifugation at a speed of between 6000 rpm and 12000 rpm. Most suitably, the nanoparticles formed in step b) are collect by centrifugation at a speed of between 8000 rpm and 10000 rpm.

[0077] When the nanoparticles of step b) of the process are collected by centrifugation, it will be understood that multiple centrifugation/washing cycles may be used. Suitably, the nanoparticles collected in step c) of the process are suspended in water or ethanol after centrifugation, before being re-centrifuged one or more times.

[0078] In another embodiment, the nanoparticles collected in step c) of the process are dried. Suitably, the nanoparticles collected in step c) of the process are dried under vacuum.

Method of stabilisation

[0079] In another aspect of the present invention, there is provided a method of stabilising an aqueously unstable anionic drug compound, the method comprising forming layered double hydroxide nanoparticles comprising the compounds as defined herein, optionally by the process defined herein.

[0080] In a further aspect of the present invention, there is provided a method of stabilising an aqueously unstable anionic drug compound, the method comprising forming a pharmaceutical composition comprising the compound as defined herein, optionally by the process defied herein.

EXAMPLES

[0081 ] Embodiments of the invention will be described, by way of example only, with reference to the accompanying drawings, in which:

Figure 1 shows the suspension of delaminated MgAI-N03 in formamide exhibiting the Tyndall effect.

Figure 2 shows the XRD patterns of MgAI-N0₃ (a) before delamination and (b) delaminated in formamide.

Figure 3 shows the powder XRD patterns of (a) MgAI-N0₃, (b) MgAI-GBP_water, (c) MgAI- GBPethanol, (d) MgAI-GBP_anhyd and (e) MgAI-PGB_anhyd.

Figure 4 shows the FTIR spectra of (a) MgAI-N0₃, (b) MgAI-GBP_water, (c) MgAI-GBP_ethanoi, (d) MgAI-GBPanhyd and (e) pristine GBP.

Figure 5 shows the FTIR spectra of (a) MgAI-N0₃, (b) MgAI-PGB_anhyd, (c) MgAI-PGB_anhyd-₂o and (e) pristine PGB.

Figure 6 shows two ¹³C solid state CP/MAS NMR spectra: (c) is the spectrum of pristine gabapentin, and (d) is the spectrum of a gabapentin containing nanohybrid, specifically

MgA|-GBPanhyd,-20.

Figure 7 shows two ¹³C solid state CP/MAS NMR spectra: (a) is the spectrum of pristine pregabalin, and (b) is the spectrum of a pregabalin containing nanohybrid, specifically MgAI-

PGBanhyd,-20.

Figure 8 shows the ¹ H NMR spectrum of gabapentin, which is seen upon deintercalation experiments of the nanohybrids containing gabapentin when stirred in Na₂C0₃/D₂0.

Figure 9 shows the ¹ H NMR spectrum of pregabalin, which is seen upon deintercalation experiments of the nanohybrids containing pregabalin when stirred in Na₂C0₃/D₂0.

Figure 10 shows SEM images of (a) MgAI-N0₃, (B) MgAI-GBP_water, (c) MgAI-GBP_ethanoi, (d) MgAI-GBPethanol-o, (e) MgAI-GBPethanol-₂o, (f) MgAI-GBPethanol-4o, (g) MgAI-GBPanhyd, (h) MgAI- GBPanhyd-₂₀, (i) MgAI-PGB_anhyd and (j) MgAI-PGB_anhyd-₂o.

Figure 1 1 shows TEM images of (a) MgAI-N0₃, (b) MgAI-GBP_water, (c) MgAI-GBPethanol, (d) MgAI-GBPanhyd, (e) MgAI-GBP_anhyd-₂o and (f) MgAI-PGB_anhyd-₂o. Figure 12 shows the full width at half maximum (FWHM) values of the (a) (003), (b) (006), (c) (009) and (d) (1 10) reflections in the XRD patterns of MgAI-GBP_ethanol (♦), MgAI-GBP_anhyd ( ●) and MgAI-PGBanhyd (■), synthesised at different stacking temperatures.

Figure 13 shows the drug loading pf MgAI-GBP_ethanoi (*),MgAI-GBP_anhyd (♦) and MgAI- PGBanhyd (■), synthesised at different temperatures, displayed as a function of (a) weight percentage and (b) percentage of the theoretical maximum.

Figure 14 shows the in vitro release profiles of (a) MgAI-GBP_anhyd-2o and (b) MgAI-PGB_anhyd-2o at 37 °C in pH 2.0 sulphate buffer (♦), pH 4.0 phosphate buffer (♦) and pH 7.0 phosphate buffer (■).

Figure 15 shows plots illustrating the change of the natural logarithm of drug concentration over time during the decomposition studies, from which he cyclisation constant, tabs, can be calculated. These studies were carried out at 80 °C, the sample are pristine GBP (♦ ), MgAI-

GBPanhyd-2o (♦), pristine PGB (■) and MgAI-PGB_anhyd-2o ( *).

Materials

[0082] GBP (> 98.0% purity) was purchased from Tokyo Chemical Industry UK, PGB was purchased from Manchester Organics (> 98.0% purity), both were used as received. All other reagents used were purchased from Sigma-Aldrich and used as received.

Synthesis and delamination of MqAI-NQ₃ LDH

[0083] Following the method described by lyi et a/.^15,16 but with modifications, highly crystalline MgAI-C0₃ LDH was synthesised through homogeneous coprecipitation, followed by decarbonation to obtain MgAI-N0₃ LDH. Solutions containing Mg(N0₃)₂-6 H₂0, (80 mmol) AI(N0₃)₃-9H₂0 (40 mmol) and hexamethylenetetramine (1 14 mmol) in 350 mL degassed, deionised water were placed in PTFE-lined autoclaves. These were sealed and treated hydrothermally at 140°C for 24 h. After air cooling, the contents were filtered and washed thoroughly with degassed, deionised water followed by methanol, and dried under vacuum. Under flowing N₂ gas, 8.4g of the resultant white solid was suspended in a solution of NaN0₃ (10.6 mmol) in 270 mL degassed methanol. To this suspension, 27 mL of 2 M HN0₃ was added dropwise, and the reaction mixture stirred for 12 h at room temperature under gently flowing N₂ gas. The suspension was then filtered and washed thoroughly with methanol, before being dried under vacuum to obtain a white powder. [0084] Delamination of the MgAI-N0₃ LDH was performed as detailed by Wu et a\}⁷ A sample of LDH (2.0 g) was dispersed in 100 mL of formamide with magnetic stirring and subsequently sonicated until it became transparent (12-24 h). The resulting 20 g L ¹ dispersion of LDH nanosheets in formamide was kept sealed under a nitrogen atmosphere until use, to prevent absorption of water. The dispersion remained stable indefinitely, becoming gel-like when left undisturbed and returning to a viscous fluid upon brief agitation.

Synthesis of MqAI-drug nanohybrids

[0085] The drug-LDH nanohybrids were synthesised by the following restacking procedure. Investigations into different variables all followed this same general procedure and are detailed subsequently. The pristine drug (1 .5 mmol) was dissolved in 20 mL degassed, deionised water or ethanol and an equimolar amount of base (either 1 M NaOH in H₂0 or 1 M NaOEt in EtOH) was added under magnetic stirring. To this solution, and whilst maintaining a stirring speed of 500 rpm, 5 mL of the 20 g L^~1 LDH dispersion in formamide was added dropwise at 1 .17 mL mirr¹ using a syringe pump. After the addition had finished, stirring was halted and the pearlescent reaction mixture was left to stand for 2 h. In all cases, the addition and standing time were conducted under a nitrogen atmosphere.

[0086] After 2 h of standing time had passed, the reaction mixture was centrifuged at 9000 rpm for 5 min. The resulting solid was resuspended in either water or ethanol and centrifuged. Centrifuge-washing cycles were repeated thrice. The white solid was then dried under vacuum for a minimum of 24 h. To remove final traces of formamide, the solid product was ground to a powder and dried for a further 12 h under high vacuum. The resulting nanohybrids will be referred to as MgAI-GBP and MgAI-PGB.

Comparison of restacking solvent

[0087] MgAI-GBP nanohybrids were synthesised using either water or ethanol as the restacking solvent. In both cases, 1 M NaOH in H₂0 was used as the base, however, same solvent that was used for restacking was also used for the centrifuge-washings. These samples are denoted as MgAI-GBP_water and MgAI-GBP_ethanoi respectively.

Investigation of water presence in restacking

[0088] To provide further comparison, samples of the Drug-LDH nanohybrids were synthesised in a rigorously anhydrous environment. Several additional measures were taken to ensure this. Reactions were carried out under a nitrogen atmosphere using standard Schlenk-line apparatus on a dual-vacuum-inlet gas manifold. During the delamination procedure, prior to the addition of formamide, the LDH sample was dried under high vacuum for 6 h. Anhydrous formamide, Hydranal®, was used as the delamination solvent and stored over molecular sieves. Anhydrous ethanol, stored on molecular sieves, was used as the restacking solvent and the base used was 1 M NaOEt in EtOH, which was prepared in situ from anhydrous ethanol and sodium metal. Prior to dissolution in ethanol, GBP and PGB samples were dried for 30 min under high vacuum. These samples are denoted as MgAI-

GBPanhyd and MgAI-PGBanhyd-

Investigation of restacking temperature

[0089] The restacking procedure was initially performed at room temperature. An attempt at increasing the crystallinity of the nanohybrids was made by performing the restacking procedure at elevated temperatures of 40 °C and 80 °C. When this was found to have a detrimental effect on the crystallinity and purity of the resulting nanohybrids, the restacking procedure was performed at reduced temperatures of 0 °C, 20 °C and 40 °C, accessed using an ice/water bath and ethylene glycol/ethanol/dry ice baths with ethylene glycohethanol ratios of 90:10 and 60:40 by volume respectively. In all cases, the desired temperature was maintained from the start of the addition of the LDH dispersion, through to the end of the standing time, after which the reaction mixtures were allowed to return to room temperature for centrifugation, washing and drying.

Release studies

[0090] Release of GBP and PGB from the nanohybrids in vitro was measured at 37 °C in sulphate (pH 2.0, 0.01 M) and phosphate (pH 4.0, 0.01 M and pH 7.0, 0.01 M) buffer solutions. For each sample measured, 50 mg nanohybrid was suspended in 200 mL buffer solution, which was kept at a constant 37 °C and under magnetic stirring at a rate of 200 rpm. At predetermined time intervals, aliquots of 3 mL were removed from the suspensions and immediately passed through 0.45 μηι syringe filters. The concentration of drug in each filtered aliquot was then obtained through a fluorospectroscopic method. Aqueous stability studies

[0091] The aqueous stability of the nanohybrids in deionised water was measured at both room temperature and 80 °C. For each sample measured, 50 mg nanohybrid was suspended in 100 mL water. To act as controls, solutions of 10 mg of each pristine drug dissolved in 100 mL water were also prepared. The suspensions and control solutions were then kept at either room temperature or 80 °C whilst being stirred gently. At predetermined time intervals, aliquots of 2 mL were removed from the suspensions and control solutions, added to 2 mL of 0.2 M Na₂C0₃ solution and stirred for 30 min. The aliquots of suspensions were then passed through 0.45 μηι syringe filters. The concentration of drug in each aliquot was then obtained through a fluorospectroscopic method.

[0092] To confirm the identities of the decomposition products, samples of nanohybrids were suspended in D₂0 in NMR tubes at either room temperature or 80 °C and left for a sufficient period of time for measurable amounts of decomposition products to have formed, typically four weeks, or two weeks for heated samples. Solutions of Na₂C0₃ in D₂0 were then added to the suspensions, which were subsequently sonicated and their ¹ H NMR spectra recorded.

Fluorospectroscopic determination of drug concentration

[0093] The concentrations of drug species in the aliquots from release and stability studies were determined according to the following method.¹⁸ A 1 mL sample was taken from each aliquot and added to 3 mL deionised water. To this was added 5 mL borate buffer (pH 9.0, 0.1 M) and 1 mL acetone solution of fluorescamine (0.72 mM) to make fluorescence samples. Fresh solutions of fluorescamine in acetone were prepared, stored at 5 °C and could be used for up to 7 days before needing to be remade. The emission of each fluorescence sample was measured in a quartz fluorimeter cuvette. Fluorescence spectra were recorded on an LS 55 Perkin-Elmer Luminescence Spectrometer in emission mode (excitation = 385 nm, scan speed = 300 nm min ¹ , scan range = 410 - 650 nm, excitation slit = 510 nm, emission slit = 5 nm). The drug concentrations of the fluorescence samples were followed by measuring the emission in the range 454.5-579.5 nm in steps of 0.5 nm. Concentrations were calculated using calibration curves obtained by measuring the emission intensity of solutions of known drug concentrations. The solutions of known drug concentration were treated with borate buffer and fluorescamine solution in the same method as the aliquots. Characterisation

[0094] Powder X-ray diffraction (XRD) data were collected on a PAN-Analytical X'Pert Pro diffractometer in reflection mode at 40 kV and 40 mA using Cu Ka radiation (αι = 1 .540 57 A, a₂ = 1 .544 33 A, weighted average = 1 .541 78 A). Scans were recorded from 2 °≤ 2Θ≤75°with varying scan speeds and a slit size of 1 mm. Samples were mounted on stainless steel sample holders.

[0095] Fourier Transform Infrared (FTIR) spectra were recorded on a Biorad FTS 6000 FTIR Spectrometer equipped with a high performance DuraSampl lR II diamond accessory by SensIR Technologies for measuring attenuated total reflection (ATR). Spectra were recorded in the range 400 - 4000 cm ¹ with 40 scans at 4 cm ¹ resolution. Absorptions in the range 1667 - 2500 cm^-1 are from the DuraSampl IR II diamond surface.

[0096] ¹³C cross-polarisation magic angle spinning (CP/MAS) Solid State NMR spectra were recorded by Dr Nicholas Rees on a Varian/Chemagnetics Infinity Spectrometer at 50.32 MHz using 7.5 mm zirconia rotors containing ca. 300 mg of sample. A double resonance MAS probe and a MAS rate of 10 kHz were used. A cross-polarisation sequence with a variable X- amplitude spin-lock pulse¹⁹ and phase-modulated proton decoupling were applied. Typically, 13000 transients were acquired using a contact time of 1 ms, an acquisition time of 41 ms (1024 data points zero-filled to 16 K) and a recycle delay of 30 s. All spectra were referenced to adamantane (the upfield methine resonance was taken to be at = 29.5 ppm²⁰ on a scale where 5((TMS) = 0) as a secondary reference.

[0097] Solution phase NMR spectroscopy was used to confirm the release of the unaltered drug species upon deintercalation and check for the presence of impurities and decomposition products. In NMR tubes, samples of nanohybrids were dispersed in 0.1 M Na₂C0₃ in D₂0 by sonication. After 15 min sonication the suspensions we allowed to settle.¹ H NMR spectra were recorded on the resulting solutions using a Bruker Ascend™ 400 MHz NMR spectrometer.

[0098] Scanning Electron Microscopy (SEM) analysis was performed using a JSM-6610LV low vacuum scanning electron microscope with an accelerating voltage of 20 kV in secondary electron imaging mode. Nanohybrids were adhered to the SEM stage using carbon tape and coated with a 2 nm coating of Pt to reduce charging and improve the image quality. Energy- dispersive X-ray spectroscopy (EDX) data were collected using an Oxford Instruments X-Max^N silicon drift detector.

[0099] Transmission Electron Microscopy (TEM) analysis was performed on a JEOL 2100 microscope with an accelerating voltage of 200 kV. Nanohybrids were dispersed in ethanol with brief sonication, then dropped onto Formvar® film-coated copper grids and left to dry. [00100] Elemental HCN analysis was performed by a quantitative oxidative combustion technique by Dr Stephen Boyer at the School of Human Sciences, London Metropolitan University.

[00101 ] Thermogravimetric analysis (TGA) measurements were used to determine the cointercalated water content of the nanohybrids, collected using a Perkin-Elmer TGA7 Thermo- gravimetric Analyser. Samples of nanohybrids (10 mg) were heated in platinum pan from 20 °C to 800 °C at a heating rate of 5 °C min ¹ under a flowing stream of nitrogen.

Results

Synthesis and drug content nanohybrids

[00102] The delaminated LDH suspension exhibited a Tyndall effect, as seen in Figure 1 confirming formation of a colloidal suspension, rather than dissolution of the precursor LDH particles. The XRD pattern of the suspension, seen in Figure 2, shows the complete absence of any reflections relating to the (001 ) reflections found in the precursor LDH, however a small refection at 2Θ = 60.5° relates to the (1 10) reflection of the precursor, indicating complete delamination to 2D sheets of the metal hydroxide layers, whilst a broad shoulder in the baseline around 2Θ = 26°can be attributed to scattering by liquid formamide, as seen in other delamination studies.^{17 21}

[00103] Powder XRD patterns of the drug intercalated nanohybrids and the precursor LDH are shown in Figure 3. All patterns can be indexed on the basis of a hexagonal lattice with R3m rhombohedral symmetry. The basal Bragg reflections, indexed as (003), are found at low values of 2Θ in the nanohybrids, (2Θ = 4.26-4.64°, d₀₀3 = 19.0-20.7 A for MgAI-GBP; 2Θ =4.05- 4.35°, d₀03 = 20.3-21 .8 A for MgAI-PGB), relative to the precursor LDH (2Θ = 9.93°, d₀₀3 = 8.9 A for MgAI-N0₃), which is indicative of intercalation of larger guest species into the interlayer region of the LDH. Bragg reflections are sharper and more intense in the patterns of samples that underwent restacking in ethanol rather than water, and sharper still for those synthesised anhydrously. Furthermore, small reflections at 2Θ = 9.91 ° and 2Θ = 19.82° in MgAI-GBP_water and MgAI-GBPethanol correspond to the (003) and (006) reflections of MgAI-N0₃, indicating that this has also formed during the restacking process of these two nanohybrids.

[00104] Cell parameters are given in Table 1 . The interlayer species of LDHs have very little effect on the a parameter, as this is predominantly determined by the metal hydroxide layers. Restacking in ethanol leads to a small decrease in the length of the a parameter compared to water, whilst anhydrous restacking leads to an additional reduction. The c parameter lies along the stacking direction, and so directly relates to the basal spacing, and the gallery height of the interlayer region, which is dependent on the interlayer species and any cointercalated molecules. Although there is variation in c parameters of the nanohybrids, it does not follow any obvious trend relating to differences in restacking conditions, and can be attributed to differences in the orientation of the nitrate and drug ions, and any cointercalated molecules.

Table 1 - Cell parameters, positions and full width at half maximum values of Bragg reflections in powder XRD patterns of the nanohybrids

[00105] Given that the thickness of metal hydroxide layers is generally reported as 4.8 A, this gives interlayer region distances of 14.9 A to 15.4 A for MgAI-GBP and of 15.2 A to 15.7 A for MgAI-PGB respectively.

[00106] The dimensions of GBP and PBG can be approximated from their crystal structures. The maximum length, width and depth of GBP given from this approximation are 8.4 A, 5.0 A and 4.5 A, and those for PGB are 8.1 A, 6.2 A and 5.2 A.^{22 23} These values, together with a values for the interlayer distances, can be used to propose possible orientations for the drug species within the layers, as illustrated in Figure 3.

[00107] Despite GBP having a greater maximum length than PGB, the greater interlayer distance is produced by PGB, due to its more bulky shape and greater conformational freedom, which prevent it from packing so closely in the interlayer region. The height of the interlayer region in the nanohybrids is sufficiently large for a bilayer of the drug ions to fit between the metal hydroxide sheets, such that the hydrophobic ends of the ions face towards each other, and the charged carboxylate and hydrophilic amine groups face towards the metal hydroxide sheets, as has been found when intercalating other surfactant-like drug ions into LDHs.^24,25 [00108] The full width at half maximum (FWHM) of Bragg reflections in XRD patterns of the nanohybrids can be used as a measure of the nanohybrids' crystallinity, relative to one another, and are detailed in Table 1 . The FWHM values of the (001 ) reflections indicate the extent of crystallinity in the z direction of individual crystalline regions, which, as this is in the direction in which stacking occurs, can be used as a measure of how well ordered successive layers are stacked together.

[00109] Clear trends can be seen in the FWHM values of the (001 ) reflections, with restacking temperature having the most influence. Reducing restacking temperature consistently results in increased crystallinity of the particles in the z direction, up until -20°, when the effect peaks and levels out. Differing the restacking solvent has a much less pronounced effect on crystallinity in the z direction, however a small improvement in crystallinity is seen when restacking is performed anhydrously in ethanol, in comparison to restacking in water or nonanhydrous ethanol.

[00110] The FWHM value for the (1 10) reflection relates to the extent of crystallinity in the xy plane, so is a measure of the crystallinity of the metal hydroxide sheets in the nanohybrids. The (1 10) FWHM values remain largely consistent across almost all nanohybrids, ranging from 0.468°to 0.580 °with no obvious trend, with the exception of MgAI-GBP_water, which shows a marginally higher FHWM of 0.653°. This indicates that the crystallinity of the individual LDH sheets is unaffected by differences in the restacking procedure, and that the individual sheets still retain a reasonably high degree of crystallinity, despite undergoing the delamination and restacking procedure.

FTIR Spectra

[00111 ] Examples of the FTIR spectra of the nanohybrids are shown in Figure 4 and Figure 5, alongside spectra of the pristine drugs and the precursor LDH for comparison. Characteristic absorption bands of the drugs can be seen in spectra of the nanohybrids. In the case of GBP, the pristine drug appears as its most stable polymorph, known in the literature as form II.²⁶

[00112] Upon intercalation, the spectra of the MgAI-GBP nanohybrids do not show a close agreement with the spectrum of a specific polymorph of GBP, but all absorptions fall within ranges that correspond to characteristic absorptions in all GBP polymorphs. However, most absorptions seen in the fingerprint region of each polymorph, below 1350 cm^-1 , are absent.²⁷

[00113] Absorptions are seen at 2928 cm^-1 and 2856 cm^-1 relating to the asymmetric and symmetric NH₂ stretches, at 1670 cm^-1 relating to the ionized asymmetric carboxylate stretch, at 1545 cm^-1 relating to the NH₂ scissoring vibration and at 1450 cm^-1 and 1392 cm^-1 relating to CH₂ bends.

[00114] The different polymorphs of PGB have been less well explored, but a similar difference is observed between the spectrum of the pristine drug, which corresponds to polymorphic form I, and the spectra of the MgAI-PGB nanohybrids, which do not agree exactly with any specific polymorph of PGB, but show good agreement within the ranges of characteristic absorptions across different polymorphs.^{28 29}

[00115] Absorptions at 2957 cm^-1 and 2928 cm^-1 relate to the asymmetric and symmetric NH₂ stretches, those at 1688 cm^-1 relate to the ionized asymmetric carboxylate stretch, those at 1549 cm^-1 scissoring vibration, and those at 1468 cm^-1 , 1387 cm^-1 and 1366 cm^-1 relate to CH₂ bends.³⁰

[00116] No absorptions characteristic of the lactam decomposition products were seen. In particular, any absorption at 1699 cm^-1 relating to the cyclic C-0 stretch is notably absent from all spectra.³¹

[00117] In addition to the absorption bands from the drug ions, absorptions typical of LDHs are seen, including broad shouldered absorptions between 670 cm^-1 and 900 cm^-1 relating to the M-OH stretch, and between 3200 cm^{- 1} and 3500 cm^{- 1} , relating to the O-H stretches of the layers (and cointercalated water, in the case of the precursor LDH).

[00118] Noticeable line broadening is seen in the spectra of the nanohybrids, which is attributable to variation in the bound conformations of the drug ions in the interlayer regions. In all nanohybrids, an absorption at 1347 cm^-1 is seen, which corresponds to NOy, indicating the presence of nitrate ions. However, this absorption is more intense in the spectra of MgAI- GBPwater and MgAI-GBPethanol than in other nanohybrids, which corroborates with the evidence from XRD data indicating the greater presence of MgAI-N0₃ in these sample. An absorption at 131 1 cm^-1 , corresponding to formamide, was seen in samples that had not been dried under high vacuum for a sufficient length of time, although it was absent from spectra after additional drying. It is also worth noting that the absorption at 1650 cm^-1 , which is derived from cointercalated water molecules, is not present in the spectra of any MgAI-GBP_anhyd or MgAI- PGBanhyd samples, as they contained no cointercalated water.

NMR spectra

[00119] Solid state ¹³C CP/MAS NMR spectra were useful in determining whether the intercalated species were the intended drug ions, their lactam decomposition products or a mixture of both (see Figures 6 and 7). The spectra of the pristine drug molecules show resonances at 29.2 ppm and 31 .8 ppm for the a-amino methylene carbon atoms and 169.4 ppm and 168.8 ppm for the carbonyl carbon atoms of GBP and PGB respectively. Lactamisation causes these resonances to shift significantly and broaden due to the adjacent ¹⁴N nucleus, which would result in distinctive resonances in the spectra.³² However, the nanohybrids present resonances at 34.4 ppm and 161 .3 ppm for MgAI-GBP and 33.4 ppm and 163.8 ppm for MgAI-PGB, which can be assigned to the same carbon atoms. Whilst there are small changes to chemical shift values, these are attributable to the changes in geometry and ordering adopted by the drug ions in the nanohybrids relative to the pristine drug crystals, as has been seen in other drugs upon intercalation, and in different polymorphs of GBP.³³ All other resonances could be assigned to the cyclohexyl and isobutyl groups of GBP and PGB respectively, indicating that the unaltered drug ions were the intercalated species.

[00120] The deintercalation experiments investigated by solution phase ¹ H NMR reveal that, upon deintercalation, most samples of the nanohybrids release only the intended drug species, along with trace amounts of residual solvents, evident from small resonances at 8.44 ppm denoting formamide and 1 .17 ppm and 3.65 ppm denoting ethanol (see Figures 8 and 9).

[00121 ] Spectra of the deintercalated drugs are in good agreement with both those of the pristine drug samples and literature values, GBP giving shift values of 1 .37 ppm to 1 .51 ppm (m), 2.42 ppm (s), 3.00 ppm (s), and PGB giving shift values of 0.89 ppm (t), 1 .22 ppm (t), 1 .66 ppm (m), 2.1 1 ppm to 2.35 ppm (m), 2.98 ppm (ddd).³⁴

[00122] The only sample that shows any evidence of drug decomposition was MgAI-GBP_water, which in addition to resonances attributable to GBP, showed resonances attributable to the lactam, with shift values of 3.06 ppm (s) and 3.29 ppm (s), in agreement with literature values.¹⁰ The ratio of GBP to decomposition product released was calculated at 1 1 :1 from integration of the NMR spectrum.

Thermogravimetric analysis (TGA)

[00123] TGA shows only very minor weight loss of the nanohybrids when heated up to 185 °C, indicating there was no appreciable cointercalated water or other solvents, such as ethanol or formamide. Between 185 °C and 410 °C, weight loss of the nanohybrids can be attributed to:

a) the thermal decomposition of the drug ions, as the carboxyl groups are lost as carbon dioxide; b) the loss of the remaining amide and hydrocarbon species between 190 °C and 270 °C in the case of GBP and 185 °C and 250 °C in the case of PGB; and

a) the liberation of nitrate ions as NO_x species between 280 °C and 410 °C.

[00124] Between 410 °C and 600 °C, weight loss is also minimal, as the temperature isn't sufficient to calcine the remaining LDH layers into oxide species.

Elemental analysis

[00125] Elemental HCN analysis was used to calculate the drug loading of the samples and, where possible, compared to values derived experimentally from release studies. EDX analysis was used to establish the Mg:AI ratio in the nanohybrids, as delamination-restacking procedures typically alter this ratio, due to partial dissolution of metal ions during delamination. Together, these data were used to estimate the overall formulae of the nanohybrids, as can be seen in Table 2.

SEM and TEM images

[00126] SEM images of the nanohybrids, seen in Figure 10, show significantly different morphology to the precursor LDH before delamination. The precursor LDH shown in Figure 10(a) exhibits well defined circular-hexagonal platelets with an average diameter of 2 μηι, whereas the nanohybrids form larger aggregates formed of rounder, thicker particle shapes with many irregularities caused by the restacking process. All nanohybrids exhibit similar morphologies, independent of the restacking conditions, with average particle diameters of 30 μηι to 40 μηι. [00127] The morphology of the nanohybrids can be examined further in TEM images, seen in Figure 1 1 . Again, difference between the clearly defined hexagonal precursor particles and the nanohybrids is evident. The TEM images of the nanohybrids still show irregular aggregated particles, but they are much smaller, with average diameters of around 700 nm, as the preparation of the TEM grids facilitates the breakup of the larger aggregates. The images also reveal that the nanohybrids are constituted of much smaller (diameter of 80-100 nm), irregularly shaped sheets of LDH layers, indicating that the large platelets of the precursor are also broken apart into much smaller sheets upon delamination. Some smaller, non- aggregated particles can also be seen surrounding the main nanohybrid particles, indicating that the aggregated particles can be readily broken apart into their smaller constituents. The small individual particles, whether they are part of an aggregate particle or separate, resemble flat platelets with both rounded, smooth edges and straight edges with sharp corners, indicating where they have broken apart from larger sheets during delamination.

Effect of restackinq temperature

[00128] The effect of temperature was investigated on three groups of samples, MgAI- GBPethanol, MgAI-GBP_anhyd and MgAI-PGBanhyd- Attempts to synthesise samples of MgAI- GBPethanol at elevated temperatures were unsuccessful. When attempted at 40 °C, restacking yielded only small amounts of nanohybrid, which turned out to be poorly crystalline and with significant MgAI-N0₃ impurity, whilst an attempt at 80 °C yielded a poorly crystalline product that contained no GBP at all, presumably due to decomposition to the lactam during restacking. Using FWHM values as a measure of crystallinity, Figure 12 displays the relationship between crystallinity and restacking temperature. Figure 13 shows the relationship between drug loading and restacking temperature on the samples studied.

Release behaviour and kinetic analysis

[00129] The release behaviour of the highest quality nanohybrid samples was investigated, specifically those with highest drug loading and highest crystallinity according to FWHM values from diffraction patterns. For both drugs, this was the sample synthesised anhydrously at -20 °C. The cumulative release profiles for both samples in each buffer solution at 37 °C are shown in Figure 14.

[00130] In all cases, release profiles typical of LDHs were seen, featuring a rapid initial release controlled primarily by dissolution of drug ions on and close to the surface of the particles, followed by more gradual release controlled by diffusion of drug ions and buffer ions though the interlayer regions of the particles.

[00131 ] At all pHs, initial release occurred much faster for the GBP containing nanohybrid, reaching 90 % release within the first 10 min to 20 min, whereas release from the PGB containing nanohybrid took 20 min to 60 min to reach 90 %.

Effects on drug stability

[00132] The rate of decomposition of both GBP and PGB in aqueous solution fits a pseudo first-order rate equation, with the cyclisation rate constant, k₀bs, providing a means of direct comparison of different conditions. As decomposition of these species occurs slowly at room temperature, decomposition studies were performed at 80 °C, as well as at room temperature. As with the release studies, the nanohybrids which showed the highest drug loading and crystallinity were chosen for decomposition studies, those synthesised anhydrously at -20 °C. Values of k₀bs were obtained by taking the gradient of plots of ln[drug] versus time, t, from the start of the decomposition experiment, as shown in the example in Figure 15.

[00133] The cyclisation rate constants are detailed in Table 3 and show that decomposition of both drugs is significantly retarded through intercalation into LDHs, both at ambient and elevated temperatures.

[00134] At 80 °C, decomposition of the pristine drugs in solution was significant over a two week period, whereas decomposition of the drugs within the intercalation compounds was only just measurable within experimental error, the cyclisation rate constant being reduced by a factor of 15.0 in the case of GBP, and 16.6 in the case of PGB.

[00135] Similarly, at 20 °C measurable decomposition of the pristine drugs occurred within a four week period, whereas decomposition of the drugs within the nanohybrids was not sufficiently significant to be measurable.

Table 3 - Drug cyclisation rate constants for the pristine drugs and nanohybrids. *Decomposition over the course of a four week period was too slow to calculate the cyclisation constant accurately, within experimental error.

[00136] While specific embodiments of the invention have been described herein for the purpose of reference and illustration, various modifications will be apparent to a person skilled in the art without departing from the scope of the invention as defined by the appended claims.

Claims

1 . A pharmaceutical composition comprising a plurality of layered double hydroxide nanoparticles and one or more pharmaceutically acceptable excipients, wherein the layered double hydroxide nanoparticles comprise layers of metal hydroxide and at least one anionic drug compound intercalated between the layers of metal hydroxide; and wherein the at least one anionic drug compound is an aqueously unstable anionic drug compound.

2. A pharmaceutical composition according to claim 1 , wherein the pharmaceutical composition is a solid dosage form, a dispersion, an emulsion or a cream.

3. A pharmaceutical composition according to claim 1 , wherein the pharmaceutical composition is a solid dosage form.

4. Layered double hydroxide nanoparticles comprising layers of metal hydroxide and at least one anionic drug compound intercalated between the layers of metal hydroxide; and wherein the at least one anionic drug compound is an aqueously unstable anionic drug compound.

5. A pharmaceutical composition according to any one of claims 1 to 3 or layered double hydroxide nanoparticles according to claim 4, wherein the layered double hydroxide nanoparticles have a mean particle size within the range of 20 to 1000 nm.

6. A pharmaceutical composition according to any one of claims 1 to 3 or layered double hydroxide nanoparticles according to claim 4, wherein the layered double hydroxide nanoparticles have a mean particle size within the range of 500 to 1000 nm.

7. A pharmaceutical composition according to any one of claims 1 to 3 or layered double hydroxide nanoparticles according to claim 4, wherein the layered double hydroxide nanoparticles have a mean particle size within the range of 600 to 800 nm.

8. A pharmaceutical composition according to any one of claims 1 to 3 or layered double hydroxide nanoparticles according to any one of claims 4 to 7, wherein the layered double hydroxide has the general formula (I), shown below:

wherein

M" is a divalent cation;

M^III is a trivalent cation; and

x is a number less than 1 .

9. A pharmaceutical composition according to claim 8 or layered double hydroxide nanoparticles according to claim 8, wherein M" is Mg or Ca and M'" is Al or Fe.

10. A pharmaceutical composition according to claim 8 or layered double hydroxide nanoparticles according to claim 8, wherein M" is Mg or Ca and M'" is Al.

1 1 . A pharmaceutical composition according to claim 8 or layered double hydroxide nanoparticles according to claim 8, wherein M" is Mg and M^III is Al.

12. A pharmaceutical composition according to any one of claims 8 to 1 1 or layered double hydroxide nanoparticles according to any one claims 8 to 1 1 , wherein the ratio of M" : M^III is 1 .5 : 1 to 5 : 1 .

13. A pharmaceutical composition according to any one of claims 8 to 12 or layered double hydroxide nanoparticles according to any one claims 8 to 12, wherein the ratio of M" : M'" is 1 .5 : 1 to 4 : 1 .

14. A pharmaceutical composition according to any one of claims 8 to 13 or layered double hydroxide nanoparticles according to any one claims 8 to 13, wherein the ratio of M" : M'" is 1 .5 : 1 to 2.5 : 1 .

15. A pharmaceutical composition according to any one of claims 8 to 14 or layered double hydroxide nanoparticles according to any one claims 8 to 14, wherein the ratio of M" : M^III is 2 : 1 .

16. A pharmaceutical composition according to any one of claims 1 to 3 or 5 to 15, or layered double hydroxide nanoparticles according to any one of claims 4 to 15, wherein the aqueously unstable anionic drug is a drug comprising at least one carboxy group.

17. A pharmaceutical composition according to any one of claims 1 to 3 or 5 to 15, or layered double hydroxide nanoparticles according to any one of claims 4 to 15, wherein the aqueously unstable anionic drug is a drug comprising at least one carboxy group and at least one amino group.

18. A pharmaceutical composition according to claim 17, or layered double hydroxide nanoparticles according to claim 17, wherein the at least one carboxy group and the at least one amino group are capable with reacting together in an aqueous environment to form a cyclic amide.

19. A pharmaceutical composition according to any one of claims 1 to 3 or 5 to 15, or layered double hydroxide nanoparticles according to any one of claims 4 to 15, wherein the aqueously unstable anionic drug is selected from Gabapentin, Pregabalin, L-Dopa, Carbidopa, Methyldopa, Baclofen, Lesogaberan, Phenibut, GABOB, Phaclofen, Saclofen or Vigabatrin.

20. A process for the preparation of layered hydroxide nanoparticles according to any one of claims 4 to 19, the process comprising:

a) delaminating particles of layered double hydroxide to form a dispersion of metal hydroxide layers;

b) mixing the dispersion of metal hydroxide layers formed in step a) with a solution of an aqueously unstable anionic drug compound in a pharmaceutically acceptable solvent to form nanoparticles comprising layers of metal hydroxide and the anionic drug compound intercalated between the layers of metal hydroxide;

c) collecting the nanoparticles formed in step b).

21 . A process according to claim 20, wherein, in step a), the layered double hydroxide has the formula (IV), shown below:

wherein

M" is a divalent cation;

M^III is a trivalent cation;

x is a number less than 1 ;

A is a displaceable anion;

n is an integer;

and wherein the compound is optionally hydrated with a stoichiometric or non- stoichiometric amount of water.

22. A process according to claim 21 , wherein M" is Mg or Ca and M'" is Al or Fe.

23. A process according to claim 21 , wherein M" is Mg or Ca and M^III is Al.

24. A process according to claim 21 , wherein M" is Mg and M^III is Al.

25. A process according to any one of claims 21 to 24, wherein the ratio of M":M^III is selected from; 1 .5:1 to 5:1 ; 1 .5:1 to 4:1 ; 1 .5:1 to 2.5:1 ; or 2:1 .

26. A process according to any one of claims 21 to 25, wherein A is selected from OH, F, CI, Br, I, S0₄, C0₃ or N0₃.

27. A process according to any one of claims 20 to 26, wherein, in step a), the LDH is delaminated by agitating (e.g. mixing and/or sonicating) the LDH in formamide.

28. A process according to any one of claims 20 to 27, wherein, in step b), the pharmaceutically acceptable solvent is selected from water, (1 -4C)alcohol, acetone, ethyl acetate, acetonitrile, methylethyl ketone or ethylene glycol.

29. A process according to any one of claims 20 to 28, wherein, in step b), the pharmaceutically acceptable solvent is ethanol.

30. A process according to any one of claims 20 to 29, wherein the aqueously unstable anionic drug is a drug comprising at least one carboxy group.

31 . A process according to any one of claims 20 to 29, wherein the aqueously unstable anionic drug is a drug comprising at least one carboxy group and at least one amino group.

32. A process according to any one of claims 20 to 31 , wherein the aqueously unstable anionic drug is selected from from Gabapentin, Pregabalin, L-Dopa, Carbidopa, Methyldopa, Baclofen, Lesogaberan, Phenibut, GABOB, Phaclofen, Saclofen or Vigabatrin.

33. A process according to any one of claims 20 to 32, wherein, in step c), the nanoparticles are collected by centrifugation or filtration.

34. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 3 or 5 to 19, wherein the process comprises mixing layered double hydroxide nanoparticles as defined in any one of claims 4 to 19 with one or more pharmaceutically acceptable excipients.

35. A process for preparing a pharmaceutical composition according to any one of claims 1 to 3 or 5 to 19, wherein the process comprises mixing layered double hydroxide nanoparticles prepared according to any one of claims 20 to 33 with one or more pharmaceutically acceptable excipients.

36. Layered double hydroxide nanoparticles prepared by a process according to any one of claims 20 to 33.

37. A pharmaceutical composition prepared by a process according to claim 34 or claim 35.

38. A method of stabilising an aqueously unstable anionic drug compound, the method comprising forming layered double hydroxide nanoparticles comprising the compounds as defined in any one of claims 4 to 19, optionally by the process defined in any one of claims 20 to 33.

39. A method of stabilising an aqueously unstable anionic drug compound, the method comprising forming a pharmaceutical composition comprising the compound as defined in any one of claims 1 to 3 or 5 to 19, optionally by the process according to claim 34 or 35.