WO2003094884A1

WO2003094884A1 - Derivatised particulate inhalation carriers

Info

Publication number: WO2003094884A1
Application number: PCT/GB2003/002044
Authority: WO
Inventors: Dima Al-Hadithi; Graham Buckton; Stephen Brocchini
Original assignee: School Of Pharmacy, University Of London
Priority date: 2002-05-10
Filing date: 2003-05-12
Publication date: 2003-11-20
Also published as: GB0210771D0; AU2003230020A1

Abstract

An inhalable composition comprising a particulate substrate having an average particle size of greater than 10 µm, comprising 5% or more of a derivatised carbohydrate compound, wherein the carbohydrate is derivatised at a hydroxyl, carboxylate or amine group with one or more groups individually selected from the group consisting of C1-24 alkyl, optionally substituted with one or more oxygen atoms in the carbon backbone, C2-24 acyl, C2-24 alkenyl and C6-32 aryl, any of which may be substituted with a halogen and/or a silicon atom; and a drug having a log P, where P is the partition coefficient between water and octanol, of greater than 1. A preferred example comprises particles of acetylated lactose with beclomethasone dipropionate. The compositions allow high drug levels in the composition and are suitable for delivery of drug to the lung.

Description

DERIVATISED PARTICULATE INHALATION CARRIERS Field of Invention

The present invention is concerned with the field of drug delivery via inhalation. Background of Invention

The delivery of drugs to the lung is becoming increasingly common, both to treat diseases of the lung, such as asthma, and as a means of systemic delivery. Dry powder inhalers are becoming ever more popular, especially since the removal of CFC based metered dose inhalers as a means of therapy. Dry powder inhalers can consist of the drug alone, in micronised form so as to allow inhalation into the deep lung, or of the micronised drug mixed with a larger carrier particle. Formulations based on drug only suffer from difficulties in dosing of small quantities of fine particles, as these tend to have very poor flow properties (Byron, P.R., 1986. Some future perspectives for unit dose inhalation aerosols. Drug Dev. Ind. Pharm., 12, 993-1015.). This is because it is generally necessary to have particles of 1-5 urn in order to achieve deep lung deposition (Neumann, S.P. and Clarke, S.W., 1983, Therapeutic Aerosols, I. Physical and practical considerations. Thorax 38, 881-886.). For drugs with carrier particles, it is necessary to first mix the fine drug so that it attaches to the large carrier, thus enabling flow and accurate dosing. Subsequently, during breath actuation of an inhaler, it is necessary for the drug particles to detach from the carrier surface, allowing the fine particles to be inhaled and the carrier to be deposited on the throat and passed down the gastrointestinal tract.

Most dry powder inhaler (DPI) devices that have a carrier particle utilise lactose, possibly with a mixture of more than one size fraction to give optimum results (Zeng et al (Zeng,X.M., Pandhal.K.H., Martin.G.P., Int. J. Pharma, vol. 197, 41-52, 2000). Studies on the influence of lactose carrier on the content homogeneity and dispersibility of beclomethasone dipropionate from dry powder aerosols have shown that addition of fines, and the order in which coarse lactose, fine lactose and drug are mixed will influence the drug deposition. A few alternatives to lactose alone have been considered, for example the use of a ternary component deposited on the lactose surface in order to fill void spaces has been proposed (Ganderton.D., Kassem,N.M., 1992. Dry powder inhaler. In Ganderton, D., (ed) Advances in Pharmaceutical Sciences. Academic Press, London pp 165-191).

Leucine has been suggested as a suitable ternary component and has been found to give favourable deposition compared to lactose alone (Staniforth,J.N., 1996. Improvement in dry powder inhaler performance: surface passivation effects. Proc. Drug Delivery Lungs (London) VII, 86-89). Kawashima et al (Kawashima,Y., Serigano.T., Hino,T., Yamamoto.H., Takeuchi.H., 1998a; Design of inhalation dry powder of pranlukast hydrate to improve dispersibility by the surface modification with anhydrous silic acid (AEROSIL 200). Int. J. Pharm., 173, 243-251) utilised colloidal silica as a ternary component in order to make the drug surface have a more hydrophilic nature (particles were either mixed with colloidal silica or lyophilised or spray dried).

Tee et al (Tee.S.K., Marriott.C., Zeng.X.M. and Martin, G. P., 2000, The use of different sugars as fine and coarse carriers for aerosolised salbutamol sulphate. Int. J. Pharm., 208, 111-123.) have considered the use of different carbohydrates (mannitol and sorbitol as well as lactose) and they concluded that the carriers were all ineffective unless fine particles were added (for the delivery of salbutamol sulphate). Furthermore, Tee et al (2000) state that the nature of the small particle is not significant, but rather the presence of small particles as an addition to the large carrier particles are the key to achieving effective drug release. Kawashima et al (Kawashima.Y., Serigano.T., Hino.T., Yamamoto.H.,

Takeuchi.H., 1998b. Effect of surface morphology of carrier lactose on dry powder inhalation property of pranlukast hydrate. Int. J. Pharm., 172, 179-188.) utilised different physical forms of lactose as carrier particles and concluded that the surface roughness was key to drug release from the carrier, it was concluded that smooth surfaces allowed more drug to be released. Changes in surface smoothness and elongation ratio of lactose crystals were found to improve deposition of salbutamol sulphate by Zeng et al (Zeng.X.M., MartinG.P., Marriott.C, Pritchard,J., 2000b. The influence of carrier morphology on drug delivery by dry powder inhalers. Int. J. Pharm., 200, 93-106.). WO01/05429 describes a method of preparation of carriers for inhalation powders, consisting of particles with a smooth surface. The method affords smooth particles starting from an industrial powder consisting of rough particles, without substantially altering their average size nor their geometry. The carrier is prepared using a high-speed mixer-granulator, an apparatus designed and normally used for agglomerating solid particles and not for smoothing them individually.

WO96/23485 discloses a powder for use in a dry powder inhaler, including active particles and carrier particles for carrying the active particles. The powder further includes additive material on the surfaces of the carrier particles to promote the release of the active particles from the carrier particles on actuation of the inhaler. The additive materials are identified as amino acids, lecithin and magnesium stearate.

A problem with the prior art is that there has been little attempt to marry a carrier to a particular drug. In particular, there has been no link made between the use of carriers which differ chemically and their performance with different classes of drugs. The present invention provides modified carrier particles which improve the delivery of particular classes of drugs. In particular, the present invention provides carrier particles which improve the delivery of hydrophobic drugs, such as steroidal drugs.

Summary of Invention

According to a first aspect of the present invention, there is provided an inhalable composition comprising a particulate substrate having an average particle size of greater than 10 μm, comprising 5% or more of a derivatised carbohydrate compound, wherein the carbohydrate is derivatised at a hydroxyl, carboxylate or amine group with one or more group selected from C₁.₂ alkyl, optionally substituted with one or more oxygen atoms in the carbon backbone, C₂-₂₄ acyl, C₂-₂ alkenyl and C₆_₃₂ aryl, any of which may be substituted with a halogen and/or a silicon atom; and a drug having a log P, where P is the partition coefficient between water and octanol, of greater than 1.

According to a second aspect of the present invention, there is provided a use of a particulate substrate composition having an average particle size of greater than 10 μm, comprising 5% or more of a derivatised carbohydrate compound, wherein the carbohydrate is derivatised at a hydroxyl, carboxylate or amine group with one or more groups individually selected from the group consisting of C₁.₂₄ alkyl, optionally substituted with one or more oxygen atoms in the carbon backbone, C₂-₂₄ acyl, C₂.₂ alkenyl and C₆.₃₂ aryl, any of which may be substituted with a halogen and/or a silicon atom, for carrying a drug having a logP greater than 1 for delivery by inhalation. According to a third aspect of the present invention there is provided a method of making an inhalable composition, by mixing substantially dry substrate particles having an average particle size of greater than 10 μm, comprising 5% or more of a derivatised carbohydrate compound, wherein the carbohydrate is derivatised at a hydroxyl, carboxylate or amine group with one or more groups individually selected from the group consisting of C₁.₂ alkyl, optionally substituted with one or more oxygen atoms in the carbon backbone, C₂-₂₄ acyl, C₂-₂₄ alkenyl and C₆.₃₂ aryl, any of which may be substituted with a halogen and/or a silicon atom; with a particulate drug having a log P, where P is the partition coefficient between water and octanol of greater than 1 , whereby drug particles are deposited on the surface of the substrate particles. Preferred Embodiments

Generally, the particulate substrate of the present invention is substantially crystalline. The particulate substrate, hereinafter referred to as a carrier particle, may be uniform in dimensions, but non-uniform carrier particles may be produced. The diameter of the carrier particles is generally in the range of 10 μm to 500 μm, preferably 20 μm to 100 μm, most preferably 45 μm to 90 μm. The carrier particle should not have a diameter of less than 10 μm otherwise inhalation of the carrier particle into the deep lung may occur. Although this is not harmful, it is undesirable. Preferably, the composition contains substantially less than 5%, more preferably less than 2%, most preferably less than 0.5 % by weight of particles having a diameter of less than 10 μm.

Preferably the particulate substrate comprises greater than 10% by weight of the derivatised carbohydrate, more preferably greater than 20%, most preferably in the range of 30 to 100% by weight of the derivatised carbohydrate.

The carbohydrate is generally a pharmaceutically inert carbohydrate material. For example, mono-, di-, tri- and polysaccharides are preferred materials for the basis of the carrier particles in the present invention.

Preferably the carbohydrate is selected from the group consisting of lactose, sucrose, glucose, galactose, fructose, trehalose, raffinose and mixtures and diastereoisomers thereof. In a particularly preferred embodiment, lactose, α- D-glucose and β-D-glucose are used as the basis for the derivatised carbohydrate. In another preferred aspect the carbohydrate is a polysaccharide such as cellulose. Where the substrates are based on saccharides, they are preferably derivatised at the free hydroxyl groups. The substrate may be partially or fully derivatised, ie some or all of the sites of possible derivatisation may be derivatised.

In particularly preferred embodiments, the saccharides are fully derivatised, i.e. all free hydroxyl groups are substituted. Preferably, where a saccharide has a degree of substitution greater than 1 , all derivatising groups are the same.

The derivatising groups are preferably selected from ₂ alkyl optionally substituted with 1 or more oxygen atoms, C₂-₁₂ acyl, C₂- ₂ alkenyl and C₆.₁₈ aryl.

More preferably, the derivatising group is selected from C₂.₈ acyl, most preferably C₂„₄ acyl. In a particularly preferred embodiment, the derivatising group is C₂.₂₄ alkanoyl, preferably C₂.₁₂ alkanoyl, more preferably C₂.₄alkanoyl, in particular, acetyl. Alternatively, the derivatising group is preferably a polyalkylene oxide, preferably selected from polyethylene oxide, polypropylene oxide and polybutylene oxide. The derivatising groups have the effect of producing a relatively hydrophobic carrier particle (compared to a particle formed of the non-derivatised carbohydrate).

Particularly preferred carrier particles include lactose octaacetate, α-D- glucose pentaacetate and β-D-glucose pentaacetate. These substrates are commercially available through Pfanstiehl, UK, and their structures are represented below. Another class of carrier particles comprise acetate.

α-D-glucose pentaacetate β-D-glucose pentaacetate

lactose octaacetate

The inhalable composition further comprises a drug, which may be delivered by inhalation. Generally the drug is deposited, preferably coated onto the surface of the carrier particle. This may be achieved by any suitable means, but generally involves mixing of particulate solids with or preferably without the presence of moisture and in a continuous phase of gas with mixing.

The drug is preferably provided for the deposition step in particulate form. The particle size should be selected based on the requirement for the particles to be respirable. Preferably the particles are in the size range 1 to 10 μm, more preferably 2 to 5 μm. The particles may be produced by any suitable means including spray or freeze-drying of solutions, precipitation grinding or other granulating, conveniently the drug is in micronised form.

The weight proportion of drug to carrier particles is generally in the range of 1:1 to 1 :100, preferably 1:3 to 1:50 although any mixture may be provided which allows delivery of a predetermined dosage of drug to the subject via inhalation of the carrier particles.

In a particularly preferred embodiment, between 1 and 5% w/w pharmaceutically active agent is dry mixed with the carrier particles, most preferably about 4%. Blending may be effected by any means allowing the substrate and drug particles to contact one another whereby the drug is deposited on the substrate particles. For example, blending takes place in a Turbula mixer. Blending generally takes place for period of between 1 minute and 1 hour, preferably about 30 minutes.

The drug is suitable for delivery by inhalation to a target subject. An exemplary but non-limiting list of suitable drugs includes, steroids and their salts, hydrates, solvates and esters, such as budesonide, testosterone, progesterone, estrogen, flunisolide, triamcinolone, beclomethasone, betamethasone, dexamethasone, fluticasone, methylprednisolone, prednisone and hydrocortisone, and pharmaceutically acceptable salts, hydrates, solvates and esters thereof. These may be deposited on the carrier particle surface and subsequently delivered to a subject.

The drug preferably has a log P value in the range 1 to 10, preferably 1 to 4, most preferably 1.5 to 4.

The partition coefficient of the drug is measured by the method described by W.M Meylon and P.H. Howard, J. Pharmaceutical Sciences, Vol. 84, 1 , P83-92, 1995. Alternatively the values may be predicted from the chemical structures using dedicated software, for instance available on a number of web-sites such as http://esc.syrres.com/interkow/kowdemo.htm.

The logP values for drugs for which the present invention has utility are given in the table below.

Log P values (OCTANOL-WATER partition coefficient)

As a comparison the logP values for terbutaline and salbutamol are less than 1 and the invention is not of use for such drugs.

The composition of the present invention may additionally comprise additives, such as diluents, solvents, anti-oxidants, surfactants and the like. These can be incorporated within the derivatised carbohydrate carrier particles or be blended into the composition.

The following examples illustrate the invention.

Example 1

Preparation of the drug-carrier blends The carriers (lactose octaacetate, lactose monohydrate, α-D-glucose pentaacetate and β-D-glucose pentaacetate) are sieved to obtain a particle size fraction of 45 to 90 μm using British Standard brass sieves. They are then blended with either micronised salbutamol sulphate (SS-reference) or micronised beclomethasone dipropionate (BDP - invention) (4% w/w). This was done in a Turbula mixer at 42 rpm for 30 minutes. It should be noted that salbutamol sulphate is a hydrophilic drug and is used as a comparative example to a carrier loaded with beclomethasone dipropionate.

The content uniformity of the formulations were assessed by UV analysis of ten 10mg samples selected from various parts of the powder bed. The salbutamol samples were dissolved in 100mL 0.1M hydrochloric acid for salbutamol blends or methanol-water mixture (70:30) for beclomethasone blends. The drug content was calculated (% w/w) and the coefficient of variation was used to describe the uniformity of the mix. Blends with coefficients of variation less than 5% were taken as uniform. Delivered through a Clickhaler (Innovata Biomed Ltd), the inhalation characteristics of the blends were assessed using a Twin impinger (European Pharmacopoeia). Each assessment comprised 10 actuations. The two stages of the glass apparatus are designed such that at airflow of 60 L/min through the system, the effective (mean) aerodynamic particle cut-off diameter of the lower impinger (stage 2) is 6.4 μm. The drug deposition profile was determined by UV spectrophotometry at 276 nm and 238 nm for salbutamol sulphate and beclomethasone dipropionate, respectively. Formulations containing lactose octaacetate and salbutamol sulphate were analysed by fluorimetry ( λ_HX 276nm and λ_EM 303nm). The aerosol performance parameters measured were as follows:

Emitted dose = the amount of drug in stages one and two (mg)

Respirable dose = the amount of drug in stage two (mg)

Fine particle fraction (FPF) the respirable dose as a percentage of the emitted dose

Salbutamol sulphate deposition

BDP deposition

This example clearly shows that BDP loaded on lactose octaacetate substrate exhibits substantially higher fine particle fraction values than the BDP loaded onto lactose monohydrate. Additionally, the hydrophobic drug BDP, when loaded on glucose pentaacetate, exhibits a markedly higher fine particle fraction value than the hydrophilic drug, salbutamol sulphate, when loaded on glucose pentaacetate. These results are unexpected as one would expect a hydrophobic carrier to be a poor substrate for a hydrophobic drug from a the point of view of its ability to release the drug. In fact, the present invention works counter-intuitively, in that hydrophobic drugs exhibit better release characteristics from a hydrophobic carrier than does a hydrophillic drug from the same carrier.

Example 2 - Cellulose acetate carrier

Cellulose acetate having a 39.8% acetyl content and an average molecular weight of 30,000 was sieved to get a size fraction of 45-90 μm. The particles were then blended with micronised BDP and, for comparison, salbutamol sulphate using the general methodology of Example 1. The content uniformity was measured by UV and HPLC for salbutamol and BDP blends, respectively. Aerosol performance parameters were assessed using the same techniques as in Example 1 except that HPLC was used to quantify BDP drug content of solutions. The results are shown in the table below.

These results show that, for cellulose-based carrier particles also, acetylated materials are good carriers for a hydrophobic drug, giving a high volume for the respirable dose and fine particle fraction.

Claims

1. An inhalable composition comprising a particulate substrate having an average particle size of greater than 10 μm, comprising 5% or more of a derivatised carbohydrate compound, wherein the carbohydrate is derivatised at a hydroxyl, carboxylate or amine group with one or more groups selected from the group consisting of C₁-₂₄ alkyl, optionally substituted with one or more oxygen atoms in the carbon backbone, C₂.₂₄ acyl, C₂„₂₄ alkenyl and C₆.₃₂ aryl, any of which may be substituted with a halogen and/or a silicon atom; and on the surface of the particulate substrate a drug having a log P, where P is the partition coefficient between water and octanol of greater than 1.

2. A composition according to claim 1 , wherein the diameter of the particulate substrate is in the range of 10 μm to 500 μm, preferably 20 μm to 100 μm, most preferably 45 μm to 90 μm.

3. A composition according to claim 1 or claim 2, wherein the carbohydrate is selected from mono-, di-, tri- and polysaccharides.

4. A composition according to any preceding claim, wherein the carbohydrate is selected from the group consisting of lactose, sucrose, glucose, galactose, fructose, trehalose, raffinose and mixtures and diastereoisomers thereof, and cellulose, preferably lactose and glucose.

5. A composition according to any preceding claim, wherein in the derivatised carbohydrate the carbohydrate is partially or fully derivatised at the hexose hydroxyl groups, preferably all free hydroxyl groups are substituted.

6. A composition according to any preceding claim, wherein the derivatising group is C₂.₂₄ alkanoyl, preferably C₂.₁₂ alkanoyl, more preferably C₂.₄ alkanoyl, in particular, acetyl.

7. A composition according to any preceding claim wherein the particulate substrate consists of the derivatised carbohydrate.

8. A composition according to any preceding claim, wherein the derivatised carbohydrate is selected from lactose octaacetate, α-D-glucose pentaacetate and β-D-glucose pentaacetate.

9. A composition according to any of claims 1 to 7 in which the derivatised carbohydrate is cellulose acetate.

10. A composition according to any preceding claim wherein the drug is selected from steroids and their salts, hydrates, solvates and esters.

11. A composition according to any preceding claim, wherein the drug has a log P value in the range of 1 to 10, preferably 1 to 4, most preferably 1.5 to 4.

12. A composition according to any preceding claim wherein the drug is selected from the group consisting of budesonide, testosterone, progesterone, estrogen, flunisolide, triamcinolone, beclomethasone, betamethasone, dexamethasone, fluticasone, methylprednisolone, prednisone and hydrocortisone, and pharmaceutically acceptable salts, hydrates, solvates and esters thereof, preferably beclomethasone dipropionate.

13. Use of a particulate substrate composition having an average particle size of greater than 10 μm, comprising 5% or more of a derivatised carbohydrate compound, wherein the carbohydrate is derivatised at a hydroxyl, carboxylate or amine group with one or more groups individually selected from the group consisting of C.,_₂₄ alkyl, optionally substituted with one or more oxygen atoms in the carbon backbone, C₂.₂ acyl, C₂.₂₄ alkenyl and C₆.₃₂ aryl, any of which may be substituted with a halogen and/or a silicon atom, for carrying a drug having a logP, where P is the partition coefficient between water and octanol, of greater than 1 for delivery by inhalation.

14. A method of making an inhalable composition, by mixing substantially dry substrate particles having an average particle size of greater than

10 μm, comprising 5% or more of a derivatised carbohydrate compound, wherein the carbohydrate is derivatised at a hydroxyl, carboxylate or amine group with one or more groups individually selected from the group consisting of C₁.₂₄ alkyl, optionally substituted with one or more oxygen atoms in the carbon backbone, C₂.₂₄ acyl, C₂.₂₄ alkenyl and C₆.₃₂ aryl, any of which may be substituted with a halogen and/or a silicon atom; with a particulate drug having a log P, where P is the partition coefficient between water and octanol of greater than 1 , whereby drug particles are deposited on the surface of the substrate particles.

15. A method according to claim 14 in which the drug is in particulate form with particle size in the range 1 to 10 μm, preferably 2 to 5 μm.