WO2011048388A2

WO2011048388A2 - Oral pharmaceutical and nutraceutical compositions

Info

Publication number: WO2011048388A2
Application number: PCT/GB2010/001968
Authority: WO
Inventors: Ingvild Johanne Haug; Kurt Ingvar Draget
Original assignee: Probio Asa; Cockbain, Julian
Priority date: 2009-10-22
Filing date: 2010-10-22
Publication date: 2011-04-28
Also published as: WO2011048388A3; GB0918590D0

Abstract

The invention provides an oral pharmaceutical or nutraceutical composition comprising a pharmaceutical or nutraceutical agent disposed within a gelatin matrix, wherein said gelatin matrix further contains carrageenan at a content such that a 5mm thick sheet of said matrix would not dissolve within 4 hours at 37°C in an aqueous 0.1M HC1 solution containing 0.034 M NaC1.

Description

Oral pharmaceutical and nutraceutical compositions

This invention relates to oral pharmaceutical or

nutraceutical compositions, in particular to

compositions in capsule or gel tablet form wherein the capsule shell or gel matrix comprises gelatin.

Pharmaceuticals and nutraceuticals , e.g. marine oils and vitamins, are frequently administered in soft gelatin capsules. In this way the dose is safe and simple to swallow, of known content, and any unpleasant taste is masked. For many pharmaceuticals and nutraceuticals (hereinafter for simplicity both referred to as "drug substances"), the rapid porosification and breakdown of the gelatin shell in the gastric fluid is not

problematical. Some drug substances, however, are themselves broken down by the acidity of and the enzymes in gastric fluid and so, if they are to be administered orally, must be encased in an enteric coating, i.e. a coating resistant to gastric fluids. Enteric coating of tablets, for example with cellulose derivatives or synthetic polymers is a well-established technique.

A need remains however for gelatin capsules, which unlike tablets can contain a liquid loading, that remain intact during passage through the stomach and release the encapsulated drug substances further down the gastrointestinal tract where the environment is not so harsh .

A need also exists for enteric tablets that can be chewed on administration but still retain their ability to release the drug substance after stomach transit. We have surprisingly found that such "enteric" gelatin capsules and chewable enteric tablets can be produced using a gelatin and carrageenan matrix.

Viewed from one aspect therefore the invention provides an oral pharmaceutical or nutraceutical composition comprising a pharmaceutical or nutraceutical agent (a "drug substance") disposed within a gelatin matrix, e.g. the drug substance is encapsulated or encased by the gelatin matrix, wherein said gelatin matrix further contains carrageenan at a content such that a 5mm thick sheet of said matrix would not dissolve within 4 hours at 37°C in an aqueous 0.1M HCl solution containing 0.034 M NaCl, and preferably also pepsin at 6.6 U/ml.

The gel matrix is preferably such that, if doped with paracetamol and immersed as a 5mm thick sheet for 4 hours at 37 °C in an aqueous 0.1M HCl solution containing 0.034 M NaCl, and preferably also pepsin at 6.6 U/ml, no more than 30% of the paracetamol is released,

particularly no more than 20%, especially no more than 15%.

Gelatin is a material produced by partial hydrolysis of the protein collagen which is the major component of white fibrous connective tissue in all animals,

including fish. Gelatins differ in their gelling properties according to their source and their manner of production. One parameter frequently used to define gelatins is Bloom strength which is a measure of the rigidity of a gel formed under standard conditions: the higher the Bloom strength, the more rigid the gel.

Mammalian gelatins are capable of having high Bloom strengths and, at Bloom strengths of 150-200, are the gelatins most commonly used for soft (i.e. flexible) capsules for drug substances. Warm water fish and avian gelatins can also be used in this regard. The Bloom strengths of cold water fish gelatins, on the other hand, are generally much lower and often are zero (i.e. no gel will form under the standard conditions) .

In the present invention, any gelatin which is capable, with carrageenan, of forming a gel at ambient

temperature (21°c) , may be used. Thus gelatins of any Bloom strength from zero upwards can be used, although preferably the Bloom strength is less than 250.

However, in general, with a lower Bloom strength

gelatin, a higher relative content of carrageenan or a higher relative content of iota carrageenan will be needed to ensure that the capsules can transit the stomach intact. While mammalian gelatins showed

particularly good results, it was found that mixtures of cold water fish gelatins, mammalian gelatins and warm water fish gelatins gave particularly good results, especially mammalian gelatins and cold water fish gelatins or of warm water fish gelatins and cold water fish gelatins. Thus it is especially preferred to use a mixture of a gelatin having a Bloom strength of 150 to 250 and a gelatin having a Bloom strength below 50, preferably zero. Such mixtures are preferably in a 5:1 to 1:1, especially 3:1 to 1.5:1, particularly 2.5:1 to 1.8:1 weight ratio.

The gelatin content in the gel matrix in the

compositions of the invention is conveniently 50 to 80% wt on a dry solids basis, preferably 65 to 75% wt, especially about 70% wt . On a total contents basis, the gelatin will preferably comprise 20 to 55% wt,

particularly 25 to 50% wt, especially 29 to 45% wt .

The matrix will preferably also contain a plasticizer, such as for example sorbitol or more preferably

glycerol. The use of plasticizers is conventional in the preparation of soft gelatin capsules. The plasticizer is conveniently present in the gel matrix at a content of up to 50% wt on a dry solids basis,

preferably 5 to 45% wt, especially 20 to 40% w . On a total contents basis, the plasticizer is preferably present at 5 to 30% wt, especially 12 to 25% wt, particularly 14 to 22% wt .

The other major component of the gel matrix, besides water, is carrageenan. Carrageenan is a polysaccharide that may be extracted from seaweed. Four main types are available commercially, lambda, kappa, iota and hybrid- carrageenan, which is a kappa/iota-mixture. The present invention is concerned particularly with kappa and iota carrageenans and mixtures thereof.

On a total contents basis, the gel matrix in the

compositions of the invention will preferably contain 0.05 to 1% wt of carrageenan, especially 0.1 to 0.6% wt, particularly 0.15 to 0.4% wt . However, the lower carrageenan contents should either be high in iota carragennan content or should be used with gelatins of Bloom strength 150 or above. Thus the relative

proportion of iota carrageenan in the carrageenan used may be up to 100% wt, preferably 5 to 100% wt, more preferably 25 to 100% wt, e.g. 25 to 80% wt . By

increasing the ratio of iota to kappa carrageenan and/or by increasing the content of Bloom strength 150 or higher gelatins, the gel matrix may be tailored to release the drug substance increasingly longer after stomach transit.

The use of iota carrageenan as a component of a gelatin matrix in pharmaceutical or nutraceutical compositions is new and forms a further aspect of the invention.

Viewed from this aspect the invention provides an oral pharmaceutical or nutraceutical composition comprising a pharmaceutical or nutraceutical agent disposed within a gelatin matrix, wherein said gelatin matrix further contains a carrageenan, characterised in that at least 25% wt, preferably at least 50% wt, especially at least 80% wt, of said carrageenan is iota carrageenan.

The gelatins, carrageenans, plasticisers , and drug substances used in the compositions of the invention are commercially available or may be produced as described in the literature.

The gel matrix of the compositions of the invention may optionally include flavours, aromas, colorants,

antioxidants, etc. as minor components. The dose units moreover may if desired be coated, e.g. with beeswax.

The gelling of carrageenans is generally promoted by the inclusion of group 1 or group 2 metal ions (see Imeson, Chapter 5 in Handbook of hydrocolloids, Ed. Phillips and Williams, Woodhead Publishing, Cambridge, 2000) for kappa and iota carrageenans respectively. In the

compositions of the invention, it is preferred to include physiologically tolerable such ions as salts with physiologically tolerable counterions, e.g. sodium, potassium or calcium salts. The metal ion concentration is preferably up to 60mM for group 1 and up to 250mM for group 2 metals, e.g. 1 to 50mM, particularly 10 to 40mM, especially 15 to 35mM. Quite surprisingly, we found that the use of group 1 metal ions, e.g. potassium ions, as gelling promoters for iota or hybrid carrageenan was also effective.

The gel matrix in the compositions of the invention, and dose units prepared from it, may be prepared by

conventional techniques, e.g. those used for the

preparation of gelatin solids and soft gelatin capsules. The filled capsules may be prepared by conventional techniques using conventional machinery. Thus for example the shell forming material (with the components in solution/dispersion/emulsion in water) in heated liquid form may be cast into flat ribbons. Pairs of ribbons may be placed between die rolls and dose units of the pharmaceutical /nutraceutical may be injected between the ribbons. On passing between the die rolls the ribbons are fused and the capsules cut out. Where the composition is in tablet form, the tablets may be produced by moulding, or extrusion and cutting, or by cutting a larger gelled mass into tablets.

If in capsule form, the compositions are preferably elongate, seamed soft gelatin capsules with the drug substance disposed in the capsule's central void.

Alternatively, but less preferably, the compositions may take the form of gel tablets with the drug substance dispersed within the gel matrix. In this format,

however, drug substance at the periphery of the matrix may be degraded by gastric fluid during stomach transit. Nonetheless, gel tablets have the advantage of being chewable and so more easily swallowed if large, e.g.

above lOOOmg, more especially 1500 to 5000mg. In the case where a large dose is required, the advantage of a single chewable dose unit may outweigh the relatively small loss of drug substance from the periphery of the chewed fragments during stomach transit. Chewable gel tablets moreover have the advantage that patient

compliance is greater for patients with a gag reaction to swallowing tablets or capsules intact, in particular juvenile or elderly patients. Gel tablets may take any desired form, e.g. spheres, ovoids, cylinders, etc.

The drug substance in the compositions of the invention may be any pharmaceutical or nutraceutical capable of uptake in the gastrointestinal tract following the stomach. Nutraceuticals , for example glycerides, i.e. marine oils such as cod liver oil, should preferably be used in conjunction with pharmaceutical agents.

Moreover, it may be a contrast agent or a drug, e.g. an antibiotic, which exerts its desired activity within the gastrointestinal tract and so need not be taken up from the gut. In general, it will be a substance which is acid-degradable or prone to lysis by proteolytic

enzymes. Examples of suitable drug substances for inclusion within the compositions of the invention include nausea-inducing drugs, stomach-irritating drugs, vitamins, hormones, statins, antibiotics (e.g.

antibacterials , antischistomals, antiprotozoans and antihelmitics) , anti-cancer agents, analgesics,

antiinflammatories and cardiovascular agents (e.g.

antihypertensives) . Particularly preferred examples include omeprazole, esomeprazole, lansoprazole,

pantoprazole, rabeprazole, leminoprazole, acetyl

salicylic acid, ibuprofen, ketoprofen, paracetamol, naproxen, erythromycin, carbencillium, emetine,

atabrine, diethylstilbestrol , iron salts, flufenamic acid, phenylbutazone, paracetamol, bephenium

hydroxynaphthoate, niclosamide, piperazine,

thiabendazole, dichlorophen, methenamine,

sulphasalazine, phthalylsulphthiazole, niridazoli, temazepam, diphenhydramine, Zolpidem, triazolam,

nitrazepam, testosterone, estradiol, progesterone, benzodiazepines, barbiturates, cyclosporine, insulin, calcitonin, dextromethorphan, pseudoephedrine,

phenylpropanolamine, bromocryptine, apomorphine,

selegiline, amitriptyline, dextroamphetamine,

phentermine, mazindol, compazine, chlorpromazine , perphenazine, fluoxetine, buspirone, clemastine,

chlorpheniramine, dexochlorpheniramine, aste izole, loratadine, simvastatin, lovastatin, fluvastatin, pravastatin, atorvastatin, rosuvastatin and folic acid. The use of paracetamol as the sole pharmaceutical agent is not preferred although it is used in the Examples below as a model system.

As mentioned above, the drug substance may be formulated with pharmaceutically acceptable carriers and

excipients. Conventional formulation aids may be used in this respect, e.g. solvents (for example water and lipids), dispersants, diluents, pH modifiers, viscosity modifiers, stabilisers, emulsifiers, antioxidants, etc. If desired, two or more drug substances may be included in the same dose units. Moreover, if desired, the drug substance may be in particulate form provided with a further release-delaying coating so as to prolong or delay drug release after stomach transit. The

preparation of sustained or delayed release

microparticles is a well known technique that may be used in this regard. In a further embodiment, the drug substance may be disposed within a liquid crystal or liquid crystal precursor, again to result in prolonged or delayed release. Suitable liquid crystal systems have been described in the patent publications of Camurus AB .

The drug substance will preferably be present within the dose units of the compositions of the invention at 10 to 100%, especially 25 to 100% of the recommended daily dose. Preferred statin contents per dose unit are about 5 to 100 mg, e.g. about 5, 10, 20, 40 or 80 mg for simvastatin, about 20, 40 or 60 mg for lovastatin, about 20, 40 or 80 mg for fluvastatin, about 10, 20, 40 or 80 mg for pravastatin, about 10, 20, 40 or 80 mg for atorvastatin, and about 5, 10, 20 or 40 mg for

rosuvastatin .

The dose units of the compositions of the invention will typically have a weight of 50 to 5000mg, particularly 100 to 2000mg, especially 200 to 1200mg. The invention will now be described further with

reference to the following non-limiting Examples and the accompanying drawings, in which:

Figures 1 to 7 are graphs showing the percentage of drug substance released over time from gelatin sheets

immersed in artificial gastric juice, optionally

followed by immersion in an artificial intestinal buffer

Figures 8 and 9 are graphs showing the delay time before detectable release of drug substance from gelatin sheets immersed in artificial gastric juice; and

Figure 10 is a graph showing the permeability to drug substance diffusion for gelatin sheets immersed in an artificial gastric juice.

The following materials are used in the Examples:

Bovine gelatin (MG) , Bloom strength 160 (Pharm. gelatin 160 Bloom type A/B, from Gelita AG

Cold water fish gelitin (CFG) , weight average molecular weight 121 kDa, poly dispersity index ( w/Mn) 1.4 (from Norland Products Inc.)

Warm water fish gelatin (VFG) , Bloom strength 200 (Fish skin gelatin GLF/F 20 from Lapi Gelatine SpA, Italy Na-Iota carrageen (ICG) from FMC Biopolymer

Na-Kappa carrageenan (KCG) , molecular weight 400 kDa (from FMC BioPolymer) (contains 91% kappa and 9% iota carrageenan)

Artificial gastric fluid (AGF) 0.1M HCl with 0.034M NaCl Artificial gastric fluid with pepsin (AGFP) as AGF with 6.6 U/mL pepsin (from Fluka BioChemika)

Artificial intestinal buffer (AIB) 136.9mM NaCl, 5.37mM KCl, 0.812mM gS0₄.7H₂0, 1.26mM CaCl₂, 0.337mM Na₂HP0₄, 0.441mM KH₂P0₄ and 4.17mM NaHC0₃ (pH 7.4) Example 1

Gelatin capsules

30 g bovine gelatin

14.8 g cold water fish gelatin

0.2 g kappa-carrageenan

20m KCl

21.6 g glycerol

ad lOOg water

The water, glycerol and kappa-carrageenan are mixed and heated to 90°C and stirred until the kappa- carrageenan has fully dissolved. The gelatins and the KCl are added, and the mixture is brought to 65-70°C and stirred until a homogeneous solution, free of solid particles, is formed.

Soft capsules are prepared in conventional fashion using this compositions for the shells and with a filling of 40 mg/capsule of rosuvastatin dissolved in an omega-3 ester (Omacor® from Pronova Biocare) .

Example 2 Gelatin tablets

To the gelatin composition of Example 1 is added 200mg paracetamol/mL . The composition is cast into 1.5mL moulds .

Example 3

Gelatin capsules Capsules are prepared as in Example 1 replacing the gelatins and carrageenan by 30g cold water fish gelatin and 0.2g iota carrageenan respectively.

Example 4

Drug release study

Sheets of gel, doped with paracetamol, were prepared using the components set out in Table 1 and water. These were immersed in artificial gastric fluid with or without pepsin (AGF and AGFP) for four hours and then optionally in artificial intestinal buffer (AIB) . The tests were performed at 37°C. The release of paracetamol from the sheets was measured and the results are shown in Figures 1 to 7. In Figure 1, the solid square, open circle, open square, cross, solid triangle and open triangle symbols respectively show the results for sheets nos. 1, 2, 3, 4, 5 and 6. In Figure 2, the solid diamond, solid square, open triangle and solid circle symbols respectively show the results for sheets nos. 7, 8, 9 and 10. In Figure 3, the open circle and open triangle symbols show results for sheet no. 4. In Figure 4, the open square, triangle and circle symbols

respectively show the results of sheets nos. 7, 11 and 12. Figures 5, 6 and 7, respectively are the results for sheets nos. 19, 20 and 21. As can be seen, with ICG, or with 0.2% KCG, paracetamol release in the stomach transit period (here approximated as four hours) was minimal, while release during the total gut transit period was essentially complete.

From Figure 1, it can be seen that the gastric juice resistance of a low Bloom strength gelatin plus kappa carrageenan based gel matrix is especially sensitive to the quantity of kappa carrageenan used. Thus where only a low Bloom strength gelatin is used, it is preferable to use a carrageenan high in iota carrageenan content or to use a relatively high kappa carrageenan content.

From Figure 4, it can be seen that mammalian gelatin alone, and combinations of warm and cold water fish gelatin with lowish levels of kappa carrageenan do not prevent full release of the drug substance before stomach transit is complete.

The delay before released paracetamol became measurable was also measured and the delay times for several sheets are shown in Figures 8 and 9. As can be seen, for gels containing relatively high concentrations of mammalian gelatin in particular, the inclusion of 0.2% wt of kappa carrageenan caused significant increase in the delay time .

The permeability of the gel matrix to diffusion of the drug substance, here paracetamol, was determined from the steepest slope of the release curve and for several sheets is shown in Figure 10. As can be seen, the permeability is significantly reduced when carrageenan is included. One sheet, sheet no. 15, showed almost negligible permeability in artificial gastric fluid.

Table 1

Sheet Gelatin Carrageenan Glycerol KCl CaCl,

(¾wt) (% t) (%wt) (mM) (mM)

1 30 CFG 0.2 KCG 15 20

2 30 CFG 0.2 ICG 15 20

3 30 CFG 0.3 KCG 15 20

4 30 BG 0.2 KCG 15 20

5 30 VFG 0 15 0

6 30 VFG 0.2 KCG 15 20

7 44.8 BG 0 21.6 0 44.8 BG 0.1 KCG 21.6 20

44.8 BG 0.2 KCG 21.6 20

44.8 BG 0.3 KCG 21.6 20

20 CFG 0.2 KCG 20 20

+ 24.8

VFG

20 CFG 0 20 0

+ 24.8

VFG

20 CFG 0.2 KCG 20 20

+ 20

VFG

20 BG + 0.2 KCG 20 20

20 VFG

30 BG 0.2 KCG 21.6 20

+14.8

CFG

20 CFG 0.2 KCG 15 20

+10 VFG

15 CFG 0.2 KCG 15 20

+ 15

VFG

15 CFG 0 15 20

+15 VFG

30 BG 0.3 ICG 20 20 +10 CFG

30 BG 0.2 ICG 20 20 +10 CFG

20 CFG 0.3 ICG 20 20 +20 VFG

Claims

Claims :

1. An oral pharmaceutical or nutraceutical composition comprising a pharmaceutical or nutraceutical agent disposed within a gelatin matrix, wherein said gelatin matrix further contains carrageenan at a content such that a 5mm thick sheet of said matrix would not dissolve within 4 hours at 37 °C in an aqueous 0.1M HCl solution containing 0.034 M NaCl.

2. A composition as claimed in claim 1 wherein said gelatin matrix contains carrageenan at a content such that a 5mm thick sheet of said matrix would not dissolve within 4 hours at 37°C in an aqueous 0.1M HCl solution containing 0.034 NaCl and 6.6 U/mL pepsin.

3. A composition as claimed in either of claims 1 and 2, wherein said pharmaceutical or nutraceutical agent is encapsulated or encased by said gelatin matrix.

4. An oral pharmaceutical or nutraceutical composition comprising a pharmaceutical or nutraceutical agent disposed within a gelatin matrix, wherein said gelatin matrix further contains a carrageenan, characterised in that at least 25% wt of said carrageenan is iota

carrageenan.

5. A composition as claimed in any one of claims 1 to 4 in capsule form.

6. A composition as claimed in any one of claims 1 to 4 in gel tablet form.

7. A composition as claimed in any one of claims 1 to

6 wherein said gelatin matrix comprises a gelatin having a Bloom strength below 50.

8. A composition as claimed in claim 7 wherein said gelatin matrix comprises a gelatin having a Bloom strength of zero.

9. A composition as claimed in any one of the

preceding claims containing a mixture of gelatin having a Bloom strength of 150 to 250 and gelatin having a Bloom strength below 50.

10. A composition as claimed in claim 9 wherein said gelatin having a Bloom strength of 150 to 250 and said gelatin having a Bloom strength below 50 are present in a weight ratio of 5:1 to 1:1.

11. A composition as claimed in any one of the

preceding claims wherein the gelatin content of said gelatin matrix is 50 to 80% wt on a dry solids basis.

12. A composition as claimed in any one of the

preceding claims wherein the carageenan content of said gelatin matrix is from 0.05 to 1% wt on a total contents basis .

13. A composition as claimed in any one of the

preceding claims wherein 25 to 80% wt of said carageenan is iota carageenan.

14. A composition as claimed in any one of the

preceding claims containing a pharmaceutical agent which is acid-degradable or lysable by proteolytic enzymes.

15. A composition as claimed in any one of the

preceding claims containing a statin.

16. A composition as claimed in any one of the

preceding claims for use in medicine.