HK1075008A - Ibuprofen solution for hard shell capsules - Google Patents

Description

Ibuprofen solution for hard shell capsules

The present invention relates to pharmaceutically acceptable stable compositions for liquid filling hard shell capsules, which are preferably clear transparent, hard shell capsules containing the same, and a process for preparing such hard shell capsules, wherein the hard capsule shells are preferably clear transparent.

Ibuprofen (2- (4-isobutylphenyl) propionic acid, a drug with anti-inflammatory and analgesic activity, is used in the treatment of rheumatoid arthritis or other arthritic conditions, soft tissue rheumatism and gout.

In general, a drug suitable for combating acute pain needs to exhibit its effect rapidly, which can only be achieved by a rapid release of the active ingredient and good bioavailability.

Although ibuprofen is soluble in certain physiologically compatible solvents, precipitation occurs immediately upon addition of a small amount of water or introduction into an aqueous medium such as artificial gastric juice. If such a solution is taken orally to the stomach, the ibuprofen precipitates and cannot be re-absorbed.

U.S. Pat. No. 4,690,823 describes a soft gelatin capsule containing 15 to 30 parts by weight of ibuprofen dissolved in 70 to 85 parts by weight of polyoxyethylene-polyoxypropylene polymer or in a mixture containing 30 to 76 parts by weight of polyalkylene glycol and 7 to 40 parts by weight of surfactant. The patent describes that such capsules release the active ingredient very rapidly and are highly bioavailable. The active ingredient does not re-precipitate when subjected to an aqueous medium such as artificial gastric juice.

U.S. Pat. No. 4,690,823 further discloses that ibuprofen can be readily dissolved in polyoxyethylene-polyoxypropylene polymers or mixtures containing polyalkylene glycols and surfactants at temperatures of 45 deg.C to 65 deg.C and remains in solution until cooled to room temperature. When this solution is introduced into an aqueous medium, more particularly into artificial gastric juice, no precipitation occurs, so that ibuprofen can be rapidly and completely absorbed from the solution. The amount of ibuprofen used is up to 40% ibuprofen. Without the addition of an alkaline hydroxide. Polyoxyethylene- (40) [ and- (60) ] -trihydroxystearin was used as a surfactant in the examples.

U.S. Pat. No. 6,096,338 discloses a carrier system for hydrophobic drugs comprising a) an digestible oil, b) a pharmaceutically acceptable surfactant, wherein the surfactant comprises a hydrophilic surfactant component which substantially inhibits in vivo lipolysis of the digestible oil, and a lipophilic surfactant component which at least substantially reduces the inhibitory effect of the hydrophilic surfactant component. This patent discloses Miglyol^*812 is generally used as the preferred medium chain fatty acid triglyceride. Any pharmaceutically acceptable hydrophilic surfactant may be used. In many instances, Cremophore^*EL and cremophone^*RH40 is mentioned as an example of a hydrophilic surfactant.

Us patent 5,141,961 relates to a process for dissolving at least one poorly soluble pharmaceutical active ingredient in a mixture comprising polyethylene glycol and polyvinylpyrrolidone.

WO 96/19202 discloses a solvent system for enhancing the solubility of ibuprofen which contains from 1% to 10% by weight of ammonium acetate as a solubilizing agent for ibuprofen. The solvent system is a pharmaceutically acceptable highly concentrated clear microcolloidal solution of ibuprofen suitable for filling soft gels for oral administration comprising, based on the weight of the clear solution, at least about 25% by weight ibuprofen, from about 1% to about 10% by weight water, and from about 50% to about 74% by weight of at least one pharmaceutically acceptable solubilizing substance selected from the group consisting of nonionic polyoxyethylated surfactants having a hydrophilic-lipophilic balance constant of from 8 to 25, alone or in combination with a solvent system having a solubility parameter of from 8.0 to 15.0.

WO 92/20334 discloses the use of sodium S (-)2- (4-isobutylphenyl) propionate (the sodium salt of S (+) ibuprofen) in a pharmaceutically acceptable composition for the treatment of inflammation, pain and fever. The liquid fill composition suitably contains a) 10-80% of sodium S (-)2- (4-isobutylphenyl) propionate and b) 20-90% of a fatty acid ester excipient containing one or more polyhydroxy esters and triglycerides of natural vegetable oil fatty acids.

WO 00/30619 discloses a self-emulsifying ibuprofen solution and soft gelatin capsules using this solution. The solution provides self-emulsifying ibuprofen formulations containing a polyoxyethylene castor oil derivative and ibuprofen which improve the stability, concentration and bioavailability of ibuprofen which is practically insoluble in water. The polyoxyethylene castor oil derivative is present in an amount of about 30% to about 35% by weight.

In a preferred embodiment of the polyoxyethylated castor oil derivatives of WO 00/30619, the hydrophobic component represents approximately 83% of the total mixture, the main component of which is glycerol polyethylene glycol ricinoleate. The hydrophilic component (about 17%) consists of polyethylene glycol and ethoxylated glycerol.

In another preferred embodiment of the polyoxyethylated castor oil derivatives of WO 00/30619, the hydrophobic component is about 75% of the total mixture. The hydrophobic component mainly contains fatty acid ester of ethylene glycol polyethylene glycol (PEG) and fatty acid ester of PEG. The hydrophilic portion (approximately 25%) consists of polyethylene glycol and ethoxylated glycerol.

The ibuprofen is present in the formulation in an amount of about 33% to 38% by weight. In order to prevent the recrystallization of ibuprofen from the solution after cooling, WO 00/30619 suggests increasing and stabilizing the concentration of the solution at room temperature by adding complexing agents such as soluble polyvinylpyrrolidone (PVP).

The drug delivery system of WO 00/30619 may be a standard gelatin capsule having two parts, but more preferably is a soft gelatin capsule having one part which is sealed with a gelatin capsule.

EP 0413171B 1 discloses a medicament for the treatment of severe pain symptoms consisting of a soft gelatin capsule containing: 30-50 parts by weight of ibuprofen and 1.5-4 parts by weight of codeine and/or its physiologically compatible salts, which are partly dissolved and partly suspended in 68.5-46 parts by weight of polyoxyethylene-polyoxypropylene-diol or in a mixture comprising 30-76 parts by weight of polyoxyethylene-polyoxypropylene-diol or polyethylene or polypropylene glycol and 7-40 parts by weight of a physiologically compatible surfactant.

US-A-5,360,615 discloses A solvent system for enhancing the solubility of an encapsulated drug, in particular an acidic medicament such as ibuprofen, to obtain A highly concentrated solution for soft gel filling, comprising 10-80% polyethylene glycol, A solubility enhancing effective amount of hydroxide or hydrogen ions and 1-20% by weight of water. Preferably, 0.2-1.0 molar equivalents of hydroxide ion are used per molar equivalent of acid in the acidic medicament.

The ibuprofen solutions disclosed in U.S. Pat. No. 5,360,615, suitable for filling soft gels or two-part capsules or for tablet formation, contain 40-80% by weight ibuprofen, 0.1-1.5 moles of hydroxide ion per mole ibuprofen, 1-20% by weight water, and 4-12% by weight glycerol or propylene glycol in polyethylene glycol solution, with the hydroxide ion more preferably being 0.2-0.5 moles of hydroxide ion per mole ibuprofen.

It is an object of the present invention to provide a pharmaceutically acceptable clear solution for filling hard capsules which overcomes the above-mentioned drawbacks of the prior art. Such filled capsules should be useful as medicaments, i.e. can be conveniently taken and can also contain ibuprofen in high concentration in the carrier, which is simple to prepare and can rapidly exhibit high activity. Such solutions for filling hard shell capsules should be shown to improve the solubility and bioavailability of ibuprofen.

Hard shell capsules are two-part, shelled pharmaceutical capsules, the shell of which is generally known to be composed of a film-forming material or composition. Suitable film-forming materials may be hydrophilic polymers, preferably gelatin. Other suitable capsule shell materials include starch, modified starches such as hydroxypropylated hydroxyethylated starch, casein, chitosan, soy protein, safflower protein, alginates, gelling gums (gellan), carrageenan, xanthan gum, pullulan, phtalylated gelatin, succinylated gelatin, cellulose phthalate-acetate, polyvinyl alcohol, polyvinyl acetate, hydroxypropylmethyl cellulose, polyvinyl acetate-phthalate, vinyl acrylate or methacrylate, or a polymerization product of a mixture thereof. The capsule shell material may also contain 0-40% of a pharmaceutically acceptable plasticizer, based on the weight of the hydrophilic polymer. Plasticizers which may be used are selected from the group consisting of polyethylene glycol, glycerol, sorbitol, dioctyl-sodium sulfosuccinate, triethyl citrate, tributyl citrate, 1, 2-propylene glycol, mono-, di-or triacetates of glycerol or mixtures thereof.

In addition, the capsule shell material may also contain 0-10% by weight of the hydrophilic polymer of a pharmaceutically acceptable lubricant. The lubricant may be selected from the group consisting of aluminum stearate, calcium stearate, magnesium stearate, tin stearate, talc, sodium lauryl sulfate, lecithin, mineral oil, stearic acid or silicone or mixtures thereof.

In addition, the capsule shell material may also contain 0-10% by weight of the hydrophilic polymer of a pharmaceutically acceptable colorant. The colorant may be selected from the group consisting of azoquinophthalone (azo-quinophthalone-), triphenylmethane, xanthene dyes (xanthene-dyes), iron oxides or hydroxides, titanium dioxide or natural dyes or mixtures thereof. Further suitable colorants are sunset yellow (sunset yellow), alloxanthin (alloura red), amaranth, carmine, azogeranine, tartrazine, brilliant black, canthaxanthin, patent blue, fast green, brilliant blue, acid green, erythrosine, quinoline yellow, indigo, acid yellow or carbon black.

In addition, the capsule shell material may contain 0-95% by weight of the hydrophilic polymer of additives. The additive may be selected from sunflower protein, soy protein, cottonseed protein, peanut protein, rapeseed protein, lactose, gum arabic, acrylates or methacrylates, cellulose acetyl phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxymethyl cellulose, polyvinylpyrrolidone, shellac, bentonite, polyvinyl acetate phthalate, phthalated gelatin, succinylated gelatin, agar, hydroxyalkyl starch or mixtures thereof.

The solid pharmaceutical dosage form according to the invention may further comprise a coating selected from cellacephate, polyvinyl acetate phthalate, methacrylic acid polymers, hypromellose phthalate, hydroxyalkyl methyl cellulose phthalate or mixtures thereof.

Preferably, the film-forming composition is suitable for making clear transparent hard capsules by conventional dip molding processes on high speed production equipment.

Accordingly, the present invention provides a pharmaceutically acceptable solution for filling hard shell capsules, preferably clear transparent and comprising, based on the total weight of the solution, a)35 to 75% by weight ibuprofen, b)1 to 10% by weight alkali hydroxide, and c)15 to 55% by weight of an emulsifier selected from polyoxyethylene alkyl ethers, medium chain triglycerides, propylene glycol esters, glycerol esters, sorbitan esters, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, castor oil or mixtures thereof, wherein the molar ratio between alkali hydroxide b) and ibuprofen a) is 0.1 to 0.5.

The invention further provides hard shell capsules comprising ibuprofen, preferably clear transparent and comprising a solution comprising a)35 to 75% by weight ibuprofen, b)1 to 10% by weight alkali hydroxide, and c)15 to 55% by weight emulsifier selected from polyoxyethylene alkyl ethers, medium chain triglycerides, propylene glycol esters, glycerol esters, sorbitan esters, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, castor oil or a combination thereof, based on the total weight of the solution, wherein the molar ratio between alkali hydroxide (alkalihydroxide) b) and ibuprofen a) is 0.1 to 0.5.

The amount of ibuprofen of component a) used according to the invention is from 35 to 75% by weight, preferably from 40 to 55% by weight, most preferably from 45 to 50% by weight, relative to the total weight of the solution.

The racemic mixture of ibuprofen is typically used in the present invention.

The component b), alkali hydroxide, is used in an amount of 1 to 10% by weight, preferably 1 to 5% by weight, relative to the total weight of the solution.

The alkali hydroxide used as component b) in the present invention is preferably sodium hydroxide (NaOH), potassium hydroxide (KOH) or a mixture thereof. The most preferred alkali hydroxide of the present invention is KOH.

In a preferred embodiment of the invention KOH is used in an amount of 0.2 to 0.35 mole per mole of ibuprofen, that is, 0.2 to 0.35 mole equivalents of alkali hydroxide per mole of ibuprofen medicament.

The component c) of the present invention is 15 to 55% by weight with respect to the total weight of the solution, and the emulsifier which can be used is selected from polyoxyethylene alkyl ethers, medium chain triglycerides, propylene glycol esters, glycerol esters, sorbitan esters, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, or mixtures thereof.

Preferred polyoxyethylene alkyl ethers of the present invention are polyhydroxyoxy (polyoxyl)2 cetyl ether, polyhydroxyoxy 10 cetyl ether, polyhydroxyoxy 20 cetyl ether, polyhydroxyoxy 4 dodecyl ether, polyhydroxyoxy 23 dodecyl ether, polyhydroxyoxy 2 oleyl ether, polyhydroxyoxy 10 oleyl ether, polyhydroxyoxy 20 oleyl ether, polyhydroxyoxy 2 octadecyl ether, polyhydroxyoxy 10 octadecyl ether, polyhydroxyoxy 20 octadecyl ether, polyhydroxyoxy 100 octadecyl ether or polyhydroxyoxy 20 hexadecyloctadecyl ether (polyoxyl 20 cetostearyl ether).

Preferred medium chain triglycerides are caprylic/capric triglycerides, such as MTC oil, Miglyol^*810 or Miglyol^*812. Particularly preferred is Miglyol^*812。

Preferred propylene glycol esters are propylene glycol dicocoate, propylene glycol distearate, propylene glycol dicaprylate, propylene glycol dinonate, propylene glycol heneicosanate, propylene glycol monostearate, propylene glycol monohydroxystearate, propylene glycol monododecanoate, propylene glycol monotetradecanoate or propylene glycol monooleate. Propylene glycol monolaurate is particularly preferred.

Preferred glycerides are glycerol monooleate, glycerol monostearate or glycerol palmitostearate. Particularly preferred is glycerol monooleate.

Preferred sorbitan esters are sorbitan diisostearate, sorbitan dioleate, sorbitan monolaurate, sorbitan monoisostearate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquiisostearate, sorbitan sesquioleate, sorbitan sesquistearate, sorbitan triisostearate, sorbitan trioleate or sorbitan tristearate. Particularly preferred is sorbitan trioleate.

Preferred polyoxyethylene castor oil derivatives are polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oilOil, polyoxyl 40 castor oil, polyoxyl 40 hydrogenated castor oil or polyoxyl 60 hydrogenated castor oil. Particularly preferred is polyoxyethylene35 castor oil (Cremophor)^*EL) or polyoxy ethylene-40-hydrogenated castor oil (Cremophor)^* RH40)。

Preferred polyoxyethylene sorbitan fatty acid esters are polyethoxy ether 20, polyethoxy ether 21, polyethoxy ether 40, polyethoxy ether 60, polyethoxy ether 61, polyethoxy ether 65, polyethoxy ether 80, polyethoxy ether 81, polyethoxy ether 85 or polyethoxy ether 120. Particularly preferred is polysorbate 60.

Preferred polyoxyethylene stearates are polyoxyl-6-stearate, polyoxyl-8-stearate, polyoxyl-12-stearate or polyoxyl-20-stearate.

The density of the emulsifiers c) can vary within a wide range, but is generally from 0.85 to 1.1 at 60 ℃.

Preferably, the emulsifier c) is a polyoxyethylated castor oil derivative, particularly preferably polyoxy-35-castor oil (Cremophor)^*EL) or polyoxy-40-hydrogenated castor oil (Cremophor)^*RH40) in an amount of from 40 to 55% by weight, in particular from 45 to 50% by weight, based on the weight of the total composition.

In a particularly preferred embodiment the amount of polyoxyethylated castor oil derivative used is from 10 to 40%, more preferably from 15 to 35% by weight, based on the weight of the total composition, while the amount of medium chain triglycerides mixed is from 7 to 35%, preferably from 10 to 25%, most preferably from 12 to 18% by weight, of which the caprylic/capric triglyceride Miglyol is particularly preferred^* 812。

The solutions of the invention comprising components a), b) and c) and/or water and/or other components are preferably clear and transparent and typically have a viscosity of 500-.

In one aspect of the invention there is provided an ibuprofen hard shell capsule comprising the above solution comprising components a), b) and c) and/or water and/or other components.

Hard shell capsules this system contains an ibuprofen formulation and a capsule shell for encapsulating the ibuprofen formulation. Because of this, not only is the filled ibuprofen formulation critical to achieve the desired bioavailability, but the shell composition is also critical and must be compatible with the ibuprofen formulation. The interaction between the potential liquid-filled fill and the capsule shell may simultaneously result in unstable physical and chemical properties of the capsule. Thus, the shell composition used to form the capsules of the ibuprofen dosage form is also critical to the present invention.

Thus, the present invention uses hard shell capsules comprised of the aforementioned film-forming materials.

Preferably, the capsules of the invention are clear transparent.

Hard shell capsules for liquid filling typically have a volume of 0.3 to 1.0 ml. The usable volume is generally from 85 to 95% by volume. Hard shell capsules generally have a much lower moisture content than soft capsules.

In the hard capsule encapsulation process, an empty capsule is generally prepared in advance, whereas in the case of the soft capsule, encapsulation and filling are performed simultaneously.

Various different methods can be used to close the hard shell capsules of the present invention. The preferred method is edge sealing with a tape material comprised of the aforementioned film-forming material and sealing with a hydroalcoholic solution.

Closures for hard shell capsules are well known in the art. The capsules are first conditioned and then transferred once or twice over a wheel rotating in a gelatin bath. A certain amount of gelatin is adhered on the gear for adhering the cap and the capsule body. The capsules are stored in a separate carrier and dried.

The sealing of hard shell capsules according to the invention is preferably based on lowering the melting point of the gelatin by applying humidity to the area between the body and the cap.

The following process is envisaged in a preferred embodiment of the invention: after the capsule is filled, the closure is made by spraying a small amount of a water/ethanol mixture over the cap and body contact area, followed by heating to fuse the two capsule portions together.

Equipment for accomplishing the encapsulation according to the above method is commercially available.

The Capsules of the invention did not show any capsule friability after storage for four weeks at 30% and 50% relative humidity, as measured by Cad and Madit, "Liquid Filling in Hard Gelatin Capsules-preparations Steps", Bulletin Technique Gattefose, 1996.

Using the solutions of the present invention, a unit dose of ibuprofen in a two-part hard shell capsule may be prepared wherein the fill solution contains a therapeutically effective amount of ibuprofen dissolved therein. The dosage to be administered may vary depending on the acidic agent used, the mode of administration, the disease to be treated, the size, age and weight of the patient to be treated, etc.

The invention is further described by the following non-limiting examples. Wherein the percentages are relative to the total weight of the solution.

Examples

Example 1

Example 1
				mg/caps	％
Ibuprofen	200.00	47.62
			Cremophor* RH40	140.71	33.50
Miglyol* 812	63.00	15.00
			KOH	16.29	3.88
				420.00	100

In example 1, 0.3 molar equivalents of KOH and 15% Miglyol were used^*。

The viscosity was 1900cps at 25 ℃ and 836cps at 35 ℃.

Example 2
				mg/caps	％
Ibuprofen	200.00	47.62
			Cremophor*EL	140.71	33.50
Miglyol* 812	63.00	15.00
			KOH	16.29	3.88
				420.00	100

In example 2, 0.3 molar equivalent of KOH/15% Miglyol was used^*。

The viscosity was 3140cp at 25 ℃.

Examples corresponding to the compositions described below were prepared analogously to examples 1 and 2.

Example 3
				mg/caps	％
Ibuprofen	201.78	48.04
			Cremophor * EL or RH40	201.78	48.04
Miglyol* 812	-	-
			KOH	16.44	3.92
				420.00	100
Examples 4 and 5
				mg/caps	％
Ibuprofen	201.43	38.74
			Cremophor * EL (example 4) or RH40 (example 5)	151.07	29.05
Miglyol* 812	151.07	29.05
			KOH	16.42	3.16
				520.00	100

Claims (10)

1. A pharmaceutically acceptable composition for liquid filling hard shell capsules comprising, based on the total weight of the composition, a)35 to 75 weight percent ibuprofen,

b) 1-10% by weight of an alkali hydroxide, and

c) 15-55% by weight of an emulsifier selected from polyoxyethylene alkyl ethers, medium chain triglycerides, propylene glycol esters, glycerol esters, sorbitan esters, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, castor oil or mixtures thereof,

wherein the molar ratio between the alkali hydroxide b) and ibuprofen a) is 0.1 to 0.5.

2. The pharmaceutical composition according to claim 1, wherein the emulsifier c) is a polyoxyethylene castor oil derivative.

3. The pharmaceutical composition according to claim 2, wherein the emulsifier c) is polyoxyl 35 castor oil or polyoxyl 40 hydrogenated castor oil.

4. A pharmaceutical composition according to claim 3, wherein the content of emulsifier c) is 45 to 50% by weight.

5. The pharmaceutical composition according to claim 1, wherein the emulsifier c) is a mixture of a polyoxyethylene castor oil derivative and a medium chain triglyceride.

6. The pharmaceutical composition according to claim 5, wherein the emulsifier c) is polyoxyl 35 castor oil or a mixture of polyoxyl 40 hydrogenated castor oil and caprylic/capric triglyceride.

7. A pharmaceutical composition according to claim 5, wherein the polyoxyethylene castor oil derivative is present in an amount of 15-35% by weight and the medium chain triglyceride is present in an amount of 12-18% by weight.

8. A liquid-filled pharmaceutical hard capsule comprising a composition comprising, based on the total weight of the composition:

a) 35-75% by weight of ibuprofen,

b) 1-10% by weight of an alkali hydroxide, and

c) 15-55% by weight of an emulsifier selected from polyoxyethylene alkyl ethers, medium chain triglycerides, propylene glycol esters, glycerol esters, sorbitan esters, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, castor oil or mixtures thereof,

wherein the molar ratio between the alkali hydroxide b) and ibuprofen a) is 0.1 to 0.5.

9. A liquid-filled pharmaceutical hard capsule comprising the composition according to claim 4.

10. A liquid-filled pharmaceutical hard capsule comprising the composition according to claim 7.