WO2004084883A1 - Complexes of isotretinoin with natural beta or gamma-cyclodextrin - Google Patents

Complexes of isotretinoin with natural beta or gamma-cyclodextrin Download PDF

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Publication number
WO2004084883A1
WO2004084883A1 PCT/FI2004/000161 FI2004000161W WO2004084883A1 WO 2004084883 A1 WO2004084883 A1 WO 2004084883A1 FI 2004000161 W FI2004000161 W FI 2004000161W WO 2004084883 A1 WO2004084883 A1 WO 2004084883A1
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isotretinoin
cyclodextrin
complex
complexes
solubility
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PCT/FI2004/000161
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French (fr)
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Pekka Jarho
Faeis Khaliefi
Saara Honkala
Tomi Järvinen
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Pekka Jarho
Faeis Khaliefi
Saara Honkala
Jaervinen Tomi
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Publication of WO2004084883A1 publication Critical patent/WO2004084883A1/en

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents

Definitions

  • the present invention describes the use of low-solubility complexes of natural cyclodextrins (CDs) in order to improve the bioavailability of isotretinoin after oral administration.
  • CDs natural cyclodextrins
  • the complexation of isotretinoin with natural CDs increases the aqueous solubility and dissolution rate of isotretinoin, which results in improved absorption of isotretinoin.
  • the present innovation can be used in various oral dosage forms (tablet, capsule, etc.) and it includes a novel method to prepare solid formulations (e.g. tablet) from isotretinoin.
  • Retinoids are a group of compounds related to vitamin A, also called retinol, a vitamin
  • Isotretinoin 13-cis retinoic acid
  • tretinoin all-trans retinoic acid
  • isotretinoin has been used orally or topically in the treatment of acne.
  • the major pharmaceutical problem of isotretinoin is its low stability and aqueous solubility. Isotretinoin has been shown to degrade under the influence of light and because of that the commercially available formulations are stored in light resistant containers. Because isotretinoin is practically insoluble in water and sparingly soluble in alcohol it is usually formulated in soft gelatin capsules containing a suspension of the drug in soybean oil.
  • the oral bioavailability of isotretinoin, after administration of these formulations, is only 25 % mainly due to poor solubility/dissolution characteristics of the compound (Orfanos et al 1998).
  • the metabolism in the gut wall and first-pass metabolism in the liver has been also reported to account for the low bioavailability of isotretinoin (Cotler et al. 1983).
  • Cyclodextrins are cyclic oligosaccharides consisting of ( ⁇ -l,4)-linked ⁇ -D- glucopyranose units, with a lipophilic central cavity and a hydrophilic outer surface (Fr ⁇ mming and Szejtli, 1994). CDs are able to form inclusion complexes with many drugs by taking up the whole drug, or more commonly, the lipophilic moiety of the molecule, into the cavity. The most abundant natural CDs are ⁇ -cyclodextrin ( ⁇ -CD), ⁇ -cyclodextrin ( ⁇ -CD) and ⁇ -cyclodextrin ( ⁇ -CD), containing six, seven, and eight glucopyranose units, respectively.
  • ⁇ -CD appears to be the most useful pharmaceutical complexing agent because of its cavity size, availability, low cost and other properties.
  • CD derivatives available, such as hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) and methylated CDs.
  • CDs have been used mainly to increase the aqueous solubility, stability and bioavailability of various drugs (Fr ⁇ mming and Szejtli, 1994).
  • CDs can also be used to convert liquid compounds into microcrystalline powders, prevent drug- drug or drug-additive interactions, reduce gastro-intestinal or ocular irritation, and reduce or eliminate unpleasant taste and smell.
  • the drug solubility may even start to decrease in B-type phase- solubility behaviour because at high CD concentrations the drug molecule forms lower solubility (higher order) complexes with CDs.
  • the B-type phase-solubility behaviour is typical for natural CDs and has been described earlier e.g. with steroids (Uekama et al 1982).
  • CDs are major problems in the use of CDs in pharmaceutical formulations. This is the reason why the use of CDs in oral formulations is usually limited to drugs containing a low therapeutic dose.
  • the benefit of natural CDs, compared to CD derivatives, is their ability sometimes to form low solubility complexes, which can be considered as "pure" complexed materials because they do not contain free drug or free CD molecules.
  • isotretinoin has been complexed with ⁇ -CD or ⁇ -CD that significantly improves the dissolution rate of isotretinoin which also improves the bioavailability of the isotretinoin.
  • the present invention is based on two novel findings. The first finding shows that isotretinoin forms low solubility complexes with ⁇ -CD and ⁇ -CD which allows the preparation of pure isotretionin/CD complexes with these natural CDs. The second finding shows that low solubility complexes of isotretinoin with ⁇ - CD and ⁇ -CD can be used to significantly improve the dissolution rate of isotretinoin, to improve the bioavailability of the compound.
  • these two novel findings provide a useful method to prepare solid isotretinoin/CD formulations with good dissolution properties for oral drug delivery, especially for the treatment of acne.
  • the invention is in a first aspect directed to the use of a complex of isotretinoin with a cyclodextrin selected from ⁇ -CD and ⁇ -CD for the preparation of a pharmaceutical composition for oral administration.
  • the invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one orally acceptable carrier, adjuvant or additive, and a therapeutically effective amount of a complex of isotretinoin with a cyclodextrin selected from ⁇ -CD and ⁇ -CD.
  • the invention is directed to a process for the preparation of a complex of isotretinoin with a cyclodextrin selected from ⁇ -CD and ⁇ -CD.
  • the present invention describes the use of ⁇ -CD and ⁇ -CD to improve the dissolution rate and bioavailability of isotretinoin in oral drug formulations.
  • the solid complexes of isotretinoin with ⁇ -CD and/or ⁇ -CD can be prepared by stirring isotretinoin in a CD containing aqueous solution which leads to the precipitation of the solid complexes of isotretinoin (i.e. , isotretinoin is inside of the cyclodextrin cavity).
  • the present invention shows that these low-solubility complexes can be used to improve the dissolution rate of isotretinoin, in order to improve the bioavailability of isotretinoin.
  • One of the major benefits of the present invention is the finding that precipitation of low solubility complexes of isotretinoin with natural ⁇ -CD and natural ⁇ -CD produces "pure" complexes of isotretinoin which improves the pharmaceutical usefulness of
  • CDs in isotretinoin formulations and enables the preparation of novel solid formulations from isotretinoin.
  • HP- ⁇ -CD improves the bioavailability of tretinoin, the all-trans form of retinoic acid.
  • HP- ⁇ -CD is a water-soluble CD derivative. From phase-solubility studies it can be calculated that in order to complex 10 mg or 20 mg of isotretinoin, 940 mg or 1880 mg of HP- ⁇ -CD is needed. This is absolutely far too much for oral solid formulations.
  • ⁇ -CD is a water-soluble CD derivative
  • CD the same result can be achieved with 180 mg and 360 mg, respectively, of natural ⁇ -CD because the complexed material contains only "pure” complexes and no free CD molecules.
  • the inclusion complexes of the present invention can be prepared in the conventional manner, known to a person skilled in art, in solution, in a heterogenous state or in the solid state, including using methods such as precipitation, freeze-drying, spray-drying, kneading, grinding, slurry-method, co-precipitation, and neutralization, and separating said complex.
  • the formation of the inclusion complex can be facilitated by using proper pH adjustment and solvents, such as organic solvents, for example methanol or ethanol.
  • solvents such as organic solvents, for example methanol or ethanol.
  • the temperature can vary to some degree, but it is typically for convenience the ambient temperature.
  • the weight ratio (dry weight to dry weight) between isotretinoin and cyclodextrin is between 1: 1 and 1: 1000.
  • the said weight ratio is 1: 1 to 1:20.
  • the pharmaceutical preparation according to the invention contains the said complex in a pharmaceutically acceptable amount together with at least one pharmaceutically acceptable carrier, adjuvant or vehicle known in the art.
  • the manufacture of such pharmaceutical formulations is well known in the art.
  • the pharmaceutical composition may be in a dosage form suitable for oral use, such as tablets, capsules, lozenges, pills, pastilles etc. All such formulations are made using per se known formulation techniques and carriers, adjuvants and/or additives.
  • the therapeutic dose to be given to a patient in need of treatment will vary depending on the body weight and age of the patient, the particular condition being treated as well as the manner of administration and are easily determined by a person skilled in the art. Generally an amount of 0.1 mg to 50 mg isotretinoin, typically 0.1 mg to 50 mg per unit dose, to be given for example 1 to 4 times a day, would be suitable for most purposes.
  • Figure 4 shows the effect of HP- ⁇ -CD on the aqueous solubility of isotretinoin at pH
  • phase-solubility diagram of isotretinoin with HP- ⁇ -CD can be classified as A L -type, which shows that isotretinoin forms a soluble complex with HP- ⁇ -CD.
  • the therapeutLc dose of isotretinoin is 10 - 20 mg (Roaccuran, Roche Ltd) and from phase-solubility studies it can be calculated that in order to complex 10 mg or 20 mg of isotretinoin, 9-40 mg or
  • HP- ⁇ -CD 1880 mg of HP- ⁇ -CD is needed.
  • the major problem in the use of HP- ⁇ -C D in oral isotretinoin formulations is the fact that after freeze- or spray-drying the solution, the material contains high amounts of free HP- ⁇ -CD molecules which increases the formulation bulk.
  • the method above produced a white precipitate which contained 5 mg of isotretinoin in 90 mg of the precipitate. Based on the isotretinoin content in the powder (assuming that the remaining part of the powder was ⁇ -CD), the stoichiometry of the isotretinoin/ ⁇ -CD complex was calculated to be 1 :4.
  • the dissolution rate of isotretinoin and isotretinoin/ ⁇ -CD was studied at pH 7.4 by using an USP 23 apparatus 2 (rotating paddle method) at 37 °C. Powdered samples containing 5 mg of isotretinoin or 90 mg isotretinoin/ ⁇ -CD complex were gently spread on the surface of the dissolution medium, which was stirred at 100 rpm. The solution was sampled (3.0 ml) at appropriate time intervals and the samples were filtered rapidly through a membrane filter (0.22 ⁇ m) and analyzed by HPLC. In all of the studies the dissolution medium contained 2 % HP- ⁇ -CD to ensure the full solubility of isotretinoin.
  • Figures 5 and 6 show that the complexation of isotretinoin with natural ⁇ -CD significantly increases the dissolution rate of isotretinoin.
  • ⁇ - CD/isotretinoin formulation isotretinoin is fully dissolved in 2 minutes. Without ⁇ - CD the dissolution rate is much slower and isotretinoin is not fully dissolved even in 5 hours.
  • Brzokewicz A Caron D, Shroot B: Topical gels containing retinoic acid and beta- cyclodextrin with gelling agent, hydroxylated amine and water.
  • WO9014082 (1990).
  • Orfanos C E, Zouboulis C C Oral retinoids in the treatment of seborrhoea and acne. Dermatology 196: 140 - 147, 1998.
  • Rolland A, Shroot B Aqueous gel based on retinoic acid and hydroxypropyl-beta- cyclodextrin. EP486395 (1992).

Abstract

The object of the present invention is the use of a complex of isotretinoin with a cyclodextrin selected from natural β-CD and Ϝ-CD for the preparation of a pharmaceutical composition for oral administration, especially for the treatment of acne.

Description

Complexes of isotretinoin with natural beta or gamma-cyclo extrin
TECHNICAL FIELD OF THE INVENTION
The present invention describes the use of low-solubility complexes of natural cyclodextrins (CDs) in order to improve the bioavailability of isotretinoin after oral administration. The complexation of isotretinoin with natural CDs increases the aqueous solubility and dissolution rate of isotretinoin, which results in improved absorption of isotretinoin. The present innovation can be used in various oral dosage forms (tablet, capsule, etc.) and it includes a novel method to prepare solid formulations (e.g. tablet) from isotretinoin.
BACKGROUND OF THE INVENTION
Retinoids are a group of compounds related to vitamin A, also called retinol, a vitamin
A alcohol. Isotretinoin (13-cis retinoic acid) is a synthetic retinoid and it is a cis configuration of tretinoin (all-trans retinoic acid), the naturally occurring acid form of vitamin A. Below are shown the chemical structures of retinol, tretinoin and isotretinoin.
Figure imgf000002_0001
B
The chemical structure of retinol (A), tretinoin (B) and isotretinoin (C).
During the last two decades isotretinoin has been used orally or topically in the treatment of acne. The major pharmaceutical problem of isotretinoin is its low stability and aqueous solubility. Isotretinoin has been shown to degrade under the influence of light and because of that the commercially available formulations are stored in light resistant containers. Because isotretinoin is practically insoluble in water and sparingly soluble in alcohol it is usually formulated in soft gelatin capsules containing a suspension of the drug in soybean oil. However, the oral bioavailability of isotretinoin, after administration of these formulations, is only 25 % mainly due to poor solubility/dissolution characteristics of the compound (Orfanos et al 1998). However, the metabolism in the gut wall and first-pass metabolism in the liver has been also reported to account for the low bioavailability of isotretinoin (Cotler et al. 1983).
Cyclodextrins (CDs) are cyclic oligosaccharides consisting of (α-l,4)-linked α-D- glucopyranose units, with a lipophilic central cavity and a hydrophilic outer surface (Frόmming and Szejtli, 1994). CDs are able to form inclusion complexes with many drugs by taking up the whole drug, or more commonly, the lipophilic moiety of the molecule, into the cavity. The most abundant natural CDs are α-cyclodextrin (α-CD), β-cyclodextrin (β-CD) and γ-cyclodextrin (γ-CD), containing six, seven, and eight glucopyranose units, respectively. Of these three CDs, β-CD appears to be the most useful pharmaceutical complexing agent because of its cavity size, availability, low cost and other properties. There is also a number of CD derivatives available, such as hydroxypropyl-β-cyclodextrin (HP-β-CD) and methylated CDs. In drug formulations,
CDs have been used mainly to increase the aqueous solubility, stability and bioavailability of various drugs (Frόmming and Szejtli, 1994). In addition, CDs can also be used to convert liquid compounds into microcrystalline powders, prevent drug- drug or drug-additive interactions, reduce gastro-intestinal or ocular irritation, and reduce or eliminate unpleasant taste and smell.
One of the major differences between natural CDs and water-soluble CD derivatives is that natural CDs have been shown to form low solubility complexes with various drugs, that is contrary to water-soluble CDs derivatives, which only form water-soluble complexes with drug-molecules. Higuchi and Connors (1965) have divided these two solubility behaviors into A- and B-type depending on the solubility of the complex. Figure 1 shows an example of B-type phase-solubility behaviour. In the B-type phase- solubility diagram the drug concentration first increases with increasing CD concentration due to complexation of the drug with CD molecules. However, after initial improvement in drug solubility, the maximum solubility of the complex is achieved and the complex starts to precipitate (highest part of the diagram). At a certain CD concentration the drug solubility may even start to decrease in B-type phase- solubility behaviour because at high CD concentrations the drug molecule forms lower solubility (higher order) complexes with CDs. The B-type phase-solubility behaviour is typical for natural CDs and has been described earlier e.g. with steroids (Uekama et al 1982).
One of the major problems in the use of CDs in pharmaceutical formulations is the effect of CDs on the mass of the formulation. This is the reason why the use of CDs in oral formulations is usually limited to drugs containing a low therapeutic dose. The drawback, especially in the case of water-soluble CD derivatives, is the fact that a freeze- or spray-dried drug/CD solution always contains free CD molecules which increase the formulation bulk. The benefit of natural CDs, compared to CD derivatives, is their ability sometimes to form low solubility complexes, which can be considered as "pure" complexed materials because they do not contain free drug or free CD molecules.
The studies dealing with the use of CDs with retinoids has been focused mainly on tretinoin, the all-trans form of retinoic acid. Pitha (1981) showed first that natural CDs and CD derivatives increase the aqueous solubility of retinoids, e.g. , retinol and retinoic acid. Amdidouche et al. (1989) developed a method to prepare solid tretinoin/natural β-CD inclusion complexes by using a mixture of water and isopropanol. However, only 20 % of the tretinoin was in complexed form after 16 days equilibration time and evaporation of the solvent. Lin et al. have recently shown that HP-β-CD increases the aqueous solubility, photo-stability and oral bioavailability of tretoinin (Lin et al. 2000a,b). In addition, Wacker-Chemie has patented and sells a powder containing retinol/γ-CD complex for nutritional, cosmetic etc. purposes (Moldenhauer et al. 1998).
The literature dealing with the use of CDs with isotretinoin has been limited to a few patent publications. In most of them, natural β-CD and HP-β-CD have been used with isotretinoin in gels and other topically applied dermal formulations (Brzokewicz et al. 1990, Rolland et al. 1992). Loftsson (1994) has also listed isotretinoin as one of the compounds which CD complexation may be improved with water-soluble polymers. In addition, Chen et al. have mentioned isotretinoin and CDs separately in two very large and general patent publications dealing with the improved delivery of ionizable hydrophobic therapeutic agents (Chen et al. 2000) and oil containing pharmaceutical compositions (Chen et al. 2001).
SUMMARY OF THE INVENTION
In the present invention isotretinoin has been complexed with β-CD or γ-CD that significantly improves the dissolution rate of isotretinoin which also improves the bioavailability of the isotretinoin. The present invention is based on two novel findings. The first finding shows that isotretinoin forms low solubility complexes with β-CD and γ-CD which allows the preparation of pure isotretionin/CD complexes with these natural CDs. The second finding shows that low solubility complexes of isotretinoin with β- CD and γ-CD can be used to significantly improve the dissolution rate of isotretinoin, to improve the bioavailability of the compound. As a summary, these two novel findings provide a useful method to prepare solid isotretinoin/CD formulations with good dissolution properties for oral drug delivery, especially for the treatment of acne.
Thus the invention is in a first aspect directed to the use of a complex of isotretinoin with a cyclodextrin selected from β-CD and γ-CD for the preparation of a pharmaceutical composition for oral administration.
In a second aspect the invention is directed to a pharmaceutical composition comprising at least one orally acceptable carrier, adjuvant or additive, and a therapeutically effective amount of a complex of isotretinoin with a cyclodextrin selected from β-CD and γ-CD.
In a third aspect the invention is directed to a process for the preparation of a complex of isotretinoin with a cyclodextrin selected from β-CD and γ-CD. DETAILED DESCRIPTION OF THE INVENTION
The present invention describes the use of β-CD and γ-CD to improve the dissolution rate and bioavailability of isotretinoin in oral drug formulations.
The solid complexes of isotretinoin with β-CD and/or γ-CD can be prepared by stirring isotretinoin in a CD containing aqueous solution which leads to the precipitation of the solid complexes of isotretinoin (i.e. , isotretinoin is inside of the cyclodextrin cavity). The present invention shows that these low-solubility complexes can be used to improve the dissolution rate of isotretinoin, in order to improve the bioavailability of isotretinoin.
One of the major benefits of the present invention is the finding that precipitation of low solubility complexes of isotretinoin with natural β-CD and natural γ-CD produces "pure" complexes of isotretinoin which improves the pharmaceutical usefulness of
CDs in isotretinoin formulations and enables the preparation of novel solid formulations from isotretinoin.
The current therapeutic dose of isotretinoin is 10 - 20 mg (Roaccuran, Roche Ltd.). Lin et al (2000b) have shown that HP-β-CD improves the bioavailability of tretinoin, the all-trans form of retinoic acid. During the present study the complexation of isotretinoin with HP-β-CD was also studied (Example 1). HP-β-CD is a water-soluble CD derivative. From phase-solubility studies it can be calculated that in order to complex 10 mg or 20 mg of isotretinoin, 940 mg or 1880 mg of HP- β-CD is needed. This is absolutely far too much for oral solid formulations. However, with natural β-
CD, the same result can be achieved with 180 mg and 360 mg, respectively, of natural β-CD because the complexed material contains only "pure" complexes and no free CD molecules.
Loftsson has also listed isotretinoin as one of the possible compounds the complexation of which with CDs may be improved together with water-soluble polymers (Loftsson 1994). This method was developed to improve the complexation of drugs with CDs and in some cases it has been used to decrease the formulation bulk because an increase in complexation efficiency usually decreases the size of the formulation (Savolainen et al 1998). However, the present innovation enables the preparation of pure isotretinoin/CD complexes and, thus, no enhancement in CD complexation is needed.
In general, the inclusion complexes of the present invention can be prepared in the conventional manner, known to a person skilled in art, in solution, in a heterogenous state or in the solid state, including using methods such as precipitation, freeze-drying, spray-drying, kneading, grinding, slurry-method, co-precipitation, and neutralization, and separating said complex.
The formation of the inclusion complex can be facilitated by using proper pH adjustment and solvents, such as organic solvents, for example methanol or ethanol. The temperature can vary to some degree, but it is typically for convenience the ambient temperature.
In the complex so obtained the weight ratio (dry weight to dry weight) between isotretinoin and cyclodextrin is between 1: 1 and 1: 1000. Preferably the said weight ratio is 1: 1 to 1:20.
The pharmaceutical preparation according to the invention contains the said complex in a pharmaceutically acceptable amount together with at least one pharmaceutically acceptable carrier, adjuvant or vehicle known in the art. The manufacture of such pharmaceutical formulations is well known in the art.
Thus the pharmaceutical composition may be in a dosage form suitable for oral use, such as tablets, capsules, lozenges, pills, pastilles etc. All such formulations are made using per se known formulation techniques and carriers, adjuvants and/or additives.
The therapeutic dose to be given to a patient in need of treatment will vary depending on the body weight and age of the patient, the particular condition being treated as well as the manner of administration and are easily determined by a person skilled in the art. Generally an amount of 0.1 mg to 50 mg isotretinoin, typically 0.1 mg to 50 mg per unit dose, to be given for example 1 to 4 times a day, would be suitable for most purposes.
The following examples illustrate the invention without limiting the same in any way.
EXAMPLE 1
In this example the aqueous solubility of isotretinoin with natural β-CD, natural γ-CD and HP-β-CD is been shown. Figure 2 and 3 shows the effect of natural β-CD and natural γ-CD on the aqueous solubility of isotretinoin at pH 7.4. According to Higuchi and Connors (1965) the phase-solubility behaviour of isotretinoin with natural β-CD and natural γ-CD can be classified as B-type, which means that at high β-CD and γ- CD concentrations the maximum solubility of the complex is achieved and the complex starts to precipitate. The B-type phase-solubility behaviour allows the prepsration of
"pure" isotretinoin/β-CD and isotretinoin/γ-CD complexes, which can be used in oral formulations of isotretinoin to improve the dissolution rate and bioavailability of isotretinoin (Example 2).
Figure 4 shows the effect of HP-β-CD on the aqueous solubility of isotretinoin at pH
7.4. According Higuchi and Connors (1965) the phase-solubility diagram of isotretinoin with HP-β-CD can be classified as AL-type, which shows that isotretinoin forms a soluble complex with HP-β-CD. As discussed before the therapeutLc dose of isotretinoin is 10 - 20 mg (Roaccuran, Roche Ltd) and from phase-solubility studies it can be calculated that in order to complex 10 mg or 20 mg of isotretinoin, 9-40 mg or
1880 mg of HP-β-CD is needed. The major problem in the use of HP-β-C D in oral isotretinoin formulations is the fact that after freeze- or spray-drying the solution, the material contains high amounts of free HP-β-CD molecules which increases the formulation bulk. EXAMPLE 2
In this example the effect of natural β-CD on the dissolution rate of isotretinoin has been described. In the present study the pure complexes of isotretinoin with natural β- CD were prepared by stirring 50 mg of isotretinoin in 1.5 % aqueous β-CD solution
(0.16 M phosphate buffer pH 7.4) for 6 days. The method above produced a white precipitate which contained 5 mg of isotretinoin in 90 mg of the precipitate. Based on the isotretinoin content in the powder (assuming that the remaining part of the powder was β-CD), the stoichiometry of the isotretinoin/β-CD complex was calculated to be 1 :4.
After preparation of the complex, the dissolution rate of isotretinoin and isotretinoin/β-CD was studied at pH 7.4 by using an USP 23 apparatus 2 (rotating paddle method) at 37 °C. Powdered samples containing 5 mg of isotretinoin or 90 mg isotretinoin/β-CD complex were gently spread on the surface of the dissolution medium, which was stirred at 100 rpm. The solution was sampled (3.0 ml) at appropriate time intervals and the samples were filtered rapidly through a membrane filter (0.22 μm) and analyzed by HPLC. In all of the studies the dissolution medium contained 2 % HP-β-CD to ensure the full solubility of isotretinoin.
Figure 5 shows the dissolution profile (dissolved isotretinoin as a function of time) of 5.0 mg of isotretinoin (Mean +_ SD, n=4) and figure 6 shows the same data with 90 mg (equivalent to 5.0 mg of isotretinoin) of isotretinoin/β-CD complex (Mean +_ SD, n=4).
Figures 5 and 6 show that the complexation of isotretinoin with natural β-CD significantly increases the dissolution rate of isotretinoin. In the case of β- CD/isotretinoin formulation, isotretinoin is fully dissolved in 2 minutes. Without β- CD the dissolution rate is much slower and isotretinoin is not fully dissolved even in 5 hours. REFERENCES
Amdidouche D, Darrouzed H, Duchene D, Poelman M-C: Inclusion of retinoic acid in β-cyclodextrin. Int. J. Pharm. 54: 175-179, 1989.
Cotler S, Bugge J L, Colburn W A: Role of gut contents, intestinal wall and liver on the first pass metabolism and absolute bioavailability of isotretinoin in dogs. Drug Metabolism and Disposition 11: 458 - 462, 1983.
Brzokewicz A, Caron D, Shroot B: Topical gels containing retinoic acid and beta- cyclodextrin with gelling agent, hydroxylated amine and water. WO9014082 (1990).
Chen F-J, Pate M: Compositions and methods for improved delivery of ionizable hydrophopic therapeutic agents. WO 00/59475 (2000).
Chen F-J, Patel M: Clear oil containing pharmaceutical compositions. WO 01/01960 (2001).
Frόmming K-H, Szejtli J: Cyclodextrins in pharmacy. Kluwer Academic Publishers, Dortrecht, 1994.
Higuchi T, Connors K A: Phase-solubility techniques. Adv. Anal. Chem. Instr. 4: 117 - 212, 1965.
Lin H S, Chean C S, Ng Y Y, Chan S Y, Ho P C: 2-hydroxypropyl- β-cyclodextrin increases aqueous solubility and photostability of all-trans-retinoic acid. J. Clin. Pharm. Ther. 25:265 - 269, 2000a.
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Claims

1 ■ Use of a complex of isotretinoin with a cyclodextrin selected from β-CD and γ-CD for the preparation of a pharmaceutical composition for oral administration.
2. The use according to claim 1, wherein the weight ratio (dry weight to dry weight) between isotretinoin and cyclodextrin is between 1:1 and 1: 1000.
3. The use according to claim lor 2, wherein the pharmaceutical composition is for the treatment of acne.
4. Pharmaceutical composition comprising at least one orally acceptable carrier, adjuvant or additive, and a therapeutically effective amount of a complex of isotretinoin with a cyclodextrin selected from β-CD and γ-CD.
5. The pharmaceutical composition according to claim 4, which is a tablet, a capsule, a lozenge, pill or pastille.
6. Process for increasing the bioavailability of isotretinoin from an orally administered pharmaceutical preparation, the process comprising the step of complexing isotretinoin with a cyclodextrin selected from β-CD and γ-CD and forming the complex obtained into an orally administered dosage form.
7. Method for the treatment of acne comprising administering orally to an individual in need of such treatment an effective amount of a complex of isotretinoin with a cyclodextrin selected from β-CD and γ-CD.
PCT/FI2004/000161 2003-03-24 2004-03-22 Complexes of isotretinoin with natural beta or gamma-cyclodextrin WO2004084883A1 (en)

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GB2421433B (en) * 2004-12-08 2008-01-02 Sytera Inc Use of compositions for treating age related macular degeneration or dystrophy
US7432307B2 (en) 2004-11-04 2008-10-07 Sirion Therapeutics, Inc. Modulators of retinol-retinol binding protein (RBP)-transthyretin (TTR) complex formation
WO2010116097A1 (en) * 2009-04-09 2010-10-14 Pierre Fabre Medicament Method for preparing molecular complexes between a retinoid agent and cyclodextrins
US8314152B2 (en) 2004-06-23 2012-11-20 Acucela, Inc. Methods and compositions for treating ophthalmic conditions with retinyl derivatives
US10716774B1 (en) 2018-01-05 2020-07-21 Yale Pharmaceuticals LLC Pharmaceutical compositions containing isotretinoin with improved dissolution profile and enhanced stability

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Publication number Priority date Publication date Assignee Title
US8314152B2 (en) 2004-06-23 2012-11-20 Acucela, Inc. Methods and compositions for treating ophthalmic conditions with retinyl derivatives
US8410168B2 (en) 2004-06-23 2013-04-02 Acucela, Inc. Methods and compositions for treating ophthalmic conditions with retinyl derivatives
US7432307B2 (en) 2004-11-04 2008-10-07 Sirion Therapeutics, Inc. Modulators of retinol-retinol binding protein (RBP)-transthyretin (TTR) complex formation
GB2421433B (en) * 2004-12-08 2008-01-02 Sytera Inc Use of compositions for treating age related macular degeneration or dystrophy
WO2010116097A1 (en) * 2009-04-09 2010-10-14 Pierre Fabre Medicament Method for preparing molecular complexes between a retinoid agent and cyclodextrins
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US10716774B1 (en) 2018-01-05 2020-07-21 Yale Pharmaceuticals LLC Pharmaceutical compositions containing isotretinoin with improved dissolution profile and enhanced stability

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