WO1990001320A1 - Water soluble branched beta cyclodextrin steroid complex - Google Patents
Water soluble branched beta cyclodextrin steroid complex Download PDFInfo
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- WO1990001320A1 WO1990001320A1 PCT/US1989/003471 US8903471W WO9001320A1 WO 1990001320 A1 WO1990001320 A1 WO 1990001320A1 US 8903471 W US8903471 W US 8903471W WO 9001320 A1 WO9001320 A1 WO 9001320A1
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- beta cyclodextrin
- steroid
- branched beta
- branched
- complex
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Classifications
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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
- 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
- A61P5/00—Drugs for disorders of the endocrine system
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
- C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
Definitions
- This invention relates to a complex of branched beta cyclodextrin and steroid and the use of such a complex to make the steroid water soluble.
- Starch occurs naturally in a variety of plants such as corn, potato, sorghum and rice and is extracted from portions of the plant by a milling operation which
- starch separates the starch from the plant. Physically the starch is in a granular form which typically comprises both amylose and amylopectin.
- Amylose is a straight chained polymer of anhydroglucose units bonded together by alpha 1,4 bonds while amylopectin is a polymer
- amylopectin the bond between the straight chain and the side chain is an alpha 1,6 bond.
- the amount of amylose and amylopectin in a starch granule depends on the source of the starch. For example, high amylose corn starch contains about a 50:50 ratio while waxy corn starch contains about a 99:1 ratio of amylopectin to amylose.
- Cyclodextrins also called Schardingers dextrins, cycloamyloses, cyclomaltoses and cycloglucans, are
- polymers of anhydroglucose polymers bonded together by alpha 1,4 bonds to form a ringed compound.
- a six membered ring is called alpha cyclodextrin, seven, beta cyclodextrin and eight, gamma cyclodextrin. These six, seven and eight membered rings are also referred to as cyclomaltohexaose, cyclomaltoheptaose and
- Beta cyclodextrins have one or more anhydroglucose units bonded onto the ring structure such that a branch extends out from the ring structure.
- the branch is bonded to the ring by an alpha 1,6 bond where the branched beta cyclodextrin is obtained from an enzymatic process.
- Steroids are typically used in aqueous media and ointments as pharmaceutical preparations for treatment of the skin and eyes. Because steroids are highly water insoluble, any aqueous medium containing steroids must be vigorously shaken before application. Steroids are classified as lipids because they are highly water insoluble and are soluble in organic solvents.
- the alpha cyclodextrin-steroid solution typically contains less than about 1% soluble steroid and the gamma cyclodextrin-steroid solution also typically contains less than about 1% soluble steroid.
- cyclodextrin be chemically modified by reacting the beta cyclodextrin with methyl groups to form dimethyl beta cyclodextrin and then form a complex with a steroid.
- cyclodextrin will form a complex with a steroid and that such a complex is highly water soluble. In fact, it has been found that such a complex may have a solubility up to about 2800 times greater than that of the steroid itself and about 100 times greater than that of the complex of beta cyclodextrin and steroid.
- steroid has a solubility comparable to a complex of dimethyl-beta cyclodextrin and steroid. This is
- Branched beta cyclodextrins are conventionally prepared by treating starch slurry high in amylopectin with an enzyme, cyclodextrin glycosyltransferase (CGT), at the appropriate pH, temperature and time for
- the starch used for this enzymatic preparation of branched beta cyclodextrin may be from any selected plant variety; however, it is preferable that the starch be high in amylopectin content.
- the enzyme CGT is obtained from microorganisms such as
- the starch is slurried in aqueous solution at a concentration up to about 35% by weight solids.
- the slurry is then subjected to gelatinization and liquefaction by enzyme or acid to about 1 to about 5 DE.
- the selected CGT is added to the gelatinized and liquefied slurry and the pH, temperature and time of the treatment are adjusted depending on the selected enzyme.
- the pH is between about 4.5 to about 8.5
- the temperature ranges between ambient to about 75°C and the length of the reaction runs for about ten hours to seven days.
- the amount of branched beta cyclodextrin will vary depending on the treatment conditions and the starch selected.
- Such solvents substantially facilitate the isolation of branched beta cyclodextrin.
- beta cyclodextrins When starch is treated with CGT, branched beta cyclodextrins, beta cyclodextrins and other dextrins are formed. In order to obtain branched beta
- the branched beta cyclodextrin must be separated from the beta cyclodextrin and the other
- branched beta cyclodextrin is separated from beta cyclodextrin and other dextrins by forming a first precipitate and a first liquor from an aqueous first solution containing branched beta cyclodextrin by the addition of a beta cyclodextrin complexant to the aqueous first solution; recovering the first precipitate; forming a second aqueous solution with the first precipitate; forming a second precipitate and a second liquor from said second solution by the addition of a beta cyclodextrin complexant to said second solution; recovering the second liquor; and, finally, recovering branched beta cyclodextrin from said second liquor.
- the aqueous starting solution is an aqueous solution containing branched and non-branched beta cyclodextrins such that about 1% or more of the total solids content of the solution is branched beta
- cyclodextrin is in an amount in excess of the branched beta cyclodextrin. Invariably, some beta cyclodextrin will be present with the branched beta cyclodextrin.
- Branched beta cyclodextrins are characterized more specifically by the length of or the number of glucose units in the branch.
- cyclodextrin which has a single glucose unit attached to the ringed structure is called 6-alpha-D-glucosylcyclomaltoheptaose or GlcG7
- a branched beta cyclodextrin having two glucose units on the branch is referred to as 6-alpha-D-maltosylcyclomaltoheptaose or G2cG7
- a branched beta cyclodextrin with three glucose units on the branch is referred to conveniently as G3cG7, four glucose units as G4cG7, and so on.
- the branched beta cyclodextrins may also be formed by a pyrolysis method, preferably as taught by the
- Such branched beta cyclodextrins have branches of anhydroglucose units which are bonded to the ring structure of the beta cyclodextrin by bonds other than a 1,6 bond.
- Branched beta cyclodextrin can also be formed by enzymatic techniques where
- branched beta cyclodextrin as used in the specification and claims means branched beta
- the branch length of the branched beta cyclodextrins used in the present invention is between about 1 to about 7 glucose units, i.e. GlcG7 to G7cG7.
- Steroids which are suitable for complexing with branched beta cyclodextrins have a molecular structure which allows at least a portion of the steroid's molecular structure to be housed inside the cavity of the branched beta cyclodextrin.
- Suitable steroids include
- corticosteroids such as dexamethasone, prednisolone and hydrocortisone; androgens; anabolic steroids; estrogens; and progestagens. Good results have been obtained with hydrocortisone, progesterone and testosterone.
- an aqueous mixture of steroid and branched beta cyclodextrin is prepared and gently mixed at ambient conditions. Stoichiometrically, the ratio of branched beta cyclodextrin to steroid is about 1:1; however, in order to complex as much of the steroid as possible, preferably an excess of branched beta cyclodextrin is added to the solution.
- the stoichiometric ratio of branched beta cyclodextrin to steroid is about 2:1, but this will vary with the individual steroid.
- an aqueous solution of branched beta cyclodextrin is prepared such that the solution has a solids concentration of between about 10 to about 50% branched beta cyclodextrin based on the total weight of solution. Good results have been obtained when the aqueous solution of branched beta cyclodextrin has a solids
- This mixing is preferably carried out at ambient conditions. In order to prepare this solution, mixing can be employed. To this aqueous solution of branched beta cyclodextrin a steroid is added in the appropriate amount. The overall mixture of water, branched beta cyclodextrin and steroid is then gently mixed by conventional means while
- steroid is then obtained from the aqueous solution in a conventional manner, typically by evaporation.
- the complex is left in solution and merely concentrated or evaporated to the appropriate
- hydrocortisone may be obtained by concentration to about
- cyclodextrin complex in a pharmaceutical preparation is accomplished in a conventional manner.
- the steroid can more readily be incorporated into a pharmaceutical preparation.
- This example illustrates preparation of a complex of branched beta cyclodextrin and steroid where the steroid is hydrocortisone.
- a solution of branched beta cyclodextrin was prepared to about 14% solids by adding branched beta cyclodextrin to water in the amounts shown below in Table 1. To this solution was added the hydrocortisone in the amounts shown in Table 1 below. The mixture was stirred for about 4 hours and then filtered to remove undissolved
- the filtrate contained the complex, the free branched beta cyclodextrin and trace free
- the hydrocortisone was a commercially available hydrocortisone having a high purity.
- the branched beta cyclodextrin was obtained by solvent precipitation and chromatographic separation from a typical CGT digest of 5 DE waxy hydrolysate.
- beta cyclodextrin and other carbohydrates which are not branched beta cyclodextrin are impurities which were not fully separated.
- This example illustrates preparation of a complex of branched beta cyclodextrin and steroid where the
- hydrocortisone hydrocortisone
- hydrocortisone was a commercially available hydrocortisone having a high purity.
- insoluble steroid after complexation was determined by the difference between the dry weight of the filter paper before filtration and the dry weight of the filter paper after washing to remove excess carbohydrate and drying.
- the branched beta cyclodextrin was obtained by
- This example illustrates preparation of a complex of branched beta cyclodextrin and steroid where the steroid is progesterone.
- a solution of branched beta cyclodextrin was prepared to about 14% solids by adding branched beta cyclodextrin to water in the amounts shown below in
- beta cyclodextrin beta cyclodextrin
- the progesterone was a commercially available progesterone having a high purity.
- the amount of carbohydrate added, free steroid added, and water were measured using a conventional analytical balance. Chromatographic procedures were used to determine the percentages of branched beta
- insoluble steroid after complexation was determined by the difference between the dry weight of the filter paper before filtration and the dry weight of the filter paper after washing to remove excess carbohydrate and drying. The remaining values in the table above were calculated.
- the branched beta cyclodextrin was obtained by
- This example illustrates preparation of a complex of branched beta cyclodextrin and steroid where the steroid is testosterone.
- a solution of branched beta cyclodextrin was prepared to about 14% solids by adding branched beta cyclodextrin to water in the amounts shown below in Table 4. To this solution was added the testosterone in the amounts shown in Table 4 below. The mixture was stirred for about 20 hours and then filtered to remove undissolved
- the filtrate contained the complex
- the testosterone was a commercially available
- the amount of carbohydrate added, free steroid added, and water were measured using a conventional analytical balance. Chromatographic procedures were used to determine the percentages of branched beta cyclodextrin, beta cyclodextrin and other carbohydrates present in the carbohydrates added. The amount of insoluble steroid after complexation was determined by the difference
- the branched beta cyclodextrin was obtained by
- This example illustrates preparation of a complex of branched beta cyclodextrin and steroid where the steroid is hydrocortisone.
- a solution of branched beta cyclodextrin was prepared to about 14% solids by adding branched beta cyclodextrin to water in the amounts shown below in Table 5. To this solution was added the hydrocortisone in the amounts shown in Table 5 below. The mixture was stirred for about 21 hours and then filtered to remove undissolved hydrocortisone. The filtrate contained the complex, the free branched beta cyclodextrin and trace free hydrocortisone. This example was run at ambient conditions. Table 5 below further illustrates this example.
- the branched beta cyclodextrin was isolated from pyrolyzed branched beta cyclodextrin by solvent precipitation and chromatographic separation.
- the hydrocortisone was a commercially available hydrocortisone having a high purity.
- insoluble steroid after complexation was determined by the difference between the dry weight of the filter paper before filtration and the dry weight of the filter paper after washing to remove excess carbohydrate and drying. The remaining values in the table above were calculated.
- This example illustrates preparation of a complex of branched beta cyclodextrin and steroid where the
- hydrocortisone hydrocortisone
- the hydrocortisone was a commercially available hydrocortisone having a high purity.
- This example illustrates preparation of a complex of branched beta cyclodextrin and steroid where the
- steroid is cholesterol.
- Table 7 To this solution was added the cholesterol in the amounts shown in Table 7 below. The mixture was stirred for about 20 hours and then filtered to remove undissolved cholesterol. The filtrate contained the complex, the free branched beta cyclodextrin and trace free cholesterol. This example was run at ambient conditions. Table 7 below further illustrates this example.
- the cholesterol was a commercially available
- the amount of carbohydrate added, free steroid added, and water were measured using a conventional analytical balance. Chromatographic procedures were used to determine the percentages of branched beta cyclodextrin, beta cyclodextrin and other carbohydrates present in the carbohydrates added. The amount of insoluble steroid after complexation was determined by the difference between the dry weight of the filter paper before filtration and the dry weight of the filter paper after washing to remove excess carbohydrate and drying. The remaining values in the table above were calculated.
- the branched beta cyclodextrin was obtained by solvent precipitation and chromatographic separation from a typical CGT digest of 5 DE waxy hydrolysate.
- beta cyclodextrin and other carbohydrates which are not branched beta cyclodextrin are impurities which were not fully separated.
- the present invention produces superior results compared to the gamma and beta cyclodextrin and comparable results to dimethyl beta cyclodextrin.
Abstract
A complex of branched beta cyclodextrin and steroid is formed by mixing a steroid and a branched beta cyclodextrin together in water for a period of about 4 to 24 hours under ambient conditions. The solubility of the steroid is increased about 95 times by employing the complex.
Description
WATER SOLUBLE BRANCHED
BETA CYCLODEXTRIN STEROID COMPLEX
This invention relates to a complex of branched beta cyclodextrin and steroid and the use of such a complex to make the steroid water soluble.
Starch occurs naturally in a variety of plants such as corn, potato, sorghum and rice and is extracted from portions of the plant by a milling operation which
separates the starch from the plant. Physically the starch is in a granular form which typically comprises both amylose and amylopectin. Amylose is a straight chained polymer of anhydroglucose units bonded together by alpha 1,4 bonds while amylopectin is a polymer
composed of a straight chain of alpha 1,4 anhydroglucose onto which side chains of alpha 1,4 anhydroglucose
polymers are bonded. In amylopectin, the bond between the straight chain and the side chain is an alpha 1,6 bond. The amount of amylose and amylopectin in a starch granule depends on the source of the starch. For example, high amylose corn starch contains about a 50:50 ratio while waxy corn starch contains about a 99:1 ratio of amylopectin to amylose.
Cyclodextrins, also called Schardingers dextrins, cycloamyloses, cyclomaltoses and cycloglucans, are
polymers of anhydroglucose polymers, bonded together by
alpha 1,4 bonds to form a ringed compound. A six membered ring is called alpha cyclodextrin, seven, beta cyclodextrin and eight, gamma cyclodextrin. These six, seven and eight membered rings are also referred to as cyclomaltohexaose, cyclomaltoheptaose and
cyclomaltooctaose, respectively.
Branched cyclodextrins were described as early as
1965 by French and his co-workers, see French et al.,
"Archives of Biochem. and Biophys.", Volume III, 1965, pages 153-150, but had been studied very little until recently. Branched beta cyclodextrins, as their name implies, have one or more anhydroglucose units bonded onto the ring structure such that a branch extends out from the ring structure. The branch is bonded to the ring by an alpha 1,6 bond where the branched beta cyclodextrin is obtained from an enzymatic process.
Steroids are typically used in aqueous media and ointments as pharmaceutical preparations for treatment of the skin and eyes. Because steroids are highly water insoluble, any aqueous medium containing steroids must be vigorously shaken before application. Steroids are classified as lipids because they are highly water insoluble and are soluble in organic solvents.
In order to increase the water solubility of the steroid, it has been suggested in U.S. Patent No.
4,383,992 issued May 17, 1983 that a complex of beta cyclodextrin and steroid be formed. It is alleged that such a complex is water soluble. Typically, a complex of a steroid and unsubstituted beta cyclodextrin contains less than about ½% soluble steroid at ambient conditions.
It has also been suggested that in order to increase the water solubility of a steroid a complex of alpha or gamma cyclodextrin and steroid be formed. Under ambient conditions, the alpha cyclodextrin-steroid solution typically contains less than about 1% soluble steroid and the gamma cyclodextrin-steroid solution also typically contains less than about 1% soluble steroid.
It has further been suggested that the beta
cyclodextrin be chemically modified by reacting the beta cyclodextrin with methyl groups to form dimethyl beta cyclodextrin and then form a complex with a steroid.
Such a chemically modified starch is not ideal for
pharmaceutical use.
It has now been discovered that branched beta
cyclodextrin will form a complex with a steroid and that such a complex is highly water soluble. In fact, it has been found that such a complex may have a solubility up to about 2800 times greater than that of the steroid itself and about 100 times greater than that of the complex of beta cyclodextrin and steroid.
These results are surprising because there had been speculation that the branch of anhydroglucose might interfere with or in some way react with the steroid itself and thus inhibit the complexation phenomenon between the steroid and the cavity of branched beta cyclodextrin. This is especially true for branched beta cyclodextrin where the branch length was greater than one anhydroglucose unit. Additionally, it is surprising that the complex of branched beta cyclodextrin and
steroid has a solubility comparable to a complex of dimethyl-beta cyclodextrin and steroid. This is
surprising because of the difference in chemical structure between the branched beta cyclodextrin and dimethyl-beta cyclodextrin.
Further, it is surprising that a complex forms between branched beta cyclodextrin and a steroid because of the hydrophillic nature of the branch itself and the hydrophobic nature of steroids.
Further, it is surprising that crystals of branched beta cyclodextrin and steroid were formed where the branch is one anhydroglucose unit because branched beta cyclodextrin having a branch of one anhydroglucose unit does not form a crystalline structure alone.
Branched beta cyclodextrins are conventionally prepared by treating starch slurry high in amylopectin
with an enzyme, cyclodextrin glycosyltransferase (CGT), at the appropriate pH, temperature and time for
the selected CGT. The starch used for this enzymatic preparation of branched beta cyclodextrin may be from any selected plant variety; however, it is preferable that the starch be high in amylopectin content. The enzyme CGT is obtained from microorganisms such as
Bacillus macerans, B. megaterium, B. circulans, B.
stearothermophilus and Bacillus sp. (alkalophilic) as well as others. Conventionally, the starch is slurried in aqueous solution at a concentration up to about 35% by weight solids. The slurry is then subjected to gelatinization and liquefaction by enzyme or acid to about 1 to about 5 DE. The preferred enzyme for
liquefaction is bacterial alpha amylase. After
deactivating the liquefying enzyme, the selected CGT is added to the gelatinized and liquefied slurry and the pH, temperature and time of the treatment are adjusted depending on the selected enzyme. Generally, the pH is between about 4.5 to about 8.5, the temperature ranges between ambient to about 75°C and the length of the reaction runs for about ten hours to seven days. The amount of branched beta cyclodextrin will vary depending on the treatment conditions and the starch selected.
In order to produce predominantly beta cyclodextrin
and branched beta cyclodextrin, the reaction between CGT and the gelatinized and liquefied starch slurry is
conducted under a solvent such as toluene or p-xylene.
Such solvents substantially facilitate the isolation of branched beta cyclodextrin.
Normally, when starch is treated with CGT, branched beta cyclodextrins, beta cyclodextrins and other dextrins are formed. In order to obtain branched beta
cyclodextrin, the branched beta cyclodextrin must be separated from the beta cyclodextrin and the other
dextrins.
The purification and separation of branched beta cyclodextrin can be successfully accomplished by employing the method taught in co-pending application Serial No.
071,097 filed July 8, 1987, which is incorporated by reference herein. As taught by that reference, branched beta cyclodextrin is separated from beta cyclodextrin and other dextrins by forming a first precipitate and a first liquor from an aqueous first solution containing branched beta cyclodextrin by the addition of a beta cyclodextrin complexant to the aqueous first solution; recovering the first precipitate; forming a second aqueous solution with the first precipitate; forming a second precipitate and a second liquor from said second solution by the addition of a beta cyclodextrin complexant to said
second solution; recovering the second liquor; and, finally, recovering branched beta cyclodextrin from said second liquor. The aqueous starting solution is an aqueous solution containing branched and non-branched beta cyclodextrins such that about 1% or more of the total solids content of the solution is branched beta
cyclodextrin and such that the non-branched beta
cyclodextrin is in an amount in excess of the branched beta cyclodextrin. Invariably, some beta cyclodextrin will be present with the branched beta cyclodextrin.
Branched beta cyclodextrins are characterized more specifically by the length of or the number of glucose units in the branch. For example, a branched beta
cyclodextrin which has a single glucose unit attached to the ringed structure is called 6-alpha-D-glucosylcyclomaltoheptaose or GlcG7 , a branched beta cyclodextrin having two glucose units on the branch is referred to as 6-alpha-D-maltosylcyclomaltoheptaose or G2cG7. A branched beta cyclodextrin with three glucose units on the branch is referred to conveniently as G3cG7, four glucose units as G4cG7, and so on.
The branched beta cyclodextrins may also be formed by a pyrolysis method, preferably as taught by the
co-pending U.S. application filed concurrently
herewith. Such branched beta cyclodextrins
have branches of anhydroglucose units which are bonded to the ring structure of the beta cyclodextrin by bonds other than a 1,6 bond. Branched beta cyclodextrin can also be formed by enzymatic techniques where
anhydroglucose units are added onto the cyclodextrin ring, see for example U.S. Patent No. 4,668,626 issued May 26, 1987. The term "branched beta cyclodextrin" as used in the specification and claims means branched beta
cyclodextrin obtained from enzyme or pyrolysis.
Preferably, the branch length of the branched beta cyclodextrins used in the present invention is between about 1 to about 7 glucose units, i.e. GlcG7 to G7cG7.
Good results have been obtained with GlcG7 to G3cG7.
It is thought that a complex forms between the steroid and the branched beta cyclodextrin where the steroid is a guest molecule inside the cavity of the branched beta cyclodextrin, which is acting as a host molecule. It is thought that not all of the steroid can physically fit inside the cavity of the branched beta cyclodextrin but that a portion of the polycyclic ring structure fits therein. Upon complexing with the branched beta cyclodextrin, the steroid, which is typically water insoluble, becomes highly water soluble.
Steroids which are suitable for complexing with branched beta cyclodextrins have a molecular structure
which allows at least a portion of the steroid's molecular structure to be housed inside the cavity of the branched beta cyclodextrin. Suitable steroids include
corticosteroids such as dexamethasone, prednisolone and hydrocortisone; androgens; anabolic steroids; estrogens; and progestagens. Good results have been obtained with hydrocortisone, progesterone and testosterone.
In order to form the complex between the branched beta cyclodextrin and the steroid, an aqueous mixture of steroid and branched beta cyclodextrin is prepared and gently mixed at ambient conditions. Stoichiometrically, the ratio of branched beta cyclodextrin to steroid is about 1:1; however, in order to complex as much of the steroid as possible, preferably an excess of branched beta cyclodextrin is added to the solution. Most
preferably, the stoichiometric ratio of branched beta cyclodextrin to steroid is about 2:1, but this will vary with the individual steroid.
Preferably, first an aqueous solution of branched beta cyclodextrin is prepared such that the solution has a solids concentration of between about 10 to about 50% branched beta cyclodextrin based on the total weight of solution. Good results have been obtained when the aqueous solution of branched beta cyclodextrin has a solids
concentration of about 14% by weight. This mixing is
preferably carried out at ambient conditions. In order to prepare this solution, mixing can be employed. To this aqueous solution of branched beta cyclodextrin a steroid is added in the appropriate amount. The overall mixture of water, branched beta cyclodextrin and steroid is then gently mixed by conventional means while
maintaining the mixture at ambient conditions. The mixing proceeds until an equilibrium is obtained,
preferably for about 4 to about 24 hours.
The complex of branched beta cyclodextrin and
steroid is then obtained from the aqueous solution in a conventional manner, typically by evaporation.
Alternatively, the complex is left in solution and merely concentrated or evaporated to the appropriate
concentration for use. Crystals of GlcG7 and
hydrocortisone may be obtained by concentration to about
30% solids. Upon cooling and standing at 30% solids the complex crystallizes from solution. The material
obtained from drying is an equilibrium mixture of complex, free branched beta cyclodextrin and a trace of free steroid. If crystals are obtained, as is the case with
GlcG7 and hydrocortisone, subsequent solutions of the crystalline complex in water may result in precipitation of free steroid unless an appropriate amount of free branched beta cyclodextrin is present.
Incorporation of the steroid-branched beta
cyclodextrin complex in a pharmaceutical preparation is accomplished in a conventional manner. However, because of the increased solubility of the complex, the steroid can more readily be incorporated into a pharmaceutical preparation.
These and other aspects of the present invention may be more fully understood by reference to the following examples. Example 1
This example illustrates preparation of a complex of branched beta cyclodextrin and steroid where the steroid is hydrocortisone.
A solution of branched beta cyclodextrin was prepared to about 14% solids by adding branched beta cyclodextrin to water in the amounts shown below in Table 1. To this solution was added the hydrocortisone in the amounts shown in Table 1 below. The mixture was stirred for about 4 hours and then filtered to remove undissolved
hydrocortisone. The filtrate contained the complex, the free branched beta cyclodextrin and trace free
hydrocortisone. This example was run at ambient
conditions. Table 1 below further illustrates this example.
TABLE 1
Element Amount (gm)
Carbohydrate added 1.390
Free branched beta cyclodextrin added 1.307 Free branched beta cyclodextrin after
complexation .413
Complexed branched beta cyclodextrin .916 Average molecular weight of
branched beta cyclodextrin 1328
Average DP of branch 1.19
Hydrocortisone complexed in branched
beta cyclodextrin .250
Free beta cyclodextrin added (impurity) .083
Free beta cyclodextrin after complexation .025 Complexed beta cyclodextrin .058
Hydrocortisone complexed in
beta cyclodextrin .019
Free hydrocortisone added .400
Free soluble hydrocortisone after
complexation .002
Insoluble hydrocortisone after
complexation .129
Complexation hydrocortisone (.271 - 002) = .269
S/S0 (S= 271 = 28.65; S0 = .36 mg/ml ) 79.57
9.46
Water 8.54 ml
Solution 9.46 ml
Total Weight of Complex 1.243
Total Weight Hydrocortisone:Branched
beta cyclodextrin 1.166
Table 1 (continued)
Total Weight Hydrocortisone : Beta
cyclodextrin .077
Efficiency (assume 1:1 complex) .916/1.307 = .7008
The hydrocortisone was a commercially available hydrocortisone having a high purity.
The amount of carbohydrate added, free steroid added, and water were measured using a conventional analytical balance. Chromatographic procedures were used to
determine the percentages of branched beta cyclodextrin, beta cyclodextrin and other carbohydrates present in the carbohydrates added. The amount of insoluble steroid after complexation was determined by the difference between the dry weight of the filter paper before
filtration and the dry weight of the filter paper after washing to remove excess carbohydrate and drying. The remaining values in the table above were calculated.
The branched beta cyclodextrin was obtained by solvent precipitation and chromatographic separation from a typical CGT digest of 5 DE waxy hydrolysate.
The beta cyclodextrin and other carbohydrates which are not branched beta cyclodextrin are impurities which were not fully separated.
The solubility of hydrocortisone in water under ambient conditions has been reported as 0.36 mg/ml.
The observed solubility in water of the branched beta
cyclodextrin and hydrocortisone complex in this example after concentration was 65.0 mg/ml under ambient conditions, By employing the present invention the solubility of the steroid has been increased by a factor of 181. Example 2
This example illustrates preparation of a complex of branched beta cyclodextrin and steroid where the
steroid is hydrocortisone.
A solution of branched beta cyclodextrin was
prepared to about 14% solids by adding branched beta
cyclodextrin to water in the amounts shown below in
Table 2. To this solution was added the hydrocortisone in the amounts shown in Table 2 below. The mixture was stirred for about 20 hours and then filtered to remove undissolved hydrocortisone. The filtrate contained the complex, the free branched beta cyclodextrin and trace free hydrocortisone. This example was run at ambient conditions. Table 2 below further illustrates this
example.
TABLE 2
Element Amount (gm)
Carbohydrate added 1.400
Free branched beta cyclodextrin added 1.202
Free branched beta cyclodextrin after
complexation .361
Table 2 (continued)
Complexed branched beta cyclodextrin .841
Average molecular weight of
branched beta cyclodextrin 1828 Average DP of branch 4.27
Hydrocortisone complexed in branched
beta cyclodextrin .167
Free beta cyclodextrin added (impurity) --
Free beta cyclodextrin after complexation -- Complexed beta cyclodextrin --
Hydrocortisone complexed in
beta cyclodextrin --
Free hydrocortisone added .2986
Free soluble hydrocortisone after
complexation .0031
Insoluble hydrocortisone after complexation .1286
Complexation hydrocortisone ( .1700-.0031 ) = .1669
S/S0 (S= 170 = 17.86; S0 = .36 mg/ml ) 49.60
9.52
Water 8.6 ml
Solution 9.52 ml
Total Weight of Complex 1.008
Total Weight Hydrocortisone:Branched
beta cyclodextrin 1.008 Total Weight Hydrocortisone : Beta
cyclodextrin
The hydrocortisone was a commercially available hydrocortisone having a high purity.
The amount of carbohydrate added, free steroid
added, and water were measured using a conventional
analytical balance. Chromatographic procedures were used to determine the percentages of branched beta
cyclodextrin, beta cyclodextrin and other carbohydrates present in the carbohydrates added. The amount of
insoluble steroid after complexation was determined by the difference between the dry weight of the filter paper before filtration and the dry weight of the filter paper after washing to remove excess carbohydrate and drying.
The remaining values in the table above were calculated.
The branched beta cyclodextrin was obtained by
solvent precipitation and chromatographic separation from a typical CGT digest of 5 DE waxy hydrolysate.
The beta cyclodextrin and other carbohydrates which
are not branched beta cyclodextrin are impurities which were not fully separated.
The solubility of hydrocortisone in water under ambient conditions has been reported as 0.36 mg/ml.
The observed solubility in water of the branched beta cyclodextrin and hydrocortisone complex in this example after concentration was 21.4 mg/ml under ambient conditions By employing the present invention the solubility of the steroid has been increased by a factor of 59.
Example 3
This example illustrates preparation of a complex of branched beta cyclodextrin and steroid where the steroid is progesterone.
A solution of branched beta cyclodextrin was prepared to about 14% solids by adding branched beta cyclodextrin to water in the amounts shown below in
Table 3. To this solution was added the progesterone in the amounts shown in Table 3 below. The mixture was stirred for about 20 hours and then filtered to remove undissolved progesterone. The filtrate contained the complex, the free branched beta cyclodextrin and trace free progesterone. This example was run at ambient conditions. Table 3 below further illustrates this example.
TABLE 3
Element Amount ( gm )
Carbohydrate added 1.400
Free branched beta cyclodextrin added 1.202
Free branched beta cyclodextrin after
complexation .677
Complexed branched beta cyclodextrin .525
Average molecular weight of
branched beta cyclodextrin 1828
Average DP of branch 4.27
Table 3 ( continued)
Progesterone complexed in branched
beta cyclodextrin .0904
Free beta cyclodextrin added (impurity) -- Free beta cyclodextrin after complexation --
Complexed beta cyclodextrin --
Progesterone complexed in
beta cyclodextrin --
Free progesterone added .3000 Free soluble progesterone after complexation .00014
Insoluble progesterone after complexation .2095
Complexation progesterone (.0905-.0001) = .0904
S/S0 (S= 90.4 = 9.50; SQ= .016 mg/ml ) 593.5
9.52
Water 8.6 ml
Solution 9.52 ml
Total Weight of Complex .615
Total Weight Progesterone:Branched
beta cyclodextrin .615 Total Weight Progesterone:Beta
cyclodextrin --
Efficiency (complexed/total branched
beta cyclodextrin) .437
The progesterone was a commercially available progesterone having a high purity.
The amount of carbohydrate added, free steroid added, and water were measured using a conventional analytical balance. Chromatographic procedures were used to determine the percentages of branched beta
cyclodextrin, beta cyclodextrin and other carbohydrates present in the carbohydrates added. The amount of
insoluble steroid after complexation was determined by the difference between the dry weight of the filter paper before filtration and the dry weight of the filter paper after washing to remove excess carbohydrate and drying. The remaining values in the table above were calculated.
The branched beta cyclodextrin was obtained by
solvent precipitation and chromatographic separation from a typical CGT digest of 5 DE waxy hydrolysate.
The beta cyclodextrin and other carbohydrates which
are not branched beta cyclodextrin are impurities which were not fully separated.
The solubility of progesterone in water under
ambient conditions has been reported as 0.016 mg/ml.
The observed solubility in water of the branched beta cyclodextrin and progesterone complex in this example after concentration was 44.8 mg/ml under ambient conditions By employing the present invention the solubility of the steroid has been increased by a factor of 2800.
Example 4
This example illustrates preparation of a complex of branched beta cyclodextrin and steroid where the steroid is testosterone.
A solution of branched beta cyclodextrin was prepared to about 14% solids by adding branched beta cyclodextrin to water in the amounts shown below in Table 4. To this solution was added the testosterone in the amounts shown in Table 4 below. The mixture was stirred for about 20 hours and then filtered to remove undissolved
testosterone. The filtrate contained the complex,
the free branched beta cyclodextrin and trace free
testosterone. This example was run at ambient conditions.
Table 4 below further illustrates this example.
TABLE 4
Element Amount ( gm )
Carbohydrate added 1 . 400
Free branched beta cyclodextrin added 1 . 202
Free branched beta cyclodextrin after
complexation .644
Complexed branched beta cyclodextrin . 558
Average molecular weight of
branched beta cyclodextrin 1828
Average DP of branch 4 . 27
Testosterone complexed in branched
beta cyclodextrin .088
Free beta cyclodextrin added (impurity)
Table 4 (continued)
Free beta cyclodextrin after complexation --
Complexed beta cyclodextrin --
Testosterone complexed in
beta cyclodextrin --
Free testosterone added .303
Free soluble testosterone after complexation .00034
Insoluble testosterone after complexation .215
Complexation testosterone (.088-.000) = .088
S/S0 (S= 88 = 9.24; S0 = .040 mg/ml) 231.1
9.52
Water 8.6 ml
Solution 9.52 ml
Total Weight of Complex .646
Total Weight Testosterone :Branched
beta cyclodextrin .646
Total Weight Testosterone: Beta
cyclodextrin
Efficiency Complexed: Total Branched
beta cyclodextrin .464
The testosterone was a commercially available
testosterone having a high purity.
The amount of carbohydrate added, free steroid added, and water were measured using a conventional analytical balance. Chromatographic procedures were used to
determine the percentages of branched beta cyclodextrin, beta cyclodextrin and other carbohydrates present in the carbohydrates added. The amount of insoluble steroid after complexation was determined by the difference
between the dry weight of the filter paper before
filtration and the dry weight of the filter paper after washing to remove excess carbohydrate and drying. The remaining values in the table above were calculated.
The branched beta cyclodextrin was obtained by
solvent precipitation and chromatographic separation
from a typical CGT digest of 5 DE waxy hydrolysate.
The beta cyclodextrin and other carbohydrates which
are not branched beta cyclodextrin are impurities which were not fully separated.
The solubility of testosterone in water under
ambient conditions has been reported as 0.040 mg/ml.
The observed solubility in water of the branched beta cyclodextrin and testosterone complex in this example after concentration was 39.8 mg/ml under ambient conditions. By employing the present invention the solubility of the steroid has been increased by a factor of 995.
Example 5
This example illustrates preparation of a complex of branched beta cyclodextrin and steroid where the
steroid is hydrocortisone.
A solution of branched beta cyclodextrin was prepared to about 14% solids by adding branched beta cyclodextrin to water in the amounts shown below in Table 5. To this solution was added the hydrocortisone in the amounts shown in Table 5 below. The mixture was stirred for about 21 hours and then filtered to remove undissolved hydrocortisone. The filtrate contained the complex, the free branched beta cyclodextrin and trace free hydrocortisone. This example was run at ambient conditions. Table 5 below further illustrates this example.
TABLE 5
Element Amount ( gm ) Carbohydrate added 1.970
Free branched beta cyclodextrin added 1.604
Free branched beta cyclodextrin after
complexation .481
Complexed branched beta cyclodextrin 1.123
Average molecular weight of
branched beta cyclodextrin 1867
Average DP of branch* 4.52
Hydrocortisone complexed in branched
beta cyclodextrin .218
Free beta cyclodextrin added (impurity) .090
Free beta cyclodextrin after complexation .023
Complexed beta cyclodextrin .071
Table 5 (continued)
Hydrocortisone complexed in
beta cyclodextrin .023
Free hydrocortisone added .545 Free soluble hydrocortisone after
complexation .0044
Insoluble hydrocortisone after complexation .299
Complexation hydrocortisone (.246-.004) = .242
S/S0 (S= 246 = 18.36; S0 = .36 mg/ml ) 51.00
13.40
Water 12.101 ml
Solution 13.40 ml
Total Weight of Complex 1.435
Total Weight Hydrocortisone:Branched
beta cyclodextrin 1.341
Total Weight Hydrocortisone:Beta
cyclodextrin .094
The branched beta cyclodextrin was isolated from pyrolyzed branched beta cyclodextrin by solvent precipitation and chromatographic separation.
The hydrocortisone was a commercially available hydrocortisone having a high purity.
The amount of carbohydrate added, free steroid
added, and water were measured using a conventional
analytical balance. Chromatographic procedures were used to determine the percentages of branched beta
cyclodextrin, beta cyclodextrin and other carbohydrates present in the carbohydrates added. The amount of
insoluble steroid after complexation was determined by the difference between the dry weight of the filter paper before filtration and the dry weight of the filter paper after washing to remove excess carbohydrate and drying. The remaining values in the table above were calculated.
The solubility of hydrocortisone in water under ambient conditions has been reported as 0.36 mg/ml.
The observed solubility in water of the branched beta cyclodextrin and hydrocortisone complex in this example after concentration was 87.1 mg/ml under ambient conditions By employing the present invention the solubility of the steroid has been increased by a factor of 242.
Example 6
This example illustrates preparation of a complex of branched beta cyclodextrin and steroid where the
steroid is hydrocortisone.
A solution of branched beta cyclodextrin was
prepared to about 14% solids by adding branched beta cyclodextrin to water in the amounts shown below in
Table 6. To this solution was added the hydrocortisone in the amounts shown in Table 6 below. The mixture was stirred for about 4 hours and then filtered to remove undissolved hydrocortisone. The filtrate contained the complex, the free branched beta cyclodextrin and trace free hydrocortisone. This example was run at ambient conditions. Table 6 below further illustrates this example.
TABLE 6
Element Amount (gm )
Carbohydrate added 1.670
Free branched beta cyclodextrin added 1.635
Free branched beta cyclodextrin after
complexation .489
Complexed branched beta cyclodextrin 1.146
Average molecular weight of
branched beta cyclodextrin 4035
Average DP of branch 17.9
Hydrocortisone complexed in branched
beta cyclodextrin .103
Free beta cyclodextrin added (impurity) --
Free beta cyclodextrin after complexation --
Complexed beta cyclodextrin --
Hydrocortisone complexed in
beta cyclodextrin --
Free hydrocortisone added .150
Free soluble hydrocortisone after
complexation .004
Table 6 ( continued)
Insoluble hydrocortisone after complexation .043
Complexation hydrocortisone (.107-.004) = .103
S/S0 (S= 107 = 9.39; S0 = .36 mg/ml ) 26.07
11.4
Water 10.3 ml
Solution 11.4 ml
Total Weight of Complex 1.249
Total Weight Hydrocortisone:Branched
beta cyclodextrin 1.249
Total Weight Hydrocortisone: Beta
cyclodextrin --
Efficiency (assume 1:1 complex)
1.146/1.635 .7009 The hydrocortisone was a commercially available hydrocortisone having a high purity.
The amount of carbohydrate added, free steroid added, and water were measured using a conventional analytical balance. Chromatographic procedures were used to
determine the percentages of branched beta cyclodextrin, beta cyclodextrin and other carbohydrates present in the carbohydrates added. The amount of insoluble steroid after complexation was determined by the difference between the dry weight of the filter paper before
filtration and the dry weight of the filter paper after washing to remove excess carbohydrate and drying. The remaining values in the table above were calculated.
The branched beta cyclodextrin was obtained by
solvent precipitation and chromatographic separation
from a typical CGT digest of 5 DE waxy hydrolysate.
The beta cyclodextrin and other carbohydrates which
are not branched beta cyclodextrin are impurities which were not fully separated.
The solubility of hydrocortisone in water under
ambient conditions has been reported as 0.36 mg/ml.
The observed solubility in water of the branched beta cyclodextrin and hydrocortisone complex in this example after concentration was 53.6 mg/ml under ambient conditions, By employing the present invention the solubility of the steroid has been increased by a factor of 149.
Example 7
This example illustrates preparation of a complex of branched beta cyclodextrin and steroid where the
steroid is cholesterol.
A solution of branched beta cyclodextrin was
prepared to about 14% solids by adding branched beta
cyclodextrin to water in the amounts shown below in
Table 7. To this solution was added the cholesterol in the amounts shown in Table 7 below. The mixture was stirred for about 20 hours and then filtered to remove undissolved cholesterol. The filtrate contained the
complex, the free branched beta cyclodextrin and trace free cholesterol. This example was run at ambient conditions. Table 7 below further illustrates this example.
TABLE 7
Element Amount (gm)
Carbohydrate added 1.400
Free branched beta cyclodextrin added 1.202
Free branched beta cyclodextrin after
complexation 1.037
Complexed branched beta cyclodextrin .165
Average molecular weight of
branched beta cyclodextrin 1828
Average DP of branch 4.27
Cholesterol complexed in branched
beta cyclodextrin .035
Free beta cyclodextrin added (impurity) --
Free beta cyclodextrin after complexation --
Complexed beta cyclodextrin -- Cholesterol complexed in
beta cyclodextrin --
Free cholesterol added .300
Free soluble cholesterol after complexation .00002 Insoluble cholesterol after complexation .265
Complexation cholesterol (.035-.000) = .035
S/S0 (S= 35 = 3.68; S0 = .002 mg/ml ) 1838
9.52
Water 8.6 ml
Table 7 (continued)
Solution 9.52 ml
Total Weight of Complex .200
Total Weight Cholesterol:Branched
beta cyclodextrin .200
Total Weight Cholesterol:Beta
cyclodextrin --
Efficiency .137
The cholesterol was a commercially available
cholesterol having a high purity.
The amount of carbohydrate added, free steroid added, and water were measured using a conventional analytical balance. Chromatographic procedures were used to determine the percentages of branched beta cyclodextrin, beta cyclodextrin and other carbohydrates present in the carbohydrates added. The amount of insoluble steroid after complexation was determined by the difference between the dry weight of the filter paper before filtration and the dry weight of the filter paper after washing to remove excess carbohydrate and drying. The remaining values in the table above were calculated.
The branched beta cyclodextrin was obtained by solvent precipitation and chromatographic separation from a typical CGT digest of 5 DE waxy hydrolysate.
The beta cyclodextrin and other carbohydrates which
are not branched beta cyclodextrin are impurities which were not fully separated.
The solubility of cholesterol in water under
ambient conditions has been reported as 0.002 mg/ml.
The observed solubility in water of the branched beta cyclodextrin and cholesterol complex in this example was 3.7 mg/ml under ambient conditions. By employing the present invention the solubility of the steroid has been increased by a factor of 1838. Example 8
This example compares the solubility of the branched beta cyclodextrin-steroid complex of the present
invention against like steroids complexed with gamma cyclodextrin, alpha cyclodextrin, beta cyclodextrin, and dimethyl beta cyclodextrin. The gamma, alpha, and dimethyl beta cyclodextrin complexes were prepared under ambient conditions with cyclodextrins at a concentration of 0.075 M. Because of the low solubility of beta cyclodextrin, the concentration of this solution was 0.0112 M in water under ambient conditions. The results of this example are reported in Table 8 below.
Table 8
Solubility (mg/ml)
Methyltestosterone(a)
Testosterone(b) Progesterone Hydrocortisone
Present
Invention 10.03(b) 10.32 20.66
(Example 4) (Example 3) (Example 1)
Dimethyl Beta
Cyclodextrin 13.70(a) 13.00 20.30
Gamma
Cyclodextrin 1.40(a) 0.09 4.30
Alpha
Cyclodextrin 0.43(a) 0.27 3.80
Beta
Cyclodextrin 0.19(a) 0.09 1.82
Clearly the present invention produces superior results compared to the gamma and beta cyclodextrin and comparable results to dimethyl beta cyclodextrin.
The values of the dimethyl beta, gamma and alpha cyclodextrin steroid complex were taken from reported data.
The values of the present invention reported above were calculated from Examples 1, 3 and 4 above for comparative purposes.
It will be understood that the preferred embodiments of the present invention herein chosen for the purpose of illustration are intended to cover all changes and modifications of the preferred embodiments of the present invention which do not constitute a departure from the spirit and scope of the present invention.
Claims
1. A water soluble compound formed by complexing branched beta cyclodextrin with a steroid having a molecular structure that can fit into the cavity of the branched beta cyclodextrin and form a complex with the branched beta cyclodextrin.
2. The water soluble compound of claim 1 wherein the steroid is selected from the group consisting of : corticosteroids, androgens, anabolic steroids, estrogens, and progestagens; that have a molecular structure that can fit into the cavity of the branched beta cyclodextrin and form a complex with the branched beta cyclodextrin.
3. The water soluble compound of claim 1 wherein the steroid is selected from the group consisting of: dexamethasone, prednisolone and cholesterol.
4. The water soluble compound of claim 1 wherein the branched beta cyclodextrin has a branch containing between about 1 glucose unit to about 7 glucose units.
5. The water soluble compound of claim 3 wherein the branched beta cyclodextrin has a branch containing between about 1 glucose unit to about 7 glucose units.
6. A method for increasing the solubility of a steroid comprising the steps of:
(a) forming an aqueous mixture of branched beta cyclodextrin and steroid in a stoichiometric ratio of about 1:1; and
(b) recovering a complex of branched beta cyclodextrin and steroid.
7. The method of claim 6 wherein the formation of the aqueous mixture of branched beta cyclodextrin and steroid is conducted under ambient conditions.
8. The method of claim 6 wherein the formation step is accomplished by adding branched beta cyclodextrin to water and then adding the steroid and mixing the branched beta cyclodextrin and steroid in water for a period of about 4 to about 24 hours under ambient conditions.
9. The method of claim 6 wherein the recovery step is accomplished by evaporation.
10. The method of claim 8 wherein the recovery step is accomplished by evaporation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US23244088A | 1988-08-15 | 1988-08-15 | |
| US232,440 | 1988-08-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1990001320A1 true WO1990001320A1 (en) | 1990-02-22 |
Family
ID=22873120
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1989/003471 WO1990001320A1 (en) | 1988-08-15 | 1989-08-14 | Water soluble branched beta cyclodextrin steroid complex |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0381747A4 (en) |
| JP (1) | JPH0643314B2 (en) |
| HU (1) | HU206366B (en) |
| WO (1) | WO1990001320A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991013100A1 (en) * | 1990-03-02 | 1991-09-05 | Australian Commercial Research & Development Limited | Cyclodextrin compositions and methods for pharmaceutical and industrial applications |
| EP0477107A1 (en) * | 1990-09-21 | 1992-03-25 | Laboratoires BESINS ISCOVESCO Société anonyme dite : | Steroids contained in cyclodextrins |
| WO2000021570A1 (en) * | 1998-10-14 | 2000-04-20 | Schering Aktiengesellschaft | Combination of norpregnane derivatives and cyclodextrin |
| GB2482868A (en) * | 2010-08-16 | 2012-02-22 | Franciscus Wilhelmus Henricus Maria Merkus | A testosterone liquid spray formulation for oromucosal administration |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0709099A3 (en) | 1994-09-28 | 1996-07-24 | Senju Pharma Co | An aqueous nasal suspension comprising cyclodextrin |
| US20070020299A1 (en) | 2003-12-31 | 2007-01-25 | Pipkin James D | Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid |
Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4303787A (en) * | 1979-06-01 | 1981-12-01 | Rikagaku Kenkyusho | Process for recovering cyclodextrins |
| US4383992A (en) * | 1982-02-08 | 1983-05-17 | Lipari John M | Water-soluble steroid compounds |
| GB2109381A (en) * | 1981-10-27 | 1983-06-02 | Richter Gedeon Vegyeszet | Inclusion complexes of steroids with delta -cyclodextrin |
| WO1985002767A1 (en) * | 1983-12-21 | 1985-07-04 | Janssen Pharmaceutica N.V. | Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation |
| US4555504A (en) * | 1981-01-23 | 1985-11-26 | Burroughs Wellcome Co. | Inclusion complex of β-cyclodextrin and digoxin |
| US4596795A (en) * | 1984-04-25 | 1986-06-24 | The United States Of America As Represented By The Secretary, Dept. Of Health & Human Services | Administration of sex hormones in the form of hydrophilic cyclodextrin derivatives |
| US4668626A (en) * | 1984-10-12 | 1987-05-26 | Director Of National Food Research Institute, Ministry Of Agriculture, Forestry And Fisheries | Method for the preparation of branched cyclodextrins |
| JPS62123196A (en) * | 1985-11-22 | 1987-06-04 | Nisshin Flour Milling Co Ltd | Prednisolone inclusion compound |
| JPS62164701A (en) * | 1986-01-14 | 1987-07-21 | Shokuhin Sangyo Baioriakutaa Syst Gijutsu Kenkyu Kumiai | Diglucosyl-alpha-cyclodextrin and its production |
| JPS62281855A (en) * | 1986-05-29 | 1987-12-07 | Daikin Ind Ltd | Clathrate compound containing vitamin, vitamin derivative or hormone |
| JPS63135402A (en) * | 1986-11-27 | 1988-06-07 | Tokuyama Soda Co Ltd | Cyclodextrin composition |
| US4834985A (en) * | 1986-06-05 | 1989-05-30 | Euroceltique S.A. | Controlled release pharmaceutical composition |
| US4840679A (en) * | 1987-07-08 | 1989-06-20 | American Maize-Products Company | Purification and separation of branched beta-cyclodextrins |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6327440A (en) * | 1986-07-18 | 1988-02-05 | Sanraku Inc | Glucosylated branched cyclodextrin-containing composition |
| US5002935A (en) * | 1987-12-30 | 1991-03-26 | University Of Florida | Improvements in redox systems for brain-targeted drug delivery |
-
1989
- 1989-08-14 EP EP19890909972 patent/EP0381747A4/en not_active Ceased
- 1989-08-14 WO PCT/US1989/003471 patent/WO1990001320A1/en not_active Application Discontinuation
- 1989-08-15 HU HU894199A patent/HU206366B/en not_active IP Right Cessation
- 1989-08-15 JP JP1210560A patent/JPH0643314B2/en not_active Expired - Lifetime
Patent Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4303787A (en) * | 1979-06-01 | 1981-12-01 | Rikagaku Kenkyusho | Process for recovering cyclodextrins |
| US4555504A (en) * | 1981-01-23 | 1985-11-26 | Burroughs Wellcome Co. | Inclusion complex of β-cyclodextrin and digoxin |
| GB2109381A (en) * | 1981-10-27 | 1983-06-02 | Richter Gedeon Vegyeszet | Inclusion complexes of steroids with delta -cyclodextrin |
| US4383992A (en) * | 1982-02-08 | 1983-05-17 | Lipari John M | Water-soluble steroid compounds |
| WO1985002767A1 (en) * | 1983-12-21 | 1985-07-04 | Janssen Pharmaceutica N.V. | Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation |
| US4596795A (en) * | 1984-04-25 | 1986-06-24 | The United States Of America As Represented By The Secretary, Dept. Of Health & Human Services | Administration of sex hormones in the form of hydrophilic cyclodextrin derivatives |
| US4668626A (en) * | 1984-10-12 | 1987-05-26 | Director Of National Food Research Institute, Ministry Of Agriculture, Forestry And Fisheries | Method for the preparation of branched cyclodextrins |
| JPS62123196A (en) * | 1985-11-22 | 1987-06-04 | Nisshin Flour Milling Co Ltd | Prednisolone inclusion compound |
| JPS62164701A (en) * | 1986-01-14 | 1987-07-21 | Shokuhin Sangyo Baioriakutaa Syst Gijutsu Kenkyu Kumiai | Diglucosyl-alpha-cyclodextrin and its production |
| JPS62281855A (en) * | 1986-05-29 | 1987-12-07 | Daikin Ind Ltd | Clathrate compound containing vitamin, vitamin derivative or hormone |
| US4834985A (en) * | 1986-06-05 | 1989-05-30 | Euroceltique S.A. | Controlled release pharmaceutical composition |
| JPS63135402A (en) * | 1986-11-27 | 1988-06-07 | Tokuyama Soda Co Ltd | Cyclodextrin composition |
| US4840679A (en) * | 1987-07-08 | 1989-06-20 | American Maize-Products Company | Purification and separation of branched beta-cyclodextrins |
Non-Patent Citations (2)
| Title |
|---|
| CHEMICAL ABSTRACTS, Volume 110, No. 14, published 03 April 1989, (Columbus, Ohio), K. KOIZUMI et al, "Pharmaceutical Compositions Containing Glucosylated alpha, beta, or gamma-Cyclodextrins to Improve Water-Solubility of Drugs," page 441, Abstract No. 121385 c, Jpn. Kokai Tokkyo Koho JP63-27440, 05 February 1988, Appl. 86/168015 18 July 1986, 7pp. * |
| See also references of EP0381747A4 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991013100A1 (en) * | 1990-03-02 | 1991-09-05 | Australian Commercial Research & Development Limited | Cyclodextrin compositions and methods for pharmaceutical and industrial applications |
| EP0477107A1 (en) * | 1990-09-21 | 1992-03-25 | Laboratoires BESINS ISCOVESCO Société anonyme dite : | Steroids contained in cyclodextrins |
| FR2667070A1 (en) * | 1990-09-21 | 1992-03-27 | Besins Iscovesco Labo | STEROIDS INCLUDED IN CYCLODEXTRINS PROCESS FOR THEIR PREPARATION COMPLEXES AND CORRESPONDING GOLENIC FORMS AND THEIR THERAPEUTIC APPLICATIONS. |
| WO1992004917A1 (en) * | 1990-09-21 | 1992-04-02 | Laboratoires Besins Iscovesco | Steroids included in cyclodextrines |
| WO2000021570A1 (en) * | 1998-10-14 | 2000-04-20 | Schering Aktiengesellschaft | Combination of norpregnane derivatives and cyclodextrin |
| GB2482868A (en) * | 2010-08-16 | 2012-02-22 | Franciscus Wilhelmus Henricus Maria Merkus | A testosterone liquid spray formulation for oromucosal administration |
| WO2012022446A1 (en) | 2010-08-16 | 2012-02-23 | Innotesto Bvba | Testosterone solutions for the treatment of testosterone deficiency |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0643314B2 (en) | 1994-06-08 |
| HUT51287A (en) | 1990-04-28 |
| HU206366B (en) | 1992-10-28 |
| EP0381747A4 (en) | 1991-09-11 |
| JPH02167228A (en) | 1990-06-27 |
| EP0381747A1 (en) | 1990-08-16 |
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