RU2173172C2 - Solid pharmaceutical preparations containing physical mixture of cyclodextrin sulfoalkyl ether and therapeutic agent - Google Patents

Abstract

FIELD: medicine, pharmacy. SUBSTANCE: invention claims a pharmaceutical composition containing acceptable carrier and physical mixture of derivatives of cyclodextrin sulfoalkyl ether and therapeutically effective amount of therapeutic agent. At least 50% of therapeutic agent does not form a complex with derivative of cyclodextrin sulfoalkyl ether of the formula (I):

where n = 4, 5 or 6; each of R₁,R₂,R₃,R₄,R₅,R₆,R₇,R₈ и R₉, means independently each of other -O- or -O-(C₂-C₆--alkylene)-SO₃- where at least one of R₁ and R₂ means independently each of other -O-(C₂-C₆alkylene)-SO₃-. Each of S₁-S₉ means independently pharmaceutically acceptable cation. Invention claims a method of preparing pharmaceutical medicinal form containing compound of the formula (I). Method involves preparing firstly solid core containing the above indicated physical mixture, pharmaceutical carrier followed by application of film coat containing film-forming agent and pore-forming agent on the core. Invention claims a pharmaceutical preparation obtained by method to be claimed. Obtained preparations exhibit increased solubility and bioavailability of an active agent. Method of their preparing does not require the preliminary preparing complexes of active components with cyclodextrin derivative. EFFECT: improved properties of agent, simplified technology of preparing. 17 cl, 20 dwg, 15 tbl, 7 ex

Description

 The invention relates to solid pharmaceutical preparations based on cyclodextrin. More specifically, the present invention relates to preparations based on sulfoalkyl ether cyclodextrin (SAE-CD), in which the bulk of the therapeutic agent does not form a complex with SAE-CD.

State of the art
US patent N 5134127 (patent '127) relates to derivatives of sulfoalkyl ether cyclodextrin (SAE-CD). Derivatives of SAE-CD are proposed for use as solubilizing agents for poorly water-soluble or water-insoluble drugs in various pharmaceutical dosage forms.

 Cyclodextrin / drug complexes are usually prepared prior to their use in pharmaceutical preparations. The '127 patent relates to compositions and preparations containing drugs that form a complex with a derivative of SAE-CD, i.e. clathrate / drug complexes or inclusion complexes. The pharmaceutical preparations contemplated herein relate to preparations that contain a clathrate complex and a pharmaceutically acceptable carrier.

 Clathrate complexes SAE-CD / drug are prepared separately to obtain the desired pharmaceutical preparation. Methods of obtaining such preparations include stages for which significant monitoring and control is necessary, which may complicate the preparation of the drug. In the pharmaceutical industry, simplified methods are preferable to complex methods, and in the case of compositions containing cyclodextrin and in particular SAE-CD, there remains a need for simplified compositions and methods for their preparation.

 Attempts have been made to obtain preparations based on cyclodextrins with drugs that are poorly soluble in water, both in the form of physical mixtures and in the form of inclusion complexes. Muranushi et al. (1988) compared the dissolution profiles of pure Benexate, a physical Benexate / cyclodextrin mixture, and a Benexate / cyclodextrin complex. They found a significantly higher solubility of Benexate complexes compared to a physical mixture or a pure product.

 Similar results were obtained by J.J. Torres-Labandeira et al. (1994). They found that the bioavailability of the glibornuride complex with β-cyclodextrin is 2–3 times higher than the bioavailability of the glibornuride / β-cyclodextrin physical mixture. D. Peri et al. (1994) also showed that in the case of tolnafate, the drug / β-cyclodextrin complex has improved solubility compared to the solubility of a physical mixture or free drug. When studying naproxen and β-cyclodextrin, it was found that the corresponding inclusion complex has a 6–9-fold higher solubility after 5 minutes compared to the solubility of the physical mixture (Otero-Espinar et al., 1991).

 Additional evidence that the drug / β-cyclodextrin inclusion complex has a significantly improved dissolution profile than the corresponding physical mixture was obtained by Lin et al. (1989) in the study of complexes and physical mixtures of β-cyclodextrin with acetaminophen, indomethacin, piroxicam and warfarin. Esclusa-Diaz et al. (1996) also reported that the ketoconazole / β-cyclodextrin complex has significantly higher solubility than the corresponding physical mixture.

 US Pat. No. 4,946,686 (McClelland et al.) Discusses another use of physical drug / cyclodextrin mixtures, but no examples are given. This composition was prepared only for a controlled release drug in which solubility modulating units are presented as slow release particles dispersed in a mixture of drug excipients. All components were surrounded by a microporous wall insoluble in water.

 Thus, it is known in the art that drug / cyclodextrin complexes will have significantly higher solubility, dissolution profile, and bioavailability than the corresponding physical mixture. In the pharmaceutical field, there is a need for pharmaceutical preparations containing a physical drug / cyclodextrin mixture that will have a dissolution profile, bioavailability and solubility that are approximately equal to the dissolution profile, bioavailability and solubility of the corresponding drug / cyclodextrin complex.

SUMMARY OF THE INVENTION
In the present description, unless otherwise specified, the terms "a" or "an" mean one or more.

 The present invention provides a method to overcome the disadvantages of the known solid pharmaceutical formulations containing a physical therapeutic agent / cyclodextrin mixture. The invention relates to simplified solid pharmaceutical compositions and preparations containing sulfoalkyl ether cyclodextrin and intended for the delivery of therapeutic agents, as well as to methods for their preparation. The pharmaceutical preparations of the present invention are advantageously prepared by simplified methods that do not require prior preparation of SAE-CD complexes with therapeutic agents prior to preparation. The preparations contain a film coating around the solid core, which contains a physical mixture of a therapeutic agent / sulfoalkyl ether cyclodextrin, which, when exposed to water or body fluids, forms a therapeutic agent / sulfoalkyl ether cyclodextrin complex. A pharmaceutical preparation containing a physical mixture of a therapeutic agent / sulfoalkyl ether cyclodextrin will have solubility, dissolution profile and / or bioavailability that are close to the solubility, dissolution profile and / or bioavailability of the corresponding inclusion complex.

 Thus, in accordance with one aspect, the present invention provides a solid pharmaceutical preparation comprising a film coating and a solid core, in which the film coating includes a film-forming agent and a pore-forming agent, and the solid core contains a pharmaceutically acceptable carrier and a physical mixture of a therapeutically effective amount of a therapeutic agent and sulfoalkyl ether cyclodextrin (SAE-CD), where the bulk of the therapeutic agent does not form a complex with SAE-CD.

 The preparations of the present invention are simple compositions obtained using a simplified method. The present invention also makes it possible to prepare a variety of dosage forms having unique characteristics.

где n принимает значения 5 или 6;
каждый из заместителей R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ и R₉ независимо друг от друга представляют собой -O- или -O-(C₂-C₆-алкилен)-SO₃-группу, где, по меньшей мере, один из заместителей R₁ и R₂ независимо друг от друга представляет собой -O-(C₂-C₆-алкилен)-SO₃-группу, предпочтительно -O-(CH₂)_m-SO₃-группу, где m принимает значение 4 (например, -OCH₂CH₂CH₂SO₃- или -OCHCH₂CH₂CH₂SO₃-); и
каждый из S₁, S₂, S₃, S₄, S₅, S₆, S₇, S₈ и S₉ независимо друг от друга представляют собой фармацевтически приемлемый катион, который включает, например, H⁺, щелочные металлы (например, Li⁺, Na⁺, K⁺), щелочноземельные металлы (например, Ca²⁺, Mg⁺²), аммонийные ионы и аминные катионы, такие как катионы (C₁-C₆)-алкиламинов, пиперидина, пиразина, (C₁-C₆)-алканоламина и (C₄-C₈)-циклоалканоламина,
где основная часть терапевтического агента не образует комплекс с производным простого сульфоалкилового эфира циклодекстрина.In one embodiment, the sulfoalkyl ether cyclodextrin is a compound of formula (1):

where n takes the values 5 or 6;
each of the substituents R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ independently from each other are —O— or —O— (C ₂ -C ₆ alkylene ) -SO ₃ group, where at least one of the substituents R ₁ and R ₂ independently from each other is a —O- (C ₂ -C ₆ alkylene) —SO ₃ group, preferably —O- ( CH ₂ ) _{m is an} —SO ₃ group, where m is 4 (for example, —OCH ₂ CH ₂ CH ₂ SO ₃ - or —OCHCH ₂ CH ₂ CH ₂ SO ₃ -); and
each of S ₁ , S ₂ , S ₃ , S ₄ , S ₅ , S ₆ , S ₇ , S ₈ and S ₉ independently of each other is a pharmaceutically acceptable cation, which includes, for example, H ⁺ , alkali metals (for example , Li ⁺ , Na ⁺ , K ⁺ ), alkaline earth metals (e.g. Ca ²⁺ , Mg ^{+ 2} ), ammonium ions and amine cations, such as cations of (C ₁ -C ₆ ) -alkylamines, piperidine, pyrazine, (C ₁ -C ₆ ) -alkanolamine and (C ₄ -C ₈ ) -cycloalkanolamine,
where the bulk of the therapeutic agent does not form a complex with a sulfoalkyl ether cyclodextrin derivative.

 The film coating serves to control the release of the therapeutic agent and sulfoalkyl ether cyclodextrin (SAE-CD) from the solid core. A film-forming agent is a major component of a film coating and typically serves to reduce the release rate of a therapeutic agent and / or SAE-CD. The use of various film-forming agents is contemplated. The pore-forming agent serves to increase the permeability of the film coating due to the formation in the film of either pores or regions with increased permeability to water formed by the film-forming agent.

 The pharmaceutical preparations described in the present invention may additionally contain one or more additional adjuvants and / or active ingredients, which can be selected from adjuvants known in the art and including substances that correct taste and smell (flavoring agents), diluents, colorants, binders substances, fillers, surfactants, dispersants, bioadhesives, penetration enhancers, stabilizers of protease inhibitors and sealing carriers.

In accordance with yet another aspect, the present invention provides a simplified process for the preparation of pharmaceutical preparations containing a sulfoalkyl ether cyclodextrin derivative. Thus, the invention provides a method for preparing a solid pharmaceutical dosage form containing SAE-CD, which comprises:
obtaining a solid core containing a physical mixture of a sulfoalkyl ether derivative and cyclodextrin of the formula (1), a pharmaceutical carrier and an effective amount of a therapeutic agent, the bulk of which does not form a complex with a sulfoalkyl ether cyclodextrin derivative; and
applying a film coating to said solid core containing a film-forming agent and a pore-forming agent to obtain a pharmaceutically acceptable solid dosage form.

 In the method of the present invention, it is not necessary that a sulfoalkyl ether cyclodextrin complex / therapeutic agent is formed. Therefore, the bulk of the therapeutic agent in the final dosage form will be in free form, and not in the form of a complex.

In accordance with another aspect, the present invention provides a method for modifying the bioavailability and / or bioabsorption rate of therapeutic agents. Therefore, in one embodiment, the present invention provides a method for modifying the bioavailability or bioabsorption rate of a therapeutic agent, which comprises the steps of:
for preparing a simple sulfoalkyl ether of cyclodextrin and a therapeutic agent, the main part of which does not form a complex with sulfoalkyl ether of cyclodextrin, and
administering to the patient a therapeutic agent and a sulfoalkyl ether cyclodextrin, wherein said sulfoalkyl ether cyclodextrin modifies the bioavailability or bioabsorption rate of said therapeutic agent.

 It is understood that the sulfoalkyl ether cyclodextrin and the therapeutic agent will be in the same dosage form. It is only necessary that SAE-CD and the therapeutic agent form a complex after administration to the patient. An acceptable dosage form will provide hydration of the physical mixture of SAE-CD and the therapeutic agent when they are in the dosage form, which will lead to the formation of the corresponding complex SAE-CD / therapeutic agent. A wide range of therapeutic agents, including water-soluble, hydrophilic and poorly water-soluble hydrophobic therapeutic agents, can be used in the preparations under consideration.

 Other features, advantages, and embodiments of the present invention will be apparent to those skilled in the art from the following description, examples, and claims.

Brief Description of the Drawings
The following drawings form part of the present description and are intended to further clarify certain aspects of the invention. The invention may be better understood by considering one or more of these drawings and a more detailed description of specific embodiments of the invention.

FIG. 1. The release profile of preparations containing methylprednisolone and SBE _7- β-CD.

FIG. 2a. Release profiles of preparations containing a physical mixture and a lyophilized complex of methylprednisolone and SBE _7- β-CD.

FIG. 2b. The release profile of SBE _7- β-CD preparations containing a physical mixture and a lyophilized methylprednisolone complex.

FIG. 3a and 3b. The release profiles of methylprednisolone (MP) and SBE _7- β-CD from preparations with a 200 μm film coating containing a physical mixture and a lyophilized complex.

FIG. 4a and 4b. The effect of film thickness on the release profile of MP and SBE _7- β-CD in a film-coated tablet preparation.

FIG. 5. Dependence of the release rate of MP and SBE _7- β-CD on the increase in film thickness from the preparation in the form of a tablet containing a physical mixture.

FIG. 6. The effect of SBE _7- β-CD on the release of MP from the core of an uncoated tablet containing either a lyophilized complex or physical mixture. Also shown is a control in which SBE _7- β-CD is absent.

FIG. 7a and FIG. 7b. The effect of the molar ratio MP / SBE _7- β-CD on the release of MP from the cores of film-coated tablets containing a physical mixture or lyophilized complex.

FIG. 7c and FIG. 7g The effect of the molar ratio MP / SBE _7- β-CD on the release profile of SBE _7- β-CD from the core of film-coated tablets containing a physical mixture or lyophilized complex.

FIG. 8. The release profile of drugs testosterone / SBE _7- β-CD with controlled release.

FIG. 9. The release profile of drugs with slow release of dipyridamole (DP) from the core of a tablet coated with a membrane of EUDRAGIT-L and urea (120 μm thick) and containing a physical mixture of DP and SBE _7- β-CD.

FIG. 10. The effect of film thickness on the release of DP through a membrane from EUDRAGIT-L and urea from the core of the tablet containing a physical mixture of DP and SBE _7- β-CD.

FIG. 11. The release profile of DP through a 180 μm thick film coating of EUDRAGIT-S and urea that surrounds the core of the tablet containing a physical mixture of DP and SBE _7- β-CD.

FIG. 12. The release profile of DP from the core of a tablet containing a physical mixture of DP and SBE _7- β-CD, which is coated with a film 90 μm thick of cellulose acetate (AC) and hydroxypropyl methylcellulose phthalate (FGPMC).

FIG. 13. The effect of film thickness on the release of DP from a tablet containing a physical mixture of DP and SBE _7- β-CD and coated with a film of AC and FGPMTS (50:50).

 FIG. 14. The release profile of DP from preparations having a combined release profile — delayed release and controlled release, and the effect of film thickness and composition on the release profile.

DETAILED DESCRIPTION OF THE INVENTION
The invention overcomes the disadvantages that distinguish known pharmaceutical preparations containing a physical mixture of a therapeutic agent and cyclodextrin by creating a preparation that is easy to prepare and which has a solubility, dissolution profile and / or bioavailability of the therapeutic agent approaching the solubility, dissolution profile and bioavailability of the corresponding pharmaceutical a preparation containing a complex of therapeutic agent and cyclodextrin. In the present invention, in the manufacture of pharmaceutical preparations, derivatives of sulfoalkyl ether cyclodextrin (SAE-CD) are used. These drugs can be used for fast, controlled, slow, timed, pulsating and long-term delivery of a wide range of therapeutic agents. The preparations can also be made in the form of various dosage forms, which are described below.

Derivatives of sulfoalkyl ether cyclodextrin
The terms "alkylene" and "alkyl", which are used in this description (for example, in the case of -O- (C ₂ -C ₆ alkylene) SO ₃ groups or alkyl amines), include linear, cyclic and branched, saturated and unsaturated ( i.e., containing one double bond) divalent alkylene groups and monovalent alkyl groups, respectively. The term "alkanol" in this case also includes linear, cyclic and branched, saturated and unsaturated alkyl components of alkanol groups in which hydroxyl groups can be in any position of the alkyl fragment. The term “cycloalkanol” includes unsubstituted or substituted (eg, methyl or ethyl) cyclic alcohols.

 The present invention provides compositions comprising a mixture of cyclodextrin derivatives having the structure of formula (1), wherein the entire composition contains on average at least 1 to 3n + 6 alkyl sulfonic acid moieties per cyclodextrin molecule. The present invention also provides compositions comprising one type of cyclodextrin derivative or at least 50% of the same type of cyclodextrin derivative.

The cyclodextrin derivatives of interest are substituted either at least one primary hydroxyl group (i.e., at least one of R ₁ -R ₃ is a substituent), or they are substituted both at the primary hydroxyl group and at the hydroxyl a group in the 3rd position (i.e., at least one of R ₁ -R ₃ and at least one of R ₄ , R ₆ and R ₈ is a substituent). Substitution on the hydroxyl group in the 2nd position, although theoretically possible, as it turned out, is not of interest to the present invention.

The cyclodextrin derivatives of the present invention are obtained in the form of purified compositions, i.e., compositions containing at least 95% by weight. a derivative (s) of cyclodextrin substituted at least in the primary hydroxyl group of the cyclodextrin molecule (i.e., R ₁ , R ₂ or R ₃ in formula 1). In a preferred embodiment, purified compositions containing at least 98% cyclodextrin derivative (s) can be prepared.

 In some compositions of the invention, unreacted cyclodextrin is substantially removed, and the remaining impurities (i.e., less than 5% by weight of the composition) do not significantly affect the properties of the composition containing the cyclodextrin derivative.

Derivatives cyclodextrin used in this case, can be generally obtained in accordance with the description of US patent N 5134127, which is given as a reference material. This method may include dissolving cyclodextrin in an aqueous base at a suitable temperature, for example at 70-80 ^° C., to obtain the highest possible concentration. For example, to obtain the necessary derivatives of cyclodextrin with vigorous stirring, to ensure maximum contact of the heterogeneous phase, a suitable alkyl sulfone is added in an amount corresponding to the number of moles of primary hydroxyl groups present in CD.

Various derivatives of SAE-CD have been evaluated, including SBE ₄ -β, SBE ₇ -β, SBE ₁₁ -β and SBE ₄ -γ, which correspond to derivatives of SAE-CD of formula 1, where n = 5, 5, 5 and 6 ; m is 4; and where 4, 7, 11, and 4 sulfoalkyl ether substituents are present, respectively. It has been established that derivatives of SAE-CD to varying degrees increase the solubility of poorly water-soluble drugs. For example, in the table. 1 summarizes the data for the binding and solubility constants observed in the case of some derivatives of SAE-CD (0.1 M at 25 ^o C) and methylprednisolone.

In another embodiment, dipyridamole (DP) is used, which is the main drug compound (pKa = 6.28) with poor water solubility of its free base (3.6 μg / ml at 25 ^° C.) and with low and variable bioavailability. SBE ₇ -β has been found to dramatically increase the solubility of DP. In the above table. 2 summarizes the data on the solubility of DP in the presence and absence of SBE _7- β-CD at various pH values.

 Although the above-described embodiments of the invention provide examples of certain derivatives of SAE-CD provided by the invention, they should not be construed as limiting the entire scope of the invention.

A pharmaceutical preparation containing a sulfoalkyl ether cyclodextrin
In order to obtain a cyclodextrin pharmaceutical composition having acceptable solubility, dissolution profile and bioavailability characteristics, it is generally understood in the art that a clathrate or cyclodextrin inclusion complex and therapeutic agent must be prepared separately prior to preparing the pharmaceutical composition containing them. However, the applicants of the present invention have found that obtaining a complex of SAE-CD / therapeutic agent is not necessary.

 The SAE-CD containing preparation of the present invention will contain a SAE-CD derivative of the formula (1) described above, a pharmaceutical carrier, a therapeutic agent, and optionally additional adjuvants and active ingredients, where the bulk of the therapeutic agent does not form a complex with the SAE-CD derivative.

 Since it is understood that only the main part of the therapeutic agent contained in the present preparation will not form a complex with SAE-CD, some SAE-CD / therapeutic agent complex may be present. The presence of the SAE-CD / therapeutic agent complex in the present preparation may or may not be intentional, i.e. the complex can be obtained separately in accordance with the patent of Stella and others, and then introduced into the drug, or the complex can be formed in the process of obtaining this drug.

 By "SAE-CD complex / therapeutic agent" is usually meant a clathrate or inclusion complex of a sulfoalkyl ester derivative of cyclodextrin of formula (1) and a therapeutic agent. The ratio of SAE-CD / therapeutic agent present in the complex can vary greatly, but is usually in the range of about 1: 2 to 2: 1 (molar ratio), respectively, and is preferably 1: 1. By the expression “forms a complex” is meant that “there is a portion of the clathrate and inclusion complex c,” i.e., the complexing therapeutic agent is a portion of the clathrate or inclusion complex with a sulfoalkyl ether cyclodextrin derivative. By the term "bulk" is meant at least about 50% by weight. therapeutic compound. Thus, the preparation in accordance with the present invention will contain a therapeutic agent, more than approximately 50% weight. which does not form a complex with SAE-CD. In various embodiments, the invention is preferably more than 60% by weight, more preferably more than 75% by weight. and even more preferably more than 90% by weight, and most preferably more than 95% by weight. the therapeutic agent will not complex with SAE-CD when the therapeutic agent is in the pharmaceutical preparation.

 It is believed that the therapeutic agent will form a complex with SAE-diabetes when administered in the form of a dosage form containing the composition of the present invention to a patient and when exposed to body fluids. For example, when a capsule containing therapeutic agent and SAE-CD powders is administered orally to a patient, the capsule will dissolve, thereby allowing the gastric juice to come into contact with the therapeutic agent and SAE-CD. As a result, a complex of SAE-DM / therapeutic agent will be formed. A suitable dosage form will facilitate the hydration of the physical mixture until it is released from the dosage form, which ensures the formation of an appropriate complex.

 The ratio of SAE-CD: therapeutic agent in the preparation will depend on a number of factors such as the intrinsic solubility of the agent, the estimated dose of the agent, and the binding constant for the formation of an inclusion complex between a particular drug (agent) and a specific SAE-CD. These factors in total will determine the amount of SAE-SD required for the dosage form and, therefore, the ratio of SAE-SD: therapeutic agent.

 The molecular weight of most SAE-CD is approximately 2000, and most therapeutic agents have molecular weights in the range of 20 ~ 500. In addition, most drugs form inclusion complexes with SAE-CD in a 1: 1 ratio. Due to such differences in molecular weights, the required amount of SAE-CD will be at least 4-10 times the amount of agent, i.e. one mole of CD will solubilize one mole of the drug. However, as shown below, this implies an infinitely high binding constant between the agent and CD. For most solid dosage forms, the best option is tablets that have a weight of less than one gram, and because of the need for tablets of other excipients should contain less than 500 mg of diabetes. Thus, based on this simple assumption, it can be understood that the amount of drug that can be used with SAE-CD should be less than 50 mg. Since most drugs do not have an infinitely high binding constant for SAE-CD, the total dose of the drug that may be in the drug will be less than 50 mg.

More specifically, agents can form inclusion complexes with SAE-CD from weak to very strong. A very weak inclusion complex is a complex in which the binding constant is less than about 500 M ^-1 . The weak complex will have a binding constant of approximately 500 to 1000 M ^-1 . With moderate binding, the complex has a binding constant of approximately 1000 to 5000 M ^-1 ; strong binding should be in combination with a binding constant of from about 5000 to 20,000 M ^-1 ; and very strong binding will be in complex with the binding constant of more than approximately 20,000 M ^-1 .

The relative increase in the solubility of a poorly soluble drug in the presence of SAE-CD is due to the binding constant and the molar concentration of the present SAE-CD. For a very weakly bound drug, a molar ratio of SAE-DM / agent of 100: 1 is required. In this case, the amount of drug in the preparation should be less than 1 mg. If the binding constant between SAE-DM and the agent is very large, a ratio of approximately 1: 1 may be acceptable. In this case, a dosage of up to 50 mg can be used, provided that the intrinsic solubility of the drug is acceptable. Consider a drug with a binding constant of 10,000 M ^-1 , which is real for a number of drugs. In the presence of 0.1 M SAE-CD, the solubility of the drug will increase by about 1000 times compared with solubility in the absence of SAE-CD. If the intrinsic solubility of the drug is approximately 1 μg / ml, then in the presence of 0.1 M SAE-CD, only approximately 1 mg / ml will be soluble; however, if the intrinsic solubility of the drug is approximately 10 μg / ml, then in the presence of 0.1 M SAE-CD, a solubility of approximately 10 mg / ml is possible.

 For the dosage forms described in this patent, the molar ratio of SAE-CD: therapeutic agent will usually be in the range from 100: 1 to about 1: 1 and preferably from about 20: 1 to 1: 1. Thus, SAE-CD will usually be present in excess with respect to the therapeutic agent for some agents, while for other agents in a minimal excess. The amount of excess will be determined by the intrinsic solubility of the agent, the expected dose of the agent and the binding constant during the formation of an inclusion complex between a specific drug (agent) and a specific SAE-CD.

 The present invention refers to various pharmaceutical preparations containing a physical mixture of a therapeutic agent and SAE-CD: an osmotic pump tablet, a layered tablet, a coated tablet, coated pellets, reconstituted powder, capsules, coated granules and hot melt extruded films.

 In the present invention, coated tablets, granules and pellets comprise a film coating and a solid core. The film coating contains a film-forming agent and a pore-forming agent. The film coating may contain a large number of film-forming agents and / or pore-forming agents, for example, combinations of film-forming agents may be used in a particular film coating.

 The terms “film-forming agent” and “release controlling agent” are used interchangeably herein and mean polymeric compounds (natural, synthetic, semi-synthetic and genetically synthesized) that will form a film coating around the solid core of the preparation and which control the release or reduce the release rate therapeutic agent or SAE-CD from a solid core. The film-forming agents, the use of which is implied in the present invention, are described additionally, and examples are given for some embodiments of the invention.

In FIG. 1 (the preparation procedure is described in detail in Example 1), the release profiles for two tablets with an osmotic pump containing methylprednisolone (MP) are presented. Tablets differ only in the formation of a complex of SAE-CD and a therapeutic agent. Of the two compositions, the first based on a physical mixture of methylprednisolone / SBE _7- β-CD, and the second containing a complex of methylprednisolone / SBE _7- β-CD, in accordance with the procedure of Example 1, tablets with a controlled release osmotic pump are prepared. MP and SBE _7- β-CD (in a 1: 7 molar ratio) together with a pharmaceutical carrier are pressed into a solid core, which is coated by spraying a mixture of ethyl cellulose, PEG3350, PEG400 and ethanol with the formation of a film with a thickness of 140 μm around the solid core. The dissolution profile is determined using the device for dissolution II (US Pharmacopoeia) (100 rpm, 37 ^o C) and HPLC method for methylprednisolone (MP). A fluorimetric assay using 2,6-toluidine naphthalenesulfonate (2,6-THS) was developed to quantify SAE-DM. The first preparation indicated in FIG. 1 hollow circles, contains separately prepared lyophilized complex MP-SBE _7- β-CD. The second drug, indicated by filled circles, contains the bulk of the MP in free form in the form of a physical mixture with SBE _7- β-CD. The third drug, indicated by squares, contains a physical mixture of lactose, fructose and MP. From the similarity of the curves corresponding to the previously obtained complex and the physical mixture, it is obvious that the latter has a release profile similar to or practically similar to the release profile of the former. It should be noted that for this particular dosage form, MP and SBE _7- β-CD have essentially the same release profile. The results are shown in FIG. 2a and 2b, respectively, for MP and SBE _7- β-CD.

If testosterone (TST) is used as a therapeutic agent, a preparation with a physical mixture of SBE _7- β-CD and TST has the same release profile as the corresponding lyophilized mixture (Fig. 8). The solid core of the tablet contains TST and SBE _7- β-CD in a 1: 1 molar ratio. The film coating of this tablet contains sorbitol, PEG400, and cellulose acetate. The release profiles of the drug with the physical mixture and the drug with the complex were compared with the release profile of the base drug TST / fructose-lactose.

With an increase in the thickness of the film coating or membrane that surrounds the core of the tablet containing either the physical mixture or the lyophilized complex of MP and SBE _7- β-CD, up to 200 μm, a slight difference is observed in the release profiles for the physical mixture and the lyophilized complex; however, SBE ₇ -β-CD actually has a release profile substantially similar to the MP release profile. These results are depicted in FIG. 3a and 3b, respectively, for MP and SBE _7- β-CD. Prepared and studied additional examples of tablets with a film coating, which have a film thickness of 38, 89, 137, 198 and 234 microns. The results are presented in FIG. 4a and 4b, which show that SBE _7- β-CD has virtually the same release profile as MP in each dosage form. In an embodiment of the invention with a film thickness of 234 μm, the lyophilized complex appears to release SBE _7- β-CD faster than MP; however, when plotting the release rate for the physical mixture of FIG. 4a and 4b, it can be seen from the film thickness that the SBE _7- β-CD has essentially the same release profile as the MP (Fig. 5).

Film thickness does not necessarily have a significant effect on the release profile of a given dosage form. In FIG. 10 shows the effect that film thickness exerts on a sustained release formulation containing a film coating of EUDRAGIT-L / urea and a solid core with a physical mixture of dipyridamole / SBE _7- β-CD. The results show that for this embodiment, the release profile of DP does not depend on the film thickness, but depends on the pH of the solution.

 By replacing the film coating composition with EUDRAGIT-S and urea, a sustained release formulation can be prepared that releases DP at a pH of approximately 7.2 rather than 6.8 (FIG. 11). A higher alkaline pH value corresponds to the pH value in the patient’s small or large intestine. Thus, it is possible to prepare a sustained release preparation for intestinal or rectal release of a therapeutic agent that contains a solid core and a film coating consisting of a film-forming agent, which is a pH-dependent solubility polymer.

The film surrounding the solid core will affect the release of MP and SBE _7- β-CD. In embodiments of the invention in which there is no film surrounding the core, a core containing a physical mixture of SBE _7- β-CD and MP can have the same or almost the same release characteristics as a core containing a complex of these components. In FIG. Figure 6 shows the MP release profile from solid nuclei containing a lyophilized complex (solid circles), physical mixture (hollow circles), and fructose-lactose-MP physical mixture (squares). In this example, the fructose-lactose mixture serves as an osmotic rather than a solubilizing agent. The physical mixture essentially has the same release profiles as the complex.

The molar ratio of MP / SBE _7- β-CD may affect the release profile of this dosage form. In FIG. 7a-7g shows the release profile of MP and SBE _7- β-CD from film-coated tablets containing MP and SBE _7- β-CD in the form of a physical mixture (Figs. 7a and 7c) and a lyophilized complex (Figs. 7b and 7g), where the molar ratios of MP / SBE _7- β-CD are 10/1, 1/7 and 1/3 (w / w). The results show that a decrease in the relative amount of SBE _7- β-CD lowers the MP release profile. Thus, dosage forms having different release profiles can be prepared by controlling the ratio of MP / SBE ₇ -β-CD. These results also show that the physical mixture and the lyophilized complex have substantially the same release characteristics.

The film coating used may contain a polymer whose solubility depends on the pH value. In FIG. 9 depicts a release profile for a sustained release formulation that consists of a tablet core and a film coating. The tablet core contains a physical mixture of SBE _7- β-CD and dipyridamole (DP). The film coating (150 μm) contains EUDRAGIT-L, which has a pH-dependent solubility. When the pH of the solution in which the tablet is immersed rises after two hours from 1.5 to 6.8, SBE _7- β-CD and DP have almost the same release profile. A two-hour delay corresponds to the dosage form, from which the main part of the DP will be released in the ileum and small intestine of the patient.

The film coatings or membranes of the present invention may contain a combination of film-forming agents. In FIG. 12 depicts one embodiment of the invention in which the film coating comprises a mixture of cellulose acetate (AD) and hydroxypropyl methylcellulose phthalate (FHPMC) in a 1: 1 ratio and a solid core consisting of SBE _7- β-CD and DP.

 This combination of film-forming agents provides a preparation having a sustained and controlled release of a therapeutic agent.

 A change in the film thickness from 90 to 170 μm, as it turns out, does not actually affect the release profile of the DP when using film-forming agents having a pH-dependent solubility. Therefore, in this embodiment, the invention provides a sustained and controlled release pharmaceutical preparation having a release profile that is only slightly dependent on film thickness (FIG. 13).

Specific embodiments of the invention may have a delayed release, a combined delayed and controlled release and a precisely controlled release. In the embodiment of the invention shown in FIG. 14, the core of the tablet containing DP / SBE _7- β-CD is coated with a mixture of AC: FHPMC in various ratios and with different film thicknesses. The option for delayed release, indicated by squares, contains a film coating 90 μm thick, which consists of a mixture of AC: FHPMC in a ratio of 1: 1. The variant of the invention with a combined delayed and controlled release, indicated by diamonds, has a film coating 105 μm thick, which consists of AC: FGPMTS in a ratio of 6: 4. Thus, by changing the ratio of AC: FHPMC, the relative contribution of controlled and delayed release to the overall release profile of the dosage form can be controlled.

 It should be noted that in the absence of SAE-CD in accordance with the present invention, a suitable drug release profile will not be obtained for the therapeutic agents discussed herein. For example, a tablet core containing DP, citric acid, and fructose-lactose, surrounded by a film 120 μm thick from AC: FGPMTS (50:50), does not release DP. In another example, in which the same tablet core is surrounded by a 120 μm film of EUDRAGIT-L and urea (50:50), an incomplete release of DP is observed.

 Thus, the present invention also provides a pharmaceutical preparation having a sustained release, controlled release or combined sustained and controlled release and consisting of a tablet core and a film coating around the tablet core, the tablet core containing a physical mixture of a therapeutic agent and SAE-CD, and a film coating consists of a combination of film-forming agents.

 In addition, in accordance with Example 2, tablets with an osmotic pump were obtained and their dissolution characteristics were evaluated. These tablets consist of a core containing DP / SAE-CD, surrounded by a film coating consisting of one or more of the following components: cellulose acetate, ethyl cellulose, wax, EUDRAGIT E100, EUDRAGIT RS and EUDRAGIT RL, EUDRAGIT L, EUDRAGIT S, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate; and hydroxypropyl methylcellulose acetate succinate. The pore-forming agents that have been studied include: poly (ethylene glycol) 3350 (PEG 3350), sorbitol, sucrose, and urea.

 The term “pore forming agent” as used herein refers to an agent that promotes the formation of pores in the film coating of the present invention or improves the permeability of the film. Examples of pore-forming agents are hydrocarbons such as lactose, dextrose, fructose, sucrose, mannose; α-hydroxy acids such as citric acid, tartaric acid, fumaric acid, succinic acid, glycolic acid, lactic acid, mixtures of these acids and their salts; halogen counterions such as bromide, fluoride, iodide and chloride; divalent metal cations, such as magnesium and calcium ions; anionic agents such as phosphates, sulfates, sulfonates, nitrates, bicarbonates, mixtures thereof and their salts; celluloses such as HPC, HPMC, hydroxyethyl cellulose, methyl cellulose; poly (ethylene oxide); poly (vinylpyrrolidone); gums and gelling agents such as kieselguhr, xanthan gum, alginic acid, gum arabic, tragacanth, their combinations and their salts; clays such as montmorillonite, bentonite, Veegum, kaolin; various components such as kieselguhr, magnesium silicate, benton, hectorite, PLURONICS, hydrophilic surfactants; polyols such as sorbitol, mannitol, xylitol; proteins such as albumin, collagen, gelatin; water soluble amino acids; dispersants, such as starch, sodium salt of starch glycolate, croscarmellose; and water soluble organic compounds; and their combinations. Pore-forming agents that are water-permeable can be used to improve the permeability of the film.

 The preparations of the present invention are intended to produce SAE-CD complexes when body fluids act on them. In one embodiment, the dosage forms of the present invention will hydrate the physical mixture of SAE-CD / therapeutic agent until the therapeutic agent is released, which promotes complex formation.

Method for modifying bioavailability and bioabsorption rate
For poorly soluble in water, hydrophobic drugs
Poor bioavailability agents The present invention provides a method for improving water solubility and modifying bioavailability and / or bioabsorption rate in a patient. For water-soluble hydrophilic drugs with extremely high bioavailability, the present invention provides a method for modifying the bioabsorption rate in a patient.

The term “poorly soluble in water” and “hydrophobic” means that at 20 ^° C. the therapeutic agent has a solubility in water with a neutral pH of less than about 1 mg / ml. By the term "water soluble" or "hydrophilic" is meant that at 20 ^° C the therapeutic agent has a solubility in neutral water of more than about 1 mg / ml.

 In some embodiments, the method of the present invention for modifying the bioavailability or absorption rate of a therapeutic agent comprises the steps of preparing a combination of a therapeutic agent and a sulfoalkyl ester of cyclodextrin derivative and administering the resulting combination to a patient. By “modifying the bioavailability and / or bioabsorption rate”, it is meant that the bioavailability and / or bioabsorption rate of a therapeutic agent when administered in combination with SAE-CD will differ from (or will be modified with respect to) the bioavailability and / or bioabsorption rate when administered according to separately.

 In other embodiments, the subject process includes the steps of preparing a sulfoalkyl ester derivative of cyclodextrin and a free (non-complexed) therapeutic agent in a single pharmaceutically acceptable dosage form and administering the dosage form to a patient.

 It is believed that SAE-CD modifies the bioavailability and / or absorption rate of the therapeutic agent due to the formation of a clathrate or inclusion complex after exposure to the patient’s body fluids. Based on the combination of SAE-CD / therapeutic agent, the drug can be obtained in various ways, which are described in more detail below. It is only necessary that the SAE-CD is present in an amount sufficient to complex with the therapeutic agent in the patient who has taken the drug.

General Provisions
The therapeutic agent used in the present invention may have a wide range of values of water solubility, bioavailability and hydrophilicity. Thus, the present invention contemplates any therapeutic agent that will form a clathrate or inclusion complex with an SAE-CD derivative of formula (I). The therapeutic agents for which the present invention is particularly suitable are poorly water soluble hydrophobic therapeutic agents and water soluble hydrophilic therapeutic agents. The present invention can be used to prepare unit dosage forms containing less than about 500 mg, in particular less than about 150 mg, and in particular less than about 50 mg of a therapeutic agent.

 The amount of therapeutic compound introduced into the subject drugs may be selected in accordance with the provisions known in the pharmaceutical art. Administration of a therapeutically effective amount of a compound is contemplated. By the term "therapeutically effective amount" is meant an amount by which, for example, in pharmaceuticals, is meant a pharmaceutically effective amount. A pharmaceutically effective amount is an amount of a drug or pharmaceutically active substance that is sufficient to cause a noticeable biological response when administered to a patient. In relation to vitamins or minerals, the term "effective amount" means an amount of at least about 10% of the US recommended daily intake (RSP) of this particular ingredient for a patient. For example, if the ingredient is Vitamin C, then an effective amount of Vitamin C should include an amount of Vitamin C sufficient to provide 10% or more of the RSP. Typically, when the tablet contains a mineral or vitamin, a larger amount, preferably about 100% or more of the CSP, will be introduced into it.

 The therapeutic compound is usually used in finely divided form, i.e. in the form of powder or granules, in order to increase the dissolution rate. It is preferable to use finely divided powdery compound to increase the dissolution rate, and more preferably, not less than 80% of the therapeutic compound, preferably not less than 90%, passes through a 100 mesh (150 μm) sieve. The amount of therapeutic compound to be administered typically lies in the range of about 0.1 to 50%, preferably about 1 to 25% by weight, based on the composition, and the ratio can be suitably modified depending on the therapeutic compound used. .

 As a therapeutic agent, antibacterial agents such as pyridone carboxylic acid, which is poorly soluble in water, such as benofloxacin, nalidixonic acid, enoxacin, ofloxacin, amifloxacin, flumequin, tozfloxacin, pyromidicin, pipemidic acid, miloxacin, zincoxin, oxoxin, oxoxinol , pefloxacin, lomefloxacin, enrofloxacin, danofloxacin, binfloxacin, sarafloxacin, ibafloxacin, difloxacin and their salts. Other therapeutic agents are penicillin, tetracycline, cephalosporins and other antibiotics, antibactericides, antihistamines and decongestants, anti-inflammatory agents, antiparasitic agents, antiviral agents, local anesthetics, antifungal agents, amoebicidal or trichomonocidal antigens, amoebicidal or trichomonocidal antigens, trichomonocidal anti-inflammatory agents anticoagulants, anticonvulsants, antidepressants, antidiabetic agents, antitumor agents, antipsychotic tics, antihypertensives and muscle relaxants. Examples of antibacterial agents are beta-lactam antibiotics, tetracyclines, chloramphenicol, neomycin, gramicidin, bacitracin, sulfonamides, nitrofurazone, nalidixonic acid and their analogs, and the antimicrobial combination fludalanine / pentisidone. Examples of antihistamines and decongestants are perilamine, chlorpheniramine, tetrahydrozoline and antazoline. Examples of anti-inflammatory drugs are cortisone, hydrocortisone, betamethasone, dexamethasone, fluocortolone, prednisone, triamcinolone, indomethacin, sulindac and their salts and the corresponding sulfides. An example of an antiparasitic agent is ivermectin.

 Examples of antiviral compounds are acyclovir and interferon. Examples of painkillers are diflunisal, aspirin, or acetaminophen. Examples of anti-arthritis agents are phenylbutazone, indomethacin, sylindac, their salts and the corresponding sulfides, dexamethasone, ibuprofen, allopurinol, oxyphenbutazone or probenecid. Examples of anti-asthma drugs are theophylline, ephedrine, beclomethasone dipropionate and epinephrine. Examples of anticoagulants are bishydroxycoumarin and warfarin. Examples of anticonvulsants are diphenylhydantoin and diazepam. Examples of antidepressants are amitriptyline, perphenazine chlordiazepoxide, protriptyline, imipramine and doxepin. Examples of antidiabetic agents are insulin, somatostatin and their analogs, tolbutamide, tolazamide, acetohexamide and chlorpropamide. Examples of antitumor agents are adriamycin, fluorouracil, methotrexate and asparaginase. Examples of antipsychotic agents are prochlorperazine, thioridazine, molindone, fluphenazine, trifluoperazin, perphenazine, amitriptyline and trifluopromazine. Examples of antihypertensive agents are spironolactone, methyldopa, hydralazine, clonidine, chlortiazide, deserpidine, timolol, propranolol, metoprolol, prazine hydrochloride and reserpine. Examples of muscle relaxants are succinylcholine chloride, danbrolen, cyclobenzaprine, methocarbamol and diazepam.

 Some specific examples of therapeutic agents that can be used, but which do not limit the invention, are adifenin, allobarbital, aminobenzoic acid, amobarbital, ampicillin, anetole, aspirin, azopropazone, azalenbarbituric acid, beclomethasone, beclomethazondipropronazene benzene, benzene, benzene, benzene, benzene, benzene, benzene, benzene, benzene, benzene benzothiazide, betamethasone, betamethasone-17-valerate, bromobenzoic acid, bromisovalerylurea, butyl p-aminobenzoate, chloral hydrate, chlorambucil, chloramphenicol, chlorobenzoic acid, chlorpromazine, cinnamic acid, clofibrate, coenzyme A, cortisone, cortisone acetate, cyclobarbital, cyclohexylanthranilate, deoxycholic acid, dexamethasone, dexamethasone acetate, diazepam, digitoxin, digoxin, estradiol, flufenufinofinufinufinovozinova, flufenufinufinovozinova, flufenufinfinovozinovuyu, hydrocortisone, hydrocortisone acetate, ibuprofen, indican, indomethacin, iodine, ketoprofen, lanacidin antibiotics, mefenamic acid, menadione, mefobarbital, metarbital, methicillin, metronidazole, mitomycin n, nitrazepam, nitroglycerin, nitroureas, parametasone, penicillin, pentobarbital, phenobarbital, phenobarbitone, phenylbutyric acid, phenylvalerianic acid, phenytoin, prednisolone, prednisolone acetate, progesterone, A series, prostaginlandin, prostaglandin F, quinolone antimicrobial agents, reserpine, spironolactone, sodium sulfacetamide, sulfonamide, testosterone, thalidomide, thiamine dilauryl sulfate, thiamphenicol palmitate, thiopental, triamcinolone, vitamin A, Vitamin D3, Vitamin E, Vitamin K3 and Warfarin.

 The therapeutic compounds contained in the pharmaceutical preparation may be in the form of their pharmaceutically acceptable salts. As implied in this description, the definition of "pharmaceutically acceptable salt" refers to derivatives of these compounds, where the therapeutic compound is modified by obtaining its acidic or basic salts. Examples of pharmaceutically acceptable salts are, but are not limited to, salts of mineral and organic acids at basic residues such as amino groups; alkaline or organic salts of acidic residues such as carboxylic acid residues; et al. Pharmaceutically acceptable salts are conventional non-toxic salts or quaternary ammonium salts of the parent compound, obtained, for example, from non-toxic inorganic or organic acids. For example, such common non-toxic salts are salts derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and other acids; and salts derived from organic acids such as amino acids, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palm, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2 acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic acid, etc.

Pharmaceutically acceptable salts of the present invention can be synthesized from a parent therapeutic compound that contains a basic or acidic residue using conventional chemical methods. Typically, such salts can be prepared by reacting the free acidic or basic forms of these compounds with a pre-calculated amount of a suitable base or acid in water or in an organic solvent or a mixture thereof. A non-aqueous medium is generally preferred. List of suitable salts is given in Remington's Pharmaceutical Sciences, 18 ^{th ed., Mack Publishing Company,} Easton, PA, ch. 40 (the work is given as a reference material).

 The term “pharmaceutically acceptable” is used herein for compounds, materials, compositions and / or dosage forms that are medically acceptable for use in contact with human and animal tissues, without excessive toxic, irritating, allergic reactions or without other problems or complications commensurate with a reasonable positive / hazard ratio.

 The term “active ingredient” as used herein means a taste or odor corrective agent, sweetener, vitamin, mineral and other compounds intended for use in pharmaceuticals. The present preparation may also contain adjuvants, such as coloring agents, dispersing agents, lubricants, bioadhesives, etc.

Dispersing agents include starches such as corn starch, potato starch, pregelatinized and modified starches, cellulose agents such as Ac-di-sol, montmorillonite clay, cross-linked PVP, sweetening agents, bentonite and microcellum, VECEGUM ^™ , crystalline cellulose alginates, sodium salt of starch glycolate, gums such as agar, kieselguhr, carob, karaya, pectin and tragacanth. In one embodiment of the invention, the inventive tablet will not dissolve too quickly so that there will be the possibility of hydration in it of a physical mixture of SAE-CD / therapeutic agent.

 Protease inhibitors that may be present in the preparations of the present invention include, but are not limited to, antipain, leipeptin, chymostatin, amistatin and puromycin.

 Penetration enhancers that may be present in the preparations of the present invention include, but are not limited to, chelating agents for calcium ions, such as ethylenediaminetetraacetic acid and polycarboxylic acids; surfactants such as sodium lauryl sulfate, sodium dodecyl sulfate and Tween; bile salts such as sodium taurocholate; fatty acids such as oleic and linoleic acids; and non-surfactant substances such as AZONE and dialkyl sulfoxides.

 Taste and odor corrective substances (flavoring agents) introduced into the composition can be selected from synthetic aromatic oils and aromatic fragrances and / or mineral oils, plant extracts, leaves, flowers, fruits, etc., and combinations thereof. These may include cinnamon oil, pear oil, peppermint oil, pigeon oil, laurel oil, anise oil, eucalyptus oil, thyme oil, cedar oil, nutmeg oil, sage oil, bitter almond oil and cassia oil. Also acceptable flavors are vanillin, citrus oil, including lemon oil, orange oil, grape oil, lime oil and grapefruit oil, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, etc. essences. Flavoring agents, which have been found to be particularly preferred, are commercially available orange, grape, cherry flavoring and chewing gum flavoring, as well as mixtures thereof. The amount of flavor may depend on a number of factors, including the desired organoleptic effect. Particularly preferred flavoring agents are grape and cherry flavoring agents, as well as citrus flavoring agents, such as orange.

 The materials that are introduced into the considered drugs can be pre-prepared in the form of granules. This process is known as the granulation process. By the definition of “granulation” is usually meant any process of increasing particle size, as a result of which small particles come together into larger, constant agglomerates with the formation of free-flowing compositions having a suitable consistency. Granulation can be carried out with stirring in mixing equipment or by pressing, extrusion and agglomeration.

 Used in this description, the term "vitamin" refers to small amounts of organic substances that are necessary for nutrition. For the purposes of the present invention, the term "vitamin (s)" includes, but is not limited to, thiamine, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B12, lipoic acid, ascorbic acid, vitamin A, vitamin D , vitamin E and vitamin K. Also, the term "vitamin" includes their coenzymes. Coenzymes are special chemical forms of vitamins. Coenzymes include thiamine pyrophosphates (TPF), flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide (NAD), nicotinamide adenine nucleotide phosphate (NANF), coenzyme A (CoA, pyridofin-cyclofenzoic acid, tetrahydrofin acid, pyridoxyinfo 1,25-dihydroxycholecalciferol The term "vitamin (s)" also includes choline, carnitine and alpha, beta and gamma carotenes.

 In the present description, the term "mineral" refers to inorganic substances, metals, etc., which are necessary for human nutrition. Thus, the term “mineral” includes, but is not limited to, calcium, iron, zinc, selenium, copper, iodine, magnesium, phosphorus, chromium, etc., as well as mixtures thereof.

 The term “food supplement” as used herein means a substance that has a significant nutritional effect when administered in small amounts. Nutritional supplements include, but are not limited to, ingredients such as bee milk, bran, wheat germ, brown seaweed, cod liver oil, ginseng and fish oil, amino acids, proteins and mixtures thereof. Nutritional supplements may include vitamins and minerals.

 Bioadhesives may also be included in the preparation of the present invention. A bioadhesive is defined as a material that attaches to a biological surface, such as a mucous membrane or skin tissue. The bioadhesive will tightly localize the dosage form on the cell membrane. A preferred bioadhesive is fiber or particles that are swellable in water but not soluble in it. A suitable ratio of bioadhesive to other components will provide strong bioadhesion. The bioadhesive polymers that can be used in the present invention are hydrophilic and water-dispersible polymers, contain free carboxyl groups and have a relatively high basic binding capacity. These polymers, as well as hydrophilic celluloses, are polycarboxylated vinyl polymers and polyacrylic acid polymers. Some hydrophilic polysaccharide gums, such as guar gum, acacia resin, psyllium seed resin, etc. can also be used in the formulation. The weight ratio of bioadhesive to the active ingredient can be in a fairly wide range. In practice, the weight ratio of bioadhesive to active ingredient may be from about 1:10 to 10: 1.

 In order to obtain an acceptable product, the pharmaceutical preparation of the present invention containing SAE-CD may require the use of certain hydrophobic or hydrophilic binders. Suitable hydrophobic binders are cellulose acetate butyrate, cellulose acetate propionate, high molecular weight cellulose propionate (200,000), medium molecular weight cellulose propionate (75,000), low molecular weight cellulose propionate (25,000), cellulose acetate, cellulose nitrate, ethyl cellulose, Other suitable hydrophilic binders are polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene oxide, water soluble or water swellable cellulose and starch derivatives etc.

 Other compounds suitable as a film-forming agent include cellulose acetate butyrate, cellulose acetate propionate, cellulose propionate, HPMC, carrageenan, cellulose acetate, cellulose nitrate, methyl cellulose, hydroxyethyl cellulose, ethyl cellulose, polyvinyl acetate and latex gum dispersion, their combinations.

 Examples of other binders that can be added to the preparation are, for example, gum arabic, tragacanth, gelatin, starch, cellulosic materials such as methyl cellulose and sodium carboxymethyl cellulose, alginic acids and their salts, polyethylene glycol, guar gum, sugar polysaccharides, , inverted sugars, poloxomers (PLURONIC F68, PLURONIC F127), collagen, albumin, gelatin, cellulose in non-aqueous solvents, pregelatinized starch, pasty starch, mixtures thereof, etc. Other binders eschestvami are, for example, polypropylene glycol, polioksietilenpolipropilenovy copolymer complex polyethylene ester, polyethylene sorbitan ester, polyethylene oxide or mixtures thereof, etc.

The melting and / or softening temperatures of these binders usually increase with increasing molecular weight. Binders having a melting or softening temperature greater than 150 ^° C. may require the use of plasticizers in the preparation of the corresponding dosage form so as to reduce the melting and / or softening temperature of the binding agent to a temperature below 150 ^° C. The binding agent may be used in any form, such as powder, granules, flakes, or thermo-molten liquid.

 In this description, the term "plasticizer" includes compounds capable of plasticizing the binder used in the invention. The plasticizer should lower the melting temperature or the transition temperature to the glassy state (softening temperature) of the binder. Plasticizers, such as low molecular weight PEG, usually extend the range of molecular weight of the binder, thereby lowering the glass transition temperature or softening temperature. Plasticizers also reduce the viscosity of the polymer. It is possible that the plasticizer will impart positive physical properties to the preparation of the present invention.

 Plasticizers that can be used in the present invention include, for example, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyl groups, ester type plasticizers, glycol ethers, poly ( propylene glycol), multiblock copolymers, block copolymers, low molecular weight poly (ethylene glycol), citric acid esters, triacetin, propylene glycol phthalate, phosphate esters, sebacin esters slots, glycol derivatives, fatty acid esters and glycerin.

 Such plasticizers can also be ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, dipropylene glycol, triethylene glycol, tetraethylene glycol and other poly (ethylene glycol) monopropylene glycol ether, mono-propylene ether glycol, mono-propylene ether glycol, mono-propylene ether, glycol, diethylene glycol ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, dimethyl sebacate, di-2-ethylhexyl sebacate, tricresyl phosphate, triethyl phosphate, triphenyl phosphate, ace tilirovannye monoglycerides, mineral oil, castor oil, glyceryl triacetate, butyl stearate, glycerol monostearate, butoksietilstearat, stearyl alcohol, tsiklogeksiletilftalat, tsiklogeksilmetildibutilftalat, diethyl phthalate, dibutyl phthalate, diisopropyl phthalate, dimethyl phthalate, dioctyl phthalate, acetyl tributyl citrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allilglikolyat. Such plasticizers are commercially available products available from Aldrich, Sigma Chemical Co. or Morflex, Inc. It is also contemplated, and it is within the scope of the invention, that a combination of plasticizers can be used in the present formulation.

 The present pharmaceutical preparations usually contain a solid core containing a sulfoalkyl ether of cyclodextrin of the formula I as described above, a pharmaceutically acceptable carrier and a therapeutically effective amount of a therapeutic agent, the majority of which does not form a complex with a sulfoalkyl ether of cyclodextrin. The solid core will be surrounded by a film coating. Such preparations can be presented in solid dosage forms, for example, (but not limited to) in the form of a chewing plate, fiber capsule, film, gel, granule, chewing gum, implant, insert, pellet, powder, tablet, tape, troches, pills , bars, strips and cachets.

 Suggested uses are for oral, buccal, nasal, implant, rectal, vaginal, sublingual, ear and urethral. The drug can be administered with pharmaceutically acceptable carriers or diluents, the amount and nature of which is determined by the solubility and properties of the selected therapeutic agent, the selected dosage form and standard pharmaceutical practice. Solid oral dosage forms may contain conventional excipients, for example, lactose, sucrose, magnesium stearate, resin and other materials, flavoring, coloring, buffering agents, preservatives or stabilizing agents. These preparations may also contain hygroscopic agents that are capable of delivering water to the tablet core. Such hygroscopic agents may include water-soluble electrolytes, small organic compounds, osmotic pressure regulating agents, in order to increase the osmotic pressure within the dosage form and absorb water.

 As used herein, the term “patient” refers to warm-blooded animals, such as, for example, cats, dogs, guinea pigs, horses, cows, sheep. This concept also applies to humans.

 The term "standard dosage form" means in this case a single or multiple dosage form containing a certain amount of the active ingredient and diluent or carrier, and the specified number is such an amount that usually requires one or more predetermined standard units for one therapeutic dose. In the case of multiple dosage forms, such as liquids or nickel tablets, the predetermined unit will be one part, such as half and a quarter of the nickel tablet of the multiple dosage form. It should be understood that the specific dose for any patient will depend on various factors, including the indications for treatment, the therapeutic agent used, the activity of the therapeutic agent, the severity of the indications, health, age, weight of the patient, diet and the pharmacological reaction used, the specific dosage dose and other similar factors.

 Various components or compounds may be used to assist in the preparation of dosage forms suitable for the present invention. Such components or compounds include, but are not limited to, an acidifying agent, an alkalizing agent, an adsorbent, an antifungal preservative, an antioxidant, a buffering agent, a coloring agent, an encapsulating agent, a flavoring agent, a thickening agent, a suppository base, a sweetening agent, a release agent, a tablet diluent, and capsule, tablet coating agent, tablet direct compression filler, tablet dispersant, glidant, lubricant, tablet / capsule opacifying agent and polishing agent nt.

 The term "acidifying agent" means a compound used to create an acidic environment in order to stabilize the product. Such compounds include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid and nitric acid, etc.

 The term “alkalizing agent” means a compound used to create an alkaline environment in order to stabilize the product. Such compounds include, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine, etc.

 The term "adsorbent" means an agent capable of retaining other molecules on its surface physically or chemically (chemisorption) by. Such compounds include, but are not limited to, powdered and activated charcoal, etc.

 The term "preservative" means a compound used to prevent the growth of microorganisms. Such compounds include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercury nitrate, thimerosal, etc.

 The term "antioxidant" means an agent that inhibits oxidation and, thus, is used to prevent spoilage of drugs due to oxidation processes. Such compounds include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, pyrophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate and sodium metabisulfite.

 The term "buffering agent" means a compound used to prevent changes in pH upon dilution or addition of acid or alkali. Such compounds include, but are not limited to, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, anhydrous sodium acetate, etc.

 The term “colorant” means a compound used to color solid pharmaceutical preparations (eg, tablets and capsules). Such compounds include, but are not limited to FD&C Red N 3, FD & C Red N 20, FD&C Yellow N 6, FD&C Blue N 2, D&C Green N 5, D&C Orange N 5, D & C Red N 8, caramel dye and oxide iron, red, etc. Coloring agents may also include titanium dioxide, natural coloring agents such as grape peel extract, red beetroot powder, beta-carotene, annatto (red-yellow vegetable dye), carmine, turmeric, paprika, etc.

 The term “encapsulating agent” means a compound used to form thin membranes to encapsulate a drug or drug to facilitate administration. Such compounds include, but are not limited to, gelatin, nylon, biodegradable polyesters, D, L-poly (lactic) acid, a copolymer of polylactic acid and glycolic acid, cellulose acetate phthalate, etc.

 The term "flavoring agent" means a compound used to give a pharmaceutical preparation a pleasant taste and often odor. In addition to natural flavoring agents, various synthetic flavoring agents may also be used. Such compounds include, but are not limited to, anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil, vanillin, etc.

 The term “sweetening agent” means a compound used to impart a sweet taste to the preparation. Such compounds include, but are not limited to, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, etc.

 The term "tablet release agent" refers to agents that prevent the ingredients of the preparation from sticking to the plungers and heads of the tabletting machine during the tablet manufacturing process. Such compounds include, but are not limited to, magnesium stearate, corn starch, silica, talc, and others.

 The term "tablet binders" means substances used to ensure the adhesion of powder particles in tablets. Such compounds include, but are not limited to, gum arabic, alginic acid, sodium carboxymethyl cellulose, extruded sugar (e.g. NuTab), ethyl cellulose, gelatin, liquid glucose, methyl cellulose, povidone, pregelatinized starch, etc.

 The term "diluent for tablets and capsules" means inert substances used as fillers to obtain the required volume, flowing properties and compression characteristics of the drug in the form of tablets and capsules. Such substances include, but are not limited to, dibasic calcium phosphate, kaolin clay, fructose, sucrose, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, calcium sulfate, starch, etc.

 The term "tablet coating agent" means a compound used to coat prepared tablets to protect the drug from degradation by atmospheric oxygen or atmospheric moisture, to provide the desired release profile of the drug after administration, to mask the taste or smell of the drug or for aesthetic purposes. The coating may be of various types, including a sugar coating, a film coating or an enteric coating. The sugar coating has a water base and is formed as a result of a thickening coating around the prepared tablet. Sugar coating usually dissolves in the gut at higher pH values. The film coating is a thin coating around the core. If the film coating is not an enteric coating, it dissolves in the stomach. Enteric-coated tablets or balls will pass through the stomach and will break down in the intestines. Some water-insoluble coatings (e.g., ethyl cellulose) can be used as a tablet and pellet coating to slow the release of the drug as it passes through the gastrointestinal tract. Such coating compounds include, but are not limited to, liquid glucose and sucrose as sugar coating agents; hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose (eg Methocel) and ethyl cellulose (eg Ethocel) as a film coating; and cellulose acetate phthalate and shellac (35% in alcohol, “pharmaceutical glaze”) as an enteric coating, etc.

 The term “direct compression tablet excipient” means a compound used in direct compression tablets. Such compounds include, but are not limited to, dibasic calcium phosphate (e.g., Ditab), microcrystalline cellulose, Avicel, dextran (EMDEX), sucrose (NUTAB), etc.

 The term “tablet glidant” means agents used in tablets and capsules to reduce friction during compression. Such compounds include, but are not limited to, colloidal or finely divided silica, magnesium stearate, corn starch, talc, etc.

 The term “tablet lubricant” means substances used in tablet formulations to reduce friction during compression. Such compounds include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, hydrogenated vegetable oil, benzoic acid, poly (ethylene glycol), NaCl, PRUV, zinc stearate, etc.

 The term “tablet / capsule dimming agent” refers to a compound used to form an opaque coating of tablets or capsules. It can be used alone or in combination with dye. Such compounds include, but are not limited to, titanium dioxide, etc.

 The term “tablet polishing agent” means a compound used to give a pleasant sheen to coated tablets. Such compounds include, but are not limited to, carnauba wax, white wax, etc.

The present formulation containing the therapeutic agent / SAE-CD physical mixture has been found to be particularly suitable for therapeutic agents, including simvastatin, cryptophycin, jaspamide, ambrosin, bisulfan, propanolol, etoposide, taxol, brefeldin A, brefeldin A prodrug (NSC # D656202), 9-amino-20 (S) -camptothecin, camptothecin, prednisolone acetate, prednisolone, pancreastatin, rhizoxin, bryostatin 1, taxotere-O ₆ -benzylguanine, androstane, guanine, chloramphenicol, dapsone, sulfacone, tamo xifencitrate, cholesterol, estrone, verapmil-HCl, equiline, warfarin, indomethacin, phenytoin, cinnarizine, amiodarone-HCl, naproxen, piroxicam, thiabendazole, papaverine, miconazole (free base), nifedipine, testosterone, progesterone dimes hydrocortisone and miconazole nitrate.

 All of the above can be better understood using the following examples, which describe in detail some of the preparation methods of the preparations in accordance with the present invention. All references cited in the examples are for illustrative purposes. They should not be construed as limiting the scope and essence of the present invention.

Example 1
Sustained Release Testosterone (SBE) _7- β-CD
This example illustrates the use of the present invention for the preparation of sustained release preparations of a pharmacologically active agent, with testosterone being an example of such an agent.

Phase solubility study
Excessive amounts of testosterone are added to SBE) _7- β-CD solutions with a volume of 0.25 ppm with concentrations from 0.0 to 0.05 mol / L. The dispersions are left to balance for at least 24 hours in a shaken water bath (100 shakes per minute, 25 ^° C.). Dispersions are centrifuged for 10 min at 2500 rpm, a 20 μl supernatant sample is taken using a 100 μl gas-tight syringe (Hamilton Co., NV), diluted with the mobile phase and analyzed by HPLC to determine the concentration of testosterone in the solution. Then, by the Higuchi and Connors method, a binding constant of testosterone- (SBE) _7- β-CD K _{1: 1 is} determined for a type A _L diagram.

Cooking core tablets
The tablet core is prepared in a molar ratio of testosterone- (SBE) _7- β-CD 1/1. The core of the tablet consists of either a complex of testosterone- (SBE) _7- β-CD, or a physical mixture of these two compounds. The complex is obtained by lyophilization of a solution of testosterone- (SBE) _7- β-CD (5-15% in (SBE) _7- β-CD). Tablets are also prepared that do not contain (SBE) _7- β-CD. They consist of a mixture with a 1/1 ratio of testosterone and a mixture of fructose / lactose (50:50 weight / weight) (Fischer Scientific, NJ). The mixture is triturated in a mortar and sieved through a 200 mesh sieve (75 μm) in low humidity conditions. Mixtures are stored in a desiccator. Tablets weighing approximately 120 mg were pressed into a dissolution matrix using a Carver Laboratory Press (Fred S. Carver Inc., NJ) at a load of 1 t / min.

Obtaining a semipermeable membrane
A coating formulation is prepared by dissolving 1.0% sorbitol (Sigma, MO) in 3.7% twice distilled water and 0.4% PEG 400 (Sigma, MO). 2.0% cellulose acetate was suspended in the solution (CA-398-10, Eastman Chemical Co., TN). 55.7% methylene chloride and 37.2% methanol are added to the mixture. The dispersion is shaken and treated with ultrasound until the solid components are completely dissolved. The coating solution is sprayed with air (Airbrush, Paasche) onto a stainless steel surface with a constant flow of air (40 ^o C), then left at room temperature for 24 hours. The membranes are removed from the surface, checked for cracks and damage under a light microscope (x70) and their thickness is measured with a micrometer (Ames, MA). Membranes are mounted on a dissolution matrix containing a tablet with the side that was sprayed onto steel facing the tablet surface.

In vitro release study
The release is studied in a dissolution matrix in a USP II dissolution apparatus (Vanderkamp 600, VanKel Industries Inc.) containing 900 ml of water at a temperature of 37 ^° C. and 100 rpm. Samples are taken at various time points. 100% release is determined by removing the membrane from the matrix and completely dissolving the drug. Samples were analyzed by HPLC to determine the concentration of testosterone.

Testosterone determination by HPLC
Testosterone concentration was determined using a 15 cm ODS Hypersil column followed by UV detection at 238 nm (Shimadzu scientific Instruments, Inc., Japan). The mobile phase consists of 60% acetonitrile and 40% twice distilled water.

EXAMPLE 2
Sustained Release Dipyridamole- (SBE) ₇ -β-CD
Analytical techniques
Dipyridamole was analyzed using a 15 cm ODS Hypersil column. The sample volume was 20 μl and the wavelength for UV detection was 285 nm (Shimadzu 6A, Shimadzu, Japan). The mobile phase, consisting of 70% methanol and 30% ammonium phosphate buffer (pH 5.0), is passed through the column at a flow rate of 1.5 ml / min. (SBE) _7- β-CD is determined using fluorimetric analysis. A solution of 0.2 ml of a 1 mM solution of 2,6-toluidinonaphthalene sulfonate and 0.8 ml of the sample was excited at 325 nm and fluorescence was observed at 455 nm using a Perkin-Elmer fluorescence detector (Perkin-Elmer, CT).

Phase Solubility Experiments
Solutions of (CBE) _7- β-CD (0-0.1 M) are prepared in various buffer solutions at pH values from 4.0 to 7.0 (citrate for pH 4 and 5, phosphate for pH 6 and 7). An excess of dipyridamole was added to 0.25 ml of these solutions and kept for equilibration for at least 24 hours in a shaken water bath at 25 ^° C (preliminary experiments showed that equilibrium solubility was achieved in 24 hours). The solutions are centrifuged for 10 minutes at 2500 rpm, a 20 μl supernatant sample is carefully taken using a 100 μl Hamilton gas-tight syringe (Hamilton Co., NV), diluted with the mobile phase and analyzed by HPLC. The solubility data is then used to determine the binding constant by Higuchi and Connors for phase behavior of type A _L.

Getting a physical mixture
Dipyridamole (SIGMA, MO), (SBE) _7- β-CD and citric acid (SIGMA, MO) (molar ratio 1: 9: 3) are physically mixed and ground with a mortar and pestle manually. Then, the ground physical mixture is sieved through a 200 mesh sieve (75 μm). This operation is repeated twice. The resulting mixture is always stored in a desiccator, if not used.

Description of the matrix for dissolving and obtaining tablets
The dissolution matrix consists of a cylindrical central part made of stainless steel, a stainless steel platform, a stainless steel top cover, two Teflon gaskets (top and bottom) and Teflon inserts. The central cylindrical part has a hole (radius 7.5 mm) in the center in which the tablet is pressed. The stainless steel top cap and Teflon top gasket both have openings of the same radius in the center. The central part is turned over and screwed to
the platform. Approximately 120 mg of the physical mixture containing the drug (SBE) _7- β-CD and citric acid are placed in the cylindrical hole and the plunger is tightly inserted into the hole. The tablet core is pressed with one ton force for one minute using a Carver press (Fred Carver Inc., NJ). The plunger is carefully removed from the central part, knocking out from the back.

Film coating
Preparation of polymer solutions
Eudragit coating is prepared by dissolving 5% (w / w) Eudragit R or S (Huls America, NJ), 5% urea (SIGMA, MO) or polyethylene glycol (PEG 3350, SIGMA, MO) and 0.75% triethyl citrate (TPP) , SIGMA, MO) in 89.25% ethanol until a clear solution forms. Polymer solutions of cellulose acetate (CA-320S, Eastman Chemical Co., TN) and hydroxypropyl methylcellulose phthalate (FGPMC, Eastman Chemical Co., TN) are prepared by dissolving 5% polymers and 1% CHP in 94% solvent containing equal amounts of methylene chloride and methanol. The ratio of cellulose acetate and FGPMC vary from 50: 50 to 75:25, but the total amount of polymer is always 5%. Dissolution is carried out until a clear solution is formed.

Coating tablets
This coating solution is then sprayed with air directly onto the surface of the tablet at a constant air flow rate (approximately 70 ^° C.). The coated tablets are further dried for 15 minutes under the same air flow. The tablets are further dried for 12-16 hours at room temperature. The thickness of the membrane is taken equal to the difference in tablet thickness after and before coating. Thicknesses are measured using a Screwgauge micrometer.

In vitro release study
A release study for tablets coated with Eudragit L and an AC: FHPMC mixture was carried out by placing the dissolution matrix in a USP II dissolution apparatus (Vanderkamp 600, VanKel Industries Inc.) containing 450 ml of HCl (pH 1.5, 37 ^° C at 100 rpm). After 2 hours, the matrix was carefully removed and placed in 450 ml of phosphate buffer (pH 1.5, 37 ^° C at 100 rpm) and the dissolution experiment was continued. Samples of 1.5 ml are taken periodically and equivalent amounts of dissolution medium are returned to the dissolution vessel. For a tablet coated with AC: FGPMC 100% release is determined by removing the membrane from the matrix and completely dissolving the drug. The release experiments for tablets coated with Eudragit S were carried out in a similar manner in 450 ml of HCl for the first 2 hours, then in a phosphate buffer (pH 6.4) for an additional 5 hours, and in a phosphate buffer at pH 7.2. Release conditions and procedures are similar to those described above.

A 0.5 ml sample is diluted halfway with the mobile phase, and the diluted samples are analyzed by HPLC to determine drug concentration as described in the last section. The remainder of the sample is filtered through a polyvinylidene fluoride (Fischer Scientific, NJ) membrane and drug-free samples are analyzed for (SBE) _7- β-CD using the fluorimetric analysis described below.

EXAMPLE 3
Sustained Release Methylprednisolone- (SBE) ₇ -β-CD
Phase solubility study
Excessive amounts of methylprednisolone (MP) are added to solutions (SBE) of _7- β-CD 0.25 ml volume with concentrations from 0.0 to 0.2 mol / L. The dispersions are left to balance for at least 24 hours in a shaken water bath (100 shakes per minute, 25 ^° C.). Dispersions are centrifuged for 10 min at 2500 rpm, a 20 μl supernatant sample is taken using a 100 μl gas-tight syringe (Hamilton Co., NV), diluted with the mobile phase and analyzed by HPLC to determine the concentration of methylprednisolone in solution. Then, by the Higuchi and Connors method, for the type A _L diagram, the binding constant of methylprednisolone- (SBE) _7- β-CD K _{1: 1 is} determined.

Cooking core tablets
The tablet core is prepared at a molar ratio of methylprednisolone / (SBE) _7- β-CD 1/7. This ratio is calculated using a predetermined binding constant to have _7- β-CD in the core of the tablet (SBE) sufficient to solubilize the methylprednisolone present. In addition, to study the effect of the ratio of methylprednisolone- (SBE) _7- β-CD, tablet cores with a ratio of 1/3 and 1/10 are prepared (cf. results 4). The tablet core consists of either the methylprednisolone- (SBE) ₇ -β-CD complex or a physical mixture of these two compounds. The complex is obtained by lyophilization of a solution of methylprednisolone- (SBE) _7- β-CD (5-15% in (SBE) _7- β-CD). Tablets are also prepared that do not contain (SBE) _7- β-CD. They consist of a 1/7 mixture of methylprednisolone and a mixture of fructose and lactose 50:50 (w / w) (Fischer Scientific, NJ). The mixture is triturated in a mortar and sieved through a 200 mesh sieve (75 μm) in low humidity conditions. Mixtures are stored in a desiccator if not in use. Tablets weighing approximately 150 mg were pressed into a dissolution matrix using a Carver laboratory press (Fred S. Carver Inc., NJ) at a load of 1 t / min.

Obtaining a semipermeable membrane
A coating formulation was prepared by mixing 4.5% ethyl cellulose (Ethocel Standart 10 Premium, Dow Chemicals, MI) with an equivalent amount of polyethylene glycol 3350 (PEG 3350, Sigma, MO). To the mixture was added 0.9% PEG 400 (Sigma, MO) and 90.1% absolute ethanol. The dispersion is shaken and treated with ultrasound until the solid components are completely dissolved. The coating solution is sprayed with air (Airbrush, Paasche) on a teflon surface with a constant flow of air (40 ^o C). After spraying, the membranes are dried in a stream of air with a temperature of 40 ^o C for 5 minutes, then left at room temperature for 24 hours. The membranes are removed from the Teflon surface, checked for cracks and damage under a light microscope (x70) and their thickness is measured with a micrometer (Ames, MA). The membranes are fixed on a dissolution matrix containing a tablet with the side that was on Teflon facing the surface of the tablet.

In vitro release study
The release study is carried out by placing the dissolution matrix in a USP II dissolution apparatus (Vanderkamp 600, VanKel Industries Inc.) containing 350 ml of water at 37 ^° C. at 100 rpm. Samples are taken at various time points. 100% release is determined by removing the membrane from the matrix and completely dissolving the drug. Samples are analyzed by HPLC and fluorimetric methods to determine the concentrations of methylprednisolone and (SBE) _7- β-CD, respectively.

Determination of methylprednisolone by HPLC
The concentration of methylprednisolone was determined using a 15 cm ODS Hypersil column followed by UV detection at 254 nm (LC-10AT, Shimadzu Scientific Instruments, Inc., Japan). The mobile phase consists of 30% acetonitrile and 70% acetate buffer with a pH of 4.7.

Fluorimetric determination (SBE) of _7- β-CD
The concentration (SBE) of _7- β-CD is determined by adding 0.2 ml of a solution of 2E-3 toluidinonaphthalene sulfonate with a concentration of 1E-3 mol / L to 0.8 ml of the sample. The solution was excited at 325 nm and fluorescence was observed at 455 nm (fluorescence spectrophotometer, 65040 Fluorescence Spectrophotometer, Perkin-Elmer, CT).

EXAMPLE 4
Tablets containing (SBE) _7- β-CD and a therapeutic agent
A tablet dosage form in accordance with the present invention can generally be prepared as follows. The therapeutic agent and (SBE) _7- β-CD are blended dry for about 10 minutes. The remaining ingredients are added to the mixture and mixed dry for about 10 minutes. The tablets are then pressed to a hardness of approximately 8-10 kg. For the preparation of dosage forms of the present invention can be used in the formulations shown in table. 3.

 Given in the table. The 3 ingredients are used to produce a 600 mg tablet core having a quick release profile. The number near the ingredient indicates the general order of addition. After adding each group of ingredients, the mixture is stirred in dry form for 5-10 minutes. Thus, PRUV and corn starch are added separately (step 3) from the other ingredients and an additional dry mixing step for 5 minutes is added to the general procedure.

 Given in the table. The 4 ingredients are used to produce a 555 mg tablet core having a quick release profile. The number near the ingredient indicates the general order of addition. After adding each group of ingredients, the mixture is stirred in dry form for 5-10 minutes. Thus, PRW and Ac-Di-Sol are added separately (step 3) from the other ingredients, and an additional dry mixing step for 5 minutes is added to the general procedure.

 Given in the table. The 5 ingredients are used to produce a 500 mg tablet core having a quick release profile. The number near the ingredient indicates the general order of addition. After adding each group of ingredients, the mixture is stirred in dry form for 5-10 minutes. Thus, PRUV and croscarmellose sodium are added separately (step 3) from the other ingredients, and an additional dry mixing step for 5 minutes is added to the general procedure.

 Given in the table. The 6 ingredients are used to produce a core of a 600 mg tablet having a quick release profile. The number near the ingredient indicates the general order of addition. After adding each group of ingredients, the mixture is stirred in dry form for 5-10 minutes. Thus, PRUV and starch glycolate sodium are added separately (step 3) from the other ingredients, and an additional dry mixing step for 5 minutes is added to the general procedure.

 Given in the table. The 7 ingredients are used to formulate a core of a 315 mg tablet having a quick release profile. The number near the ingredient indicates the general order of addition. After adding each group of ingredients, the mixture is stirred in dry form for 5-10 minutes. Thus, PRUV is added separately (step 3) from the other ingredients, and an additional dry mixing step for 5 minutes is added to the general procedure.

 Given in the table. The 8 ingredients are used to produce a 560 mg tablet core having a quick release profile. The number near the ingredient indicates the general order of addition. After adding each group of ingredients, the mixture is stirred in dry form for 5-10 minutes. Thus, PRUV is added separately (step 3) from the other ingredients, and an additional dry mixing step for 5 minutes is added to the general procedure.

 Given in the table. The 9 ingredients are used to produce a 600 milligram hard gelatin capsule consisting of 3 x 200 mg film-coated mini-tablets in accordance with the present invention. Uncoated minicell cores have a fast release profile. Mini-tablets are prepared as follows. The number near the ingredient indicates the general order of addition. After adding each group of ingredients, the mixture is stirred in dry form for 5-10 minutes. Thus, PRUV and corn starch are added separately (step 3) from the other ingredients and an additional dry mixing step for 5 minutes is added to the general procedure. Then the mixture is divided into three equal parts and each part is pressed into a mini-tablet. After coating the core of the tablet with the film-forming agent of the present invention, in accordance with the following example, coated mini-tablets are placed inside a hard gelatin capsule.

 It should be noted that in some of the above examples, binders such as EMDEX and polyox-0.4 M can be replaced by release controlling agents such as HPMC (hydroxypropyl methyl cellulose), HPC (hydroxypropyl cellulose), cellulose acetate butyrate, cellulose acetate propionate, propionate cellulose, carrageenan, cellulose acetate, cellulose nitrate, methyl cellulose, hydroxyethyl cellulose, ethyl cellulose, polyvinyl acetate, latex dispersion, gum arabic, tragacanth, guar gum, etc. Thus, uncoated tablet cores that have a controlled or gradual release profile can be prepared. After additional coating with the film-forming agents of the present invention, a tablet preparation is obtained which has a combined delayed and controlled or gradual release profile, i.e. upon reaching a predetermined part of the gastrointestinal tract, the tablet shell becomes porous and allows the therapeutic agent to be released from the core of the tablet with a controlled or gradual profile. The core of a controlled or gradual release tablet may be used to prepare a tablet preparation consisting of a water-soluble film-forming agent, a very porous film, a large amount of an osmotic or solubilizing agent, and other similar conditions.

 Other methods for producing a tablet core include, for example, dry granulation, wet granulation, and compression - grinding - re-compression. Accordingly, the dry granulation method may include pre-forming the tablet or grains from all of the tablet ingredients except SAE-CD, grinding the preformed tablet or grains, mixing the ground product with SAE-CD, and compressing the mixture to obtain the desired tablet formulation.

 Given in the table. The 10 ingredients are used to produce a 525 mg tablet core having a controlled or gradual release profile. The number near the ingredient indicates the general order of addition. After adding each group of ingredients, the mixture is stirred in dry form for 5-10 minutes. Thus, PRUV and corn starch are added separately (step 3) from the other ingredients and an additional dry mixing step for 5 minutes is added to the general procedure.

Example 5
The core of the tablets obtained from granules containing (SBE ₇ ) -β-CD and a therapeutic agent
Dosage forms in accordance with the present invention may contain granules made by wet granulation as follows. The percentages given mean weight percentages relative to the weight of the final preparation. The present example is based on a dose of 10 mg methylprednisolone (MP). The therapeutic agent (20%) and (SBE) _7- β-CD (375) are mixed in dry form. Using an aqueous suspension of polyvinylpyrrolidone (PVP), lactose (40%) and dextrose (8%) are granulated by wet granulation to obtain a 2% weight increase to form the required granules. NaHCO ₃ (3.5%), PRUV (4.5%), SiO ₂ (0.5%) and xylitol (2%) are mixed in dry form with granules and the resulting mixture is pressed into tablets to a hardness of 8-10 kg.

Example 6
Film coating tablets
Film coatings for tablets in accordance with the present invention can be made using the following ingredients and conditions. Film coatings can be made on the basis of water or a solvent, for example alcohol. Typically, the film-forming agent is dissolved or suspended in half the volume of the estimated volume of the solution, and the remaining ingredients are added. If necessary, the mixture is then brought to the final volume by adding water or a solvent. The prepared solution or suspension is used in accordance with Example 7 for coating the core tablets obtained as described above. Given in the table. 11-17 film formulations refer to the volume of the final solution or suspension in 100 ml.

 EUDRAGIT RS receive from the manufacturer in the form of 30% weight. suspensions. The film-forming agent EUDRAGIT RS is dissolved in water (50 ml) with stirring and CHP, talc and HPMC (pore former) are added sequentially. The final volume of the solution was adjusted to 100 ml by adding water. Other pore-forming and film-forming agents can be used.

 The EUDRAGIT RL formulation can be prepared in isopropanol (IPA). EUDRAGIT RL is dissolved in IPA (50 ml) with stirring, then CHP, talc and HPC are added sequentially. The final volume of the solution was adjusted to 100 ml using IPA.

 EUDRAGIT RL and EUDRAGIT RS are mixed with stirring in water (50 ml), then CHP, talc and GPC are added sequentially. The final volume of the solution was adjusted to 100 ml with water. EUDRAGIT RL is used to improve the permeability of films from EURODRAGIT.

 Ethyl cellulose is dissolved in water (50 ml) with stirring, and dibutyl sebacate, talc and HPMC E5 are added sequentially. The final volume of the solution was adjusted to 100 ml with water. A similar technique can be carried out using IPA instead of water and HPC (1.0 g) instead of HPMC E5.

In water (50 ml), cellulose acetate is dissolved with stirring, and thermal power plants, talc and lactose are added sequentially. The final volume of the solution was adjusted to 100 ml with water. When using this film formulation, it may be necessary to use a Hi-Coater at a temperature of 45 ^° C or higher.

 EUDRAGIT polymers are dissolved or suspended in water (50 ml) with stirring, and thermal power plants and talc are added sequentially. The final volume of the solution was adjusted to 100 ml with water. Other film forming agents, such as cellulose acetate and HPMC, can be used in these combined film formulations.

 EUDRAGIT L is dissolved or suspended in water (50 ml) with stirring and CHP and talc are added sequentially. The final volume of the solution was adjusted to 100 ml with water. This film can be used to prepare the tablet formulation in the small intestine and to coat tablets already coated with other film coatings of the present invention. The resulting tablet preparation will be a drug having a delayed controlled or gradual release of a therapeutic agent from the tablet core.

Example 7
Coating tablet cores with film-forming agents
A film-coated tablet preparation can usually be prepared as follows. It is contemplated that other equivalent conditions and equipment known to one of skill in the art can be used to obtain the present preparations without any further experimentation.

Under the following conditions, use a Hi-Coater (Vector) device (a device for coating tablets with a perforated tray):
Inlet temperature - 65-75 ^o C
Outlet temperature - 30-35 ^o C
Spraying rate - 2-3 g / min
Tablet loading - 300 g
Rotation speed - 20 rpm
After receiving a solution or suspension containing a film-forming agent and other ingredients (in accordance with example 6), the tablet cores are placed inside the Hi-Coater apparatus and the film is applied until a coating is formed with a thickness of 100-125 μm. The coated tablets were dried at approximately 40 ^° C. overnight. The tablet thickness and film composition may vary. The present method can be used with water-based or solvent-based coating compositions.

 The above is a detailed description of specific embodiments of the present invention. In the light of the present invention, one skilled in the art should understand that obvious modifications to the embodiments described herein can be made without departing from the spirit and scope of the present invention. Therefore, all described and claimed embodiments of the invention can be carried out without additional experiments. The entire scope of the invention and its equivalents is presented in the following claims. Thus, the claims and description should not be used to unjustifiably narrow down the full scope of protection to which the present invention is entitled.

References
The following links, to the extent that they give examples of techniques or other details in addition to those described, are specifically introduced as reference material.

 1. Pharmaceutical Dosage Forms-Tablets vol. 1, 2nd edition, Herbert A. Lieberman, ed. pp. 372-376.

 2. US patent 3426011, Parmerter et al.

 3. US patent 3816393, Hayashi et al.

 4. US patent 4497803, Harada et al.

 5. US Patent 4,535,152, Szejtli et al.

6. US patent 4555504, Jones
7. US Patent 4,582,900, Brandt et al.

8. US Patent 4,596,795, Pitha
9. US Patent 4,638,058, Brandt et al.

10. US patent 4727064, Pitha
11. US patent 4746734, Tsuchiyama et al.

12. US Patent 4,764,604, Mueller
13. US patent 4774329, Friedman
14. US patent 4808232, Beesley
15. US patent 4869904, Uekama et al.

 16. B. W. Mueller et al. Proceedings of the Fourth International Symposium on Cyclodextrins, (1988) pp. 369-382, "Cyclodextrin Derivatives for Solubilization, Stabilization, and Absorption of Drugs".

 17. Josef Pitha, Third International Symposium on Recent Advances in Drug Delivery Systems, (1987), pp. 1-12, "Amorphous Water Soluble Derivatives of Cyclodextrins: From Test Tube to Patent."

 18. US Patent 5134127, Stella et al.

19. ME Brewster et al. , J. Pharm. Sci. (1988), 77 (11), 981-985; "Improved delivery through biological membranes. XXXL: Solubilization and stabilization of an estradiol chemical delivery system by modified SBE _7- β-CD-Cyclodextrins."

 20. N. Muranushi et al., Nippon Yakurigaku Zasahi (Japan) (1988), 91 (6), 377-383; "Studies on benexate. CD: effect of inclusion compound formation on the anti-ulcer activity of benexate, the effective ingredient in benexate. CD."

 21. J.J. Torres-Labandeira et al., STP Pharma. Sci. (1994), 4 (3), 235-239; "Biopharmaceutical stability of the glibomuride / β-cyclodextrin inclusion complex after one year of storage."

 22. D. Peri et al. Drug Dev. Ind. Pharm. (USA) (1994), 20 (4), 1401-1410; "Inclusion complexes of tolnaftate with β-cyclodextrin and hydroxypropyl β-cyclodextrin."

 23. F. J. Otero-Espinar, et al. Int. J. Pharm. (Netherlands) (1991), 75 (1), 3744; "Oral bioavailability of naproxen-β-cyclodextrin inclusion complex."

 24. S.Y. Lin et al. Int. J. Pharm. (Netherlands) (1989), 56 (3), 249-259; "Solid particulates of drug-β-cyclodextrin inclusion complexes directly prepared by a spray-drying technique."

 25. M.T. Esclusa-Diaz et al. Int. J. Pharm. (Amsterdam) (1996), 142 (2), 183-187; "Preparation and evaluation of ketoconazole-β-cyclodextrin multi-component complexes."

 26. US patent 5134127, Stella, et al.

Claims (17)

1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a physical mixture of a sulfoalkyl ether cyclodextrin derivative and a therapeutically effective amount of a therapeutic agent, wherein at least 50% of the therapeutic agent does not complex with a sulfoalkyl ether cyclodextrin derivative and a sulfoalkyl ether cyclodextrin is a compound of the formula (1)

where n is 4, 5 or 6;
each of R ₁ , R ₂ , R ₃ , R ₄ R ₅ , R ₆ , R ₇ , R ₈ and R ₉ independently of one another is —O— or —O— (C ₂ -C ₆ alkylene) —SO ₃ -, where at least one of R ₁ and R ₂ independently from each other represents-O- (C ₂ -C ₆ alkylene) -SO ₃ -; and
each of the substituents S ₁ , S ₂ , S ₃ , S ₄ , S ₅ , S ₆ , S ₇ , S ₈ and S ₉ independently of each other represents a pharmaceutically acceptable cation. 2. The pharmaceutical composition according to claim 1, in which at least one of the substituents R ₁ and R ₂ is —O- (CH ₂ ) _m —SO ₃ -, am is 2, 3, 4, 5, or 6 . 3. The pharmaceutical composition according to claim 2, in which S ₁ , S ₂ , S ₃ , S ₄ , S ₅ , S ₆ , S ₇ , S ₈ and S _{9 are} independently selected from the group consisting of alkali metal cations, alkaline earth metal cations; quaternary, tertiary and secondary ammonium cations.  4. The pharmaceutical composition according to claim 2, in which more than 75% of the therapeutic agent is not contained in the form of a complex.  5. The pharmaceutical composition according to claim 3, in which more than 95% of the therapeutic agent is not contained in the form of a complex. 6. A method of obtaining a pharmaceutical dosage form containing sulfoalkyl ether cyclodextrin, comprising the steps of: obtaining a solid core containing a physical mixture of a derivative of sulfoalkyl ether cyclodextrin of formula (1), a pharmaceutical carrier and an effective amount of a therapeutic agent, at least 50% of which does not form a complex with a derivative of sulfoalkyl ether cyclodextrin, and applying to the specified solid core film coating containing a film-forming agent and pore-forming a a gent, wherein the sulfoalkyl ether of cyclodextrin is a compound of the formula (1)

where n is 4, 5 or 6;
each of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ R ₇ , R ₈ and R ₉ independently of one another is —O— or —O— (C ₂ -C ₆ alkylene) —SO ₃ -, where at least one of R ₁ and R ₂ independently from each other represents-O- (C ₂ -C ₆ alkylene) -SO ₃ -;
each of the substituents S ₁ , S ₂ , S ₃ , S ₄ , S ₅ , S ₆ , S ₇ , S ₈ and S ₉ independently of each other represents a pharmaceutically acceptable cation. 7. The method according to claim 6, in which the derivative of sulfoalkyl ether cyclodextrin of the formula (1) is defined as follows: n takes the values 4, 5 or 6; each of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ independently of one another is —O— or —O— (C ₂ -C ₆ alkylene) - SO ₃ -, where at least one of R ₁ and R ₂ independently from each other is —O- (C ₂ -C ₆ alkylene) -SO ₃ -, and each of the substituents S ₁ , S ₂ , S ₃ , S ₄ , S ₅ , S ₆ , S ₇ , S ₈ and S ₉ independently represent a pharmaceutically acceptable cation. 8. The method according to claim 6, in which the derivative of sulfoalkyl ether cyclodextrin of the formula (1) is defined as follows: each of R ₁ , R ₂ and R ₃ independently from each other represents-O- (C ₂ -C ₆ alkylene) - SO ₃ -. 9. The method according to claim 6, in which the derivative of sulfoalkyl ether cyclodextrin of the formula (1) is defined as follows: at least one of the substituents R ₄ , R ₆ and R ₈ independently from each other represents-O- (C ₂ -C ₆ -alkylene) -SO ₃ and all the substituents R ₇ , R ₈ and R ₉ represent —O—. 10. The method according to claim 6, in which the derivative of sulfoalkyl ether cyclodextrin of the formula (1) is defined as follows: each of the substituents R ₄ , R ₆ and R ₈ independently from each other represent-O- (C ₂ -C ₆ alkylene) -SO ₃ -. 11. A solid pharmaceutical preparation containing a film coating and a solid core, in which the film coating consists of a film-forming agent and a pore-forming agent, and the solid core contains a pharmaceutically acceptable carrier and a physical mixture of a therapeutically effective amount of a therapeutic agent and sulfoalkyl ether cyclodextrin, with at least , 50% of the therapeutic agent does not complex with the sulfoalkyl ether cyclodextrin derivative of the formula (1)

where n is 4, 5 or 6;
each of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ independently of one another is —O— or —O— (C ₂ -C ₆ alkylene) - SO ₃ -, where at least one of R ₁ and R ₂ independently of one another is —O— (C ₂ -C ₆ alkylene) —SO ₃ -; and
each of the substituents S ₁ , S ₂ , S ₃ , S ₄ , S ₅ , S ₆ , S ₇ , S ₈ and S ₉ independently of each other represents a pharmaceutically acceptable cation.  12. The solid pharmaceutical preparation according to claim 11, wherein said film-forming agent is selected from the group consisting of: cellulose acetate, ethyl cellulose, methyl cellulose, wax, EUDRAGIT EIDD, EUDRAGIT RS, EUDRAGIT RL, EUDRAGIT L, EUDRAGIT S, cellulose acetate phthalate hydroxypropylate , hydroxypropyl methyl cellulose acetate succinate, cellulose acetate butyrate, cellulose acetate propionate, cellulose propionate, hydroxypropyl methyl cellulose, carrageenan, cellulose nitrate, hydroxyethyl cellulose, poly (vinyl) acetate, gum arabic, tragacanth, gu b, gelatin and combinations thereof.  13. The solid pharmaceutical preparation of claim 11, wherein said pore-forming agent forms pores in said film coating when said drug is exposed to water.  14. The solid pharmaceutical preparation according to claim 11, wherein said pore-forming agent increases the permeability of said film coating.  15. The solid pharmaceutical preparation of claim 11, wherein said preparation is a tablet, mini-tablet, granule, pellet, powder or crystal.  16. The solid pharmaceutical preparation of claim 11, wherein said preparation has a sustained, prolonged, or controlled release profile of said therapeutic agent and said sulfoalkyl ether cyclodextrin.  17. The solid pharmaceutical preparation of claim 16, wherein said preparation has substantially the same release profile of said therapeutic agent and said sulfoalkyl ether cyclodextrin.

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