RU2417103C2 - Compositions of simple sulfoalkyl ether of cyclodextrin and methods for preparing thereof - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compositions of particle-like sulfoalkyl ether of cyclodextrin SAE-CD. The SAE-CD composition has a primary combination of physical properties which are not found out in common solid forms of SAE-CD.

EFFECT: SAE-CD compositions under the invention have improved fluidity, crushing resistance, tableting ease and improved water dissolution rate.

21 cl, 4 dwg, 13 ex

Description

FIELD OF THE INVENTION

The present invention relates to derivatives of a simple sulfoalkyl ether cyclodextrin having improved physical properties, and to methods for their manufacture.

State of the art

The profile of the non-chemical physical properties of the composition can dramatically change the handling and functioning of the process and, possibly, the in vitro and in vivo functioning of a particular material. In other words, a chemical composition having a first profile of physical properties may be suitable for inhalation; while the same chemical composition having a different second profile of physical properties may not be suitable for inhalation. Similarly, a particular filler having a first physical property profile may be more suitable for compression molding than the same filler having a different second physical property profile.

For example, the suitability of the various physical forms of the material used as a carrier for inhalation of the dry powder will vary according to the profile of the non-chemical, physical properties of the various physical forms of the material. Drug delivery by inhalation allows the deposition of the drug in various parts of the respiratory tract, such as the throat, trachea, bronchi and alveoli. In general, the smaller the particle size, the longer the particle will remain suspended in air, and the drug can be delivered further down the airways. Medicines are delivered by inhalation using a nebulizer, a metered dose inhaler (MDI) or a dry powder inhaler (DPI).

Dry powder inhalers deliver aerosolized powdered pharmaceuticals to patients. To generate an aerosol, the powder in its static state must be fluidized and captured by the air stream inhaled by the patient. The powder is exposed to numerous cohesive and adhesive forces, which must be overcome if it is subject to dispersion. Fluidization and capture by air flow require energy to enter the static layer of the powder. The size, shape, surface morphology of the particles, and the chemical composition of the carrier particles can affect aerosol dispersion. Increased dispersion and precipitation of the drug as a whole is observed with a smaller carrier size and an increased proportion of small particles. Elongated carriers generally increased the dispersion ability of the aerosol and the FPF (fraction of fine particles) of the drug, possibly due to an increase in the duration of the action of the air flow carrying it away. Carriers with smooth surfaces created higher respirable fractions. Low respirable fractions were obtained from carriers with macroscopic surface roughness or smooth surfaces, while high respirable fractions were obtained from carriers with microscopic surface roughness, where less contact area and reduced drug adhesion occurred on very small convex surfaces. Thus, for preparative forms of dry powder inhalers, the particle size of the carrier should be selected based on the balance between these mutually related functional characteristics. In particular, the forces between the particles must be such that the particles of the drug adhere to the carrier (to facilitate mixing, uniformity and enable the inclusion of the drug in the stream of inhaled air), while also providing the ability to detach small particles of the drug from the surface of larger particles carrier in order to facilitate delivery to the lungs. In connection with the foregoing, various physical forms of the known solid lactose carrier may be suitable for inhalation of the dry powder.

The same general effect of the physical form on the behavior of the excipient is valid for other pharmaceutical methods used for the manufacture of dosage forms, such as a tablet, liquid, suspension, emulsion, film, layered structure, cake, powder, ball, granules, suppository, ointment, cream and etc. In other words, one filler will need to be made in various physical forms so that it is better suited for certain applications. For example, for improved compression molding tableting, the filler should preferably have improved flowability. Good flow characteristics are desirable to facilitate handling and processing in a tablet press or capsule filling machine. It should also have the ability to compress within a certain range, depending on the role of the excipient in the tablet. If the filler is to be used in the formulated liquid formulation, the filler should preferably not accumulate in groups when placed in a liquid, and it should dissolve completely and quickly. Even though many of these features are very desirable in a solid filler, it is very difficult to obtain any single filler having all of these features. For this reason, along with others, many different types of excipients are being developed in the pharmaceutical industry.

In the pharmaceutical industry, drying methods such as tray drying, lyophilization, spray drying, fluidized bed granulation and fluidized bed agglomeration are used, among others, to prepare solid dosage forms from feed solutions, emulsions, suspensions or emulsions. The physical properties of an isolated solid will depend on the properties of the feed material and the parameters used in the equipment used for the particular drying method.

Spray drying involves spraying a solid-containing feed solution or suspension to form atomized droplets directed into a stream of hot gas in a drying chamber, thereby evaporating the liquid carrier from the droplets, resulting in the formation of spherical particles. Spray drying the fluidized bed is a modified form of spray drying, where the spray drying method is carried out in the presence of a fluidized bed (fluidized by a stream of hot gas) of small particles, so that the atomized droplets collide with each other and adhere to the fluidized particles. By modifying the solids content in the feed solution and in the drying chamber, it is possible to manufacture a drying device for agglomerating or granulating the solids in a method called fluidized bed spray agglomeration or fluidized bed granulation, respectively. In addition, the use of a rectangular instead of a cylindrical spray drying device will affect the physical properties of the resulting product.

In illustrative agglomeration / granulation in a fluidized bed with a cylindrical device, the supplied powder enters the solids inlet, and the liquid atomizer sprays the supplied liquid from the upper or lower part of the fluidized bed into the material. The heated fluidized gas flows upward from the inlet through the bottom screen, fluidizing the feed powder or seed particles in the fluidized bed chamber. At the same time, the classification gas flows upward through the exhaust pipe at a speed that is controlled to blow small particles back into the fluidized bed, allowing only larger particles to fall at a rate higher than the air velocity of the classification pipe to discharge through the pipe. This makes it possible to control the particle size of the product, while maintaining the absence of dust in the product. Dust removed from the exhaust air by the external dedusting equipment of the circular unit can be recycled to the recirculation inlet for further processing. During this process, smaller particles coalesce with each other or with larger particles to form agglomerates. As a result, the particle size distribution in the fluidized bed is increased so that the percentage of fine particles present in the product is reduced compared to the fluidized bed material.

The solubilization of compounds that are poorly soluble in water in aqueous media is often very difficult. Therefore, those skilled in the art have used solubilization enhancers in the aquatic environment, such as cyclodextrins (CD). The original (unmodified) cyclodextrins and their derivatives are well known excipients that contain 6, 7 or 8 units of glucopyranose, and are referred to as α-, β- and γ-cyclodextrin, respectively. Each cyclodextrin subunit has secondary hydroxyl groups at positions 2 and 3 and a primary hydroxyl group at position 6. Cyclodextrins can be depicted as hollow truncated cones with hydrophilic external surfaces and hydrophobic internal cavities.

According to reports, β-CD was obtained in a variety of different forms using various finishing methods. American Maize Products (French Patent No. 2,597,485) recommends lyophilization and spraying as suitable methods for recovering cyclodextrin ethers from aqueous solutions. However, powders obtained in accordance with these various methods have poor solubility. In addition, these powders have low fluidity and have mediocre compression properties.

US Pat. No. 6,555,139 to Sharma discloses a method for microfluidizing β-CD in combination with a hydrophobic drug to yield a uniform, latex-like microsuspension.

US Pat. No. 5,674,854 to Bodley et al. Discloses a composition comprising a β-CD inclusion complex and diclofenac. The composition can be obtained by spray agglomeration.

Schleifenbaum U.S. Patent Application No. 2004,0234479 discloses a flavoring or fragrance comprising a cyclodextrin particle and a flavoring or flavoring wherein the cyclodextrin particle has a particle size in the range of 50 to 1000 microns. The cyclodextrin particle includes cellulose ether and cyclodextrin, where the cyclodextrin particle is obtained in a single-stage fluidized bed method from a spray mixture and where the gas injection temperature is from 80 ° C to 180 ° C and the gas discharge temperature is from 40 ° C to 95 ° C.

European patent application EP 392608 describes a method for producing powder cyclodextrin complexes, wherein the particle size is less than 12 microns, preferably less than 5 microns. Suitable methods for this include spray drying and lyophilization. The '608 application states that small particle sizes of CDs often exhibit reduced porosity or fluidity and can be easily sprayed. For this reason, the use of particles of a cyclodextrin complex having a particle size of at least 50 μm is proposed in the art.

U.S. Patent Application No. 20030065167 Lis et al. A method for producing directly compressible β-CD is disclosed. The method includes the step of dehydrating hydrogenated beta-cyclodextrin to a water content of less than 6%, preferably less than 4%, and even more preferably less than or equal to 2 wt.%, Followed by forced rehydration to a water content of more than 10%, preferably , more than 12%, and even more preferably, more than or equal to 13 wt.%.

The effect of the drying step or the final step in the preparation of hydroxypropyl-β-cyclodextrin (HP-β-CD) from a syrup containing HP-β-CD was investigated. In U.S. Patent Application No. 200330028014 to Sikorski et al. Agglomerated HP-β-CD and a process for its preparation are disclosed. The agglomerated product is manufactured in a double drum dryer. It is reported to have low atomization and good dissolution in water. The particle size of the product is from about 30 to 200 microns.

US Patent No. 5756484 to Fuertes et al. Discloses an HP-β-CD powder composition and a process for its preparation. HP-β-CD has a centered particle size devoid of small particles and a markedly improved ability to dissolve in an aqueous medium. HP-β-CD is obtained by spraying a solution of HP-β-CD on a moving powder layer of HP-β-CD particles.

The physical and chemical properties of the starting cyclodextrins can be modified by altering the hydroxyl groups with other functional groups. One such derivative is a sulfoalkyl ether cyclodextrin.

where R = (- H) _21-n or (- (CH ₂ ) ₄ - SO ₃ Na) _n ; n = 6.0-7.1

Β-cyclodextrin sulfobutyl ether (Captisol®)

Derivatives of sulfoalkyl ether cyclodextrin (SAE-CD) are well known, as well as their use in a wide range of uses. Derivatives of SAE-CD, in particular, can be used in the solubilization and / or stabilization of drugs. A beta-cyclodextrin sulfobutyl ether derivative (SBE-β-CD), in particular a derivative with an average of about 7 substituents per cyclodextrin molecule (SBE7-β-CD), was manufactured for sale by CyDex, Inc. In the form of CAPTISOL®. The anionic sulfobutyl ether substituent dramatically improves the water solubility of the present cyclodextrin. In addition, the presence of charges reduces the ability of the molecule to complex with cholesterol compared to the hydroxypropyl derivative. The reversible, in general, non-covalent formation of complexes of drugs with cyclodextrin provides the possibility of increased solubility and stability of drugs in aqueous solutions.

Spray-dried CAPTISOL® is used in the commercially available VFEND® and GEOGON® formulations. It has become a leading derivative of cyclodextrin for use in pharmaceutical formulations and is thus important to the industry.

Methods for preparing SAE-CD derivatives vary, but generally include general sulfoalkylation steps followed by isolation. The chemical profile of SAE-CD is established during the sulfoalkylation step. For example, a change in the reaction conditions during sulfoalkylation can change the average degree of solubilization and the average regiochemical distribution of sulfoalkyl groups in SAE-CD. The alkyl chain length of the sulfoalkyl functional group is determined according to the sulfoalkylating agent used. And the use of a specific alkylating agent during alkylation would lead to the formation of a specific salt of SAE-CD, while the stage of ion exchange is carried out after sulfoalkylation.

In general, known methods of the sulfoalkylation step include, for example: 1) exposing the unaltered starting cyclodextrin to alkaline conditions with an alkylating agent, for example, an alkyl sulfone or a haloalkyl sulfonate; 2) optionally adding additional alkylating agent to the reaction medium to consume excess alkylating agent; and 3) neutralizing the reaction medium with an acidifying agent. In the vast majority of methods described in the literature, the sulfoalkylation step is carried out in aqueous media; however, some references disclose the use of pyridine, dioxane or DMSO as a reaction solution for sulfoalkylation. After the sulfoalkylation step is completed, SAE-CD is isolated and purified.

Several different methods for the isolation of SAE-CD after sulfoalkylation and neutralization are described. In general, an aqueous liquid containing SAE-CD is dried to remove water to form a solid. Various methods have been proposed in the literature for removing water from an aqueous solution containing SAE-CD. Such methods include conventional lyophilization, spray drying, oven drying, vacuum drying, rotary evaporation under reduced pressure, vacuum drying or vacuum drum drying. See, for example, Ma (STPPharma. Sciences (1999), 9 (3), 261-266), CAPTISOL® (sulfobutyl ether beta-cyclodextrin sodium; Pharmaceutical Excipients 2004: Eds. RCRowe, PJSheskey, SCOwen; Pharmaceutical Press and American Pharmaceutical Association, 2004) and other references related to derivatization of SAE-CD.

Therefore, in this area there is no data on methods for producing and using derivatives of SAE-CD having certain profiles of non-chemical physical properties. Given the importance of SAE-CD for the pharmaceutical industry, it would be a significant improvement in this area to provide derivatives of SAE-CD having certain non-chemical physical properties profiles so that such forms can be tailored for specific purposes.

Summary of the invention

The present invention aims to overcome the disadvantages present in known dry powder compositions SAE-CD. In particular, a composition based on a derivatized cyclodextrin, for example, based on a simple sulfoalkyl ether cyclodextrin (SAE-CD), is provided. The present composition SAE-CD excludes the main active agent. However, the composition has unexpectedly advantageous physical properties that exist as a result of the method used to remove water from an aqueous medium containing SAE-CD. The composition obtained by the method of the invention provides solid particulate SAE-CD.

The physical properties of SAE-CDs are modulated through a variety of techniques to produce different types of SAE-CDs (types of SAE-CDs or compositions of SAE-CDs), where each is suitable for use in certain dosage forms, such as a tablet, capsule, powder, inhaler dry powder , sachet, tortilla and lozenge. Properties can also be modified for improved handling, packaging, storage, and other process related activities. Also, chemical properties can be adapted to specific applications by changing the identity of the counterion, changing the length of the alkyl chain, the average degree of substitution, or the ring size of the starting cyclodextrin from which SAE-CD is made. Properties can also be adapted to specific applications by changing the non-chemical physical properties of SAE-CD, for example, changing the average particle diameter, particle size distribution range, SAE-CD water content, SAE-CD particle surface characteristics, particle dissolution rate, bulk density, density after compaction by tapping, Carr index, compressibility, flowability, etc.

The SAE-CD compositions of the invention have numerous advantages over the known SAE-CD compositions, i.e., compositions prepared according to known methods, which differ in stages after sulfoalkylation. The SAE-CD compositions provided in the present invention provide unexpectedly improved dissolution rates in water, crush resistance, ease of tabletting and / or improved handling of solids.

One form of a SAE-CD composition is provided, containing not more than about 20 wt.% Moisture. An SAE-CD composition can be included in a dry formulation in admixture with an active agent so that all or substantially all of the active agent does not form a complex with SAE-CD. The SAE-CD composition may be included in a dry formulation in admixture with one or more excipients. The composition SAE-CD can also be included in the formulation.

Particle SAE-CD compositions of the invention have morphological and physicochemical properties that predispose them to faster dissolution than previously known SAE-CD compositions, such as spray dried compositions. SAE-CD compositions prepared by methods described herein have particular combinations of morphological and physicochemical properties. In some embodiments, implementation, the method is agglomeration by spraying on a fluidized bed. In some embodiments, particle formulated SAE-CD compositions are prepared by spray granulation on a fluidized bed, and the resulting SAE-CD composition has a combination of physical properties different from the SAE-CD composition obtained by spray agglomeration on a fluidized bed.

When SAE-CD particles are prepared by known methods, they do not have such an advantageous combination of physical properties as that found in the SAE-CD composition of the invention. The SAE-CD composition disclosed herein is prepared by a process including:

providing a feed material in the form of an aqueous liquid containing water and SAE-CD; and

subjecting the liquid feed to a combined fluidized-bed spray drying process whereby the SAE-CD agglomerates (and / or granulates) and is dried to a point below the solubility point to form a particulate SAE-CD composition including agglomerated (and / or granular) particles where at least 90% of the particle volume of the SAE-CD composition is made from particles having calculated diameters greater than about or equal to about 25 microns. (Cut-off of particle diameter for a 10% cumulative volume fraction is 25 μm or more). The SAE-CD composition may have a density after tapping in the range of from about 0.66 to 0.75 g / cm ³ or from about 0.49 to 0.75 g / cm ³ as determined in accordance with USP Method 1 (USP ) <616>, and / or bulk density in the range from about 0.55 to 0.66 g / cm ³ or from about 0.38 to 0.66 g / cm ³ when determined in accordance with USP method 1, density after tapping seals are higher than bulk density.

The moisture content of the SAE-CD composition is below its solubility point. However, certain embodiments include those having a moisture content of ≤18 wt.%, ≤16 wt.%, ≤15 wt.%, ≤10 wt.% Or ≤5 wt.%.

The SAE-CD composition is a particulate material and has an average particle diameter of from about 92 to about 200 microns, or less than or equal to about 110 microns, or less than or equal to about 200 microns. The average particle diameter was determined in accordance with Example 3 with a Malvern instrument. The device measures the particle diameter by scattering at a low angle of laser light and calculates the particle diameter based on the volume of the proposed spherical shape. The term "average particle diameter" is defined as the average value of the moment of volume, otherwise known as the average diameter of De Brouckere, D [3,4]. The SAE-CD composition can be obtained by spray agglomeration on a fluidized bed or by spray granulation on a fluidized bed.

The SAE-CD composition has a combination of physical properties that make it more suitable than previously known SAE-CD compositions for use in compressed tablet formulations. For example, the SAE-CD composition has a crush resistance in the range of about 1.0 to about 20 kP when 200 mg of the SAE-CD composition is pressed into a tablet having a diameter of 0.345 inches using Pmax (maximum compression pressure) in the range of about 30 to about 275 MPa, and the SAE-CD composition has a moisture content in the range of from about 2 to about 3 wt.% according to the definition of LOD (logarithm of the value of the probability ratio). Alternatively, the SAE-CD composition has a crush resistance in the range of about 0.5 to 11 kP when 200 mg of the SAE-CD composition is pressed into a tablet having a diameter of 0.345 inches using Pmax MPa in the range of about 15-70 MPa, and the SAE composition -CD has a moisture content in the range of about 5-6 wt.%.

The SAE-CD composition has a higher dissolution rate in water than the SAE-CD obtained by conventional spray drying. When 2.5 g of an SAE-CD composition are evaluated according to Example 6, it has an average dissolution time when placed in water of 2.5 minutes or less, 4.5 minutes or less, or 3.5 minutes or less.

The invention provides a SAE-CD composition having an advantageous flow property. For example, the SAE-CD composition has a minimum gravity flow hole diameter of about 3-7 mm, or about 4-6 mm, or less than about 10 mm, or less than about 20 mm. You can perform the method of example 5 to determine the minimum diameter of the hole of the gravitational flow.

The density of the SAE-CD composition can be adjusted. The SAE-CD composition has an absolute density of from 1.25 to 1.35 g / cm ³ or from 1.1 to 1.5 g / cm ³ . Embodiments of the SAE-CD composition include those having a bulk density of from about 0.55 to about 0.66 g / cm ³ , from about 0.38 to less than about 0.55 g / cm ³ , or from about 0, 38 to about 0.66 g / cm ³ when performed in accordance with method 1 of USP <616>. In other embodiments, implementation, the density of the composition after sealing by tapping is from about 0.66 to about 0.75 g / cm ³ , or from about 0.49 to about 0.66 g / cm ³ , or from about 0.49 to about 0.75 g / cm ³ when performed in accordance with method 1 of USP <616>. Additionally or alternatively, the SAE-CD composition has a Carr index of less than or about 24%, or less than or about 18%, or less than or about 16%.

Another aspect provides a SAE-CD composition having a moisture content below its solubility point, a bulk density in the range of about 0.55 to 0.66 g / cm ^3, and a density after tapping in the range of about 0.66 to 0.75 g / cm ³ ; the Carr index is less than or about 24% and, optionally, a moisture content of less than about 18 wt.%, optionally, an absolute density in the range of about 1.1 to 1.5 g / cm ³ , optionally, a minimum diameter of the hole of the gravitational flow is less than less than about 20 mm, optionally where the SAE-CD composition is obtained by spray agglomeration on a fluidized bed or by spray granulation on a fluidized bed.

Another aspect provides the use of SAE-CD compositions as tablet fillers, capsule fillers, DPI fillers (dry powder inhaler), extrusion fillers, PMDI (metered-dose metered-dose inhaler) fillers, DPI or PMDI drug delivery vehicles, dispersible fillers in the oral cavity of tablets taken inside powders, dry granulation fillers, granular fillers, aerosolized powders and / or powdered powders lascivious.

An SAE-CD composition may be included in a formulation (e.g., solid, liquid, gel, suspension, emulsion or other known formulation) comprising one or more active agents and, optionally, one or more excipients. Therefore, the invention also provides a method of treating diseases or disorders by administering to a subject an SAE-CD composition in a formulation further comprising an active agent.

In one embodiment, the properties of the SAE-CD composition can be modulated so that various physicochemical properties are matched to the properties of the particles of the preparation to optimize dispersion from dry powder inhalers.

Additional embodiments of the invention include those in which: 1) the SAE-CD composition comprises a compound of formula 1 or a mixture thereof; 2) the formulation contains an SAE-CD composition, further comprising an antioxidant, an acidifying agent, an alkaline agent, a buffering agent, a solubility enhancer, a penetration enhancer, an electrolyte, perfume, glucose, a moving agent, a stabilizer, a volume increasing agent, a cryoprotectant, a plasticizer , flavors, sweeteners, surface tension modifier, density modifier, volatility modifier, or combinations thereof; and / or 3) SAE-CD is a compound of formula 2 or a mixture thereof.

Another aspect of the invention provides an improved solid formulation, the improvement being the inclusion of the SAE-CD composition of the invention, where the SAE-CD was obtained by spray drying in a fluidized bed (agglomeration or granulation), or an SAE-CD composition having a physical profile properties as defined herein. These and other aspects of the present invention will become apparent by reference to the following detailed description, examples, claims, and the accompanying drawings.

Brief Description of the Drawings

The following drawings are provided by way of illustration only, and are therefore not intended to limit the scope of the present invention.

Figure 1 shows the SEM (obtained by scanning electron microscope) photograph of an illustrative batch of the composition SAE-CD obtained in accordance with the invention. SAE-CD particles were prepared according to various post-sulfoalkylation processes.

Figure 2 shows a General view of an illustrative spray drying in a fluidized bed.

Figure 3 shows a General view of another illustrative spray drying in a fluidized bed.

4 is a graph depicting the relationship between crush resistance and compression pressure for SAE-CD compositions of the invention containing various amounts of moisture.

DETAILED DESCRIPTION OF THE INVENTION

Compositions AE-CD, adapted for use in special cases of administration. When used with the indicated types of administration, the present SAE-CD compositions have advantages over previously known SAE-CD compositions for these types of administration and provide improved properties. By changing the final conditions (stages after sulfoalkylation; stages following the sulfoalkylation step), the physicochemical and morphological properties of SAE-CD can be modified. For example, various SAE-CD compositions can be obtained by varying the drying and isolation conditions.

Even though the SAE-CD composition of the invention does not require abrasion, it can be abraded to further obtain modified SAE-CD compositions. For example, abrasion of an SAE-CD composition having different bulk density, density after tapping and / or particle diameter. As used herein, the term “abrasion” means the physical abrasion of a solid to reduce its particle size. Any such method used in the pharmaceutical industry is suitable for use in the method of the invention. Abrasion methods include, by way of example and without limitation, grinding in a micron colloid mill, grinding in a ball mill, jet grinding, grinding in a hammer mill, grinding in a pin mill, tumbling, sieving and crushing with a mortar in a pestle. Both low and high energy methods can be used.

The present invention provides a “SAE-CD composition”, which means a sulfoalkyl ether cyclodextrin composition having a combination of various physical properties and excluding the active agent or pharmaceutical excipient. In relation to the composition of SAE-CD, the term “excluding” means without intentional addition. Therefore, the SAE-CD composition may contain fillers endogenous to the method for its manufacture. For example, the first SAE-CD composition will have a first combination of physical properties, i.e., the first profile of physical properties, and the second SAE-CD composition will have a second combination of physical properties. Due to various combinations of physical properties, the first SAE-CD composition will be more preferred for a particular application, and the second SAE-CD composition will be more preferred for another specific application.

The present invention provides compositions SAE-CD, where SAE-CD is a compound of formula I, or a combination thereof:

where n = 4, 5 or 6;

each R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are independently —O— or a group —O— (C ₂ -C ₆ alkylene) —SO ₃ ^- where at least one of R ₁ -R ₉ independently represents a —O- (C ₂ -C ₆ alkylene) -SO ₃ ^- group, preferably a —O- (CH ₂ ) _m SO ₃ ^- group, where m = 2-6, preferably 2-4, (for example, -OCH ₂ CH ₂ CH ₂ SO ₃ ^- or -OCH ₂ CH ₂ CH ₂ CH ₂ SO ₃ ^- ); and

each S ₁ , S ₂ , S ₃ , S ₄ , S ₅ , S ₆ , S ₇ , S ₈ and S ₉ are independently pharmaceutically acceptable cations that include, for example, H ⁺ , alkali metals (e.g. 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.

Suitable methods for preparing SAE-CD feedstocks for use in preparing the SAE-CD composition of the invention are disclosed in US Pat. US patent No. 3426011 from Parmerter et al .; Lammers et al. (Recl. Trav. Chim. Pays-Bas (1972), 91 (6), 733-742); Staerke (1971), 23 (5), 167-171); Qu et al. (J. Inclusion Phenom. Macro. Chem., (2002), 43, 213-221); U.S. Patent No. 5,241,059 to Yosliinaga; U.S. Patent No. 6,153,746 to Shah; PCT International Publication No. WO 2005/042584 from Stella et al; Adam et al. (J. Med. Chem. (2002), 45, 1806-1816); PCT International Publication No. WO 01/40316 by Zhang et al .; Tarver et al. (Bioorganic & Medicinal Chemistry (2002), 10, 1819-1827); Ma (S.T. P. Pharma, Sciences (1999), 9 (3), 261-266); Jung et al. (J. Chromat. 1996, 755, 81-88); and Luna et al. (Carbohydr. Res. 1997, 299, 103-110), the entire contents of which are incorporated herein by reference.

SAE-CD feed is included in the liquid feed used in the fluidized-bed spray drying process used to prepare the SAE-CD composition of the invention.

The SAE-CD composition of the invention may also include a combination of altered cyclodextrin (SAE-CD) and unchanged cyclodextrin. For example, an SAE-CD composition can be made to include unchanged cyclodextrin in an amount of from 0 to less than 50% by weight of the total cyclodextrin present. Illustrative embodiments of the SAE-CD composition include those containing 0-5 wt.%, 5-50 wt.%, Less than 5%, less than 10%, less than 20%, less than 30%, less than 40% or less than 50% unchanged cyclodextrin.

As used herein, the terms “alkylene” and “alkyl” (for example, in the —O- (C ₂ -C ₆ alkylene) -SO ₃ ^- group or in alkyl amines) include linear, cyclic or branched and saturated or unsaturated (i.e. containing one double bond) respectively divalent alkylene groups or monovalent alkyl groups. The term "alkanol" in this text likewise includes linear, cyclic and branched, saturated and unsaturated alkyl components of alkanol groups in which hydroxyl groups can be located at any position on the alkyl part. The term “cycloalkanol” includes unsubstituted or substituted (eg, methyl or ethyl) cyclic alcohols.

Some embodiments of the present invention provide compositions containing one type of cyclodextrin derivative having the structure shown in formula (I), wherein the composition as a whole contains at least 1 and up to 3n + 6 parts of alkylsulfonic acid per cyclodextrin molecule. The invention also includes compositions containing cyclodextrin derivatives having a narrow or wide range of degree of substitution, and high or low degree of substitution. These combinations can be optimized if necessary to provide cyclodextrins having specific properties.

Illustrative derivatives of SAE-CDs include SBE4-β-CD, SBE7-β-CD, SBE11-β-CD, SBE7-γ-CD and SBE5-γ-CD, which correspond to the SAE-CD derivatives of formula I, where n = 5, 5, 5, 6 and 6, respectively; and on average there are, respectively, 4, 7, 11, 7 and 5 present substituents in the form of a simple sulfoalkyl ether. Other illustrative derivatives of SAE-CD include derivatives of the formula SAEx-R-CD (Formula 2), wherein SAE is sulfomethyl ether (SME), sulfoethyl ether (SPE), sulfobutyl ether (SBE), sulfopentyl ether (SPtE) or sulfohexyl ether (SHE); x (average or defined degree of substitution) = 1-18, 1-21, 1-24, where R (the ring structure of the starting cyclodextrin) is, respectively, α, β or γ; and CD is cyclodextrin. The SAE functional group includes a cationic counterion, as disclosed herein, or generally used in the pharmaceutical industry, for the counterion of any acid group.

Since SAE-CD is a polyionic cyclodextrin, it can be provided in various salt forms. Suitable counterions for the SAE functional group (s) include cationic organic atoms or molecules and cationic inorganic atoms or molecules. SAE-CD may include one type of pro-ion or a mixture of different counterions. The properties of SAE-CD can be modified by changing the identity of the present counterion. For example, the first salt form of SAE-CD may have a greater electrostatic charge than the other second salt form of SAE-CD. It was found that the calcium salt form is more electronegative than the sodium salt form. Similarly, an SAE-CD having a first degree of substitution can have a greater electrostatic charge than a second SAE-CD having a different degree of substitution.

When the SAE-CD composition is intended for intrapulmonary administration, the median particle diameter may be in the range from about 0.1 to about 10 microns, or from about 0.5 to about 6.4 microns. If it is desired that the particles reach the lower regions of the airways, i.e., the alveoli and terminal bronchi, then the median particle diameter may be in the range of about 0.5 to about 2.5 microns. If it is desired that the particles reach the upper respiratory tract, the particle diameter range may be from 2.5 μm to 10 μm. An SAE-CD composition with this median particle diameter size can be obtained by abrasion of an SAE-CD composition having a larger median particle diameter size range.

The particle diameter range (defined as the ratio = (average particle diameter of the 90th percentile - average particle diameter of the 10th percentile) / average diameter of the 50th percentile) of an SAE-CD composition can also affect its properties. SAE-CDs having a wide, moderate, and narrow particle size distribution can be used in the invention. A larger range indicates a wider particle size distribution, and a smaller range indicates a narrower particle size distribution. Certain embodiments include those where the range is from about 1.5 to 2.9, from 1.1 to 1.9, or from 1.4 to 1.7.

Since the particles are present as a size distribution, the distribution may be monomodal, bimodal or multimodal, preferably a monomodal distribution.

The SAE-CD composition is a particulate composition containing agglomerated and non-agglomerated particles. Agglomerated particles can be obtained by spray drying in a fluidized bed, which may include agglomeration and / or granulation. The term "agglomeration", which can be used interchangeably with "granulation", is taken to mean a method in which dispersed small particles in a composition merge with other particles in the composition to form the composition as larger particles, thereby reducing the number of small particles and increasing the total the average particle diameter of the composition. The resulting collection of particles can be called agglomerate or granulate. The SAE-CD composition of the invention can be distinguished by SEM (scanning electron microscopy) from other SAE-CD compositions made in accordance with other methods. Figure 1 shows the SEM of an illustrative composition SAE-CD, manufactured by spray drying in a fluidized bed. The particles have a rough surface texture and include a significant amount of agglomerated particles.

Illustrative methods for preparing the SAE-CD composition include fluid bed agglomeration or fluid bed agglomeration.

FIG. 2 illustrates an exemplary fluidized bed spray dryer apparatus that can be used to produce the SAE-CD composition of the invention. This device includes a reservoir for the supplied liquid material (1), a cylindrical block for spray drying in a fluidized bed (2), a cyclone particle classifier (3), a container for collecting the final product (4), a gas filtration unit (5), a container for collecting waste products (6), condensers (7) and fluidized bed chambers (8-10). The device operates as follows. To start the process, the supplied aqueous liquid containing the SAE-CD feed is transferred from the reservoir (1) to the dryer (2) through a pipe (M). The supplied liquid is sprayed into the drying chamber countercurrently against the flow of hot gas (A) to form the initial fluidized bed of particles. The formed small particles exit the drying chamber and are directed through the pipeline (B) to the cyclone (3), which classifies the particles and returns small particles of the corresponding size in the same direction through the pipe (C) back to the upper part of the drying chamber to the area adjacent to the channel fluid supply. Since the additional supplied liquid is sprayed into the drying chamber, larger particles and small particles are formed, and larger particles (those that are not considered to be “small” particles) form a fluidized bed in the chamber (8). When the particles reach the estimated average particle diameter size, they are sent to the chamber (9) and, subsequently, to the chamber (10). Each chamber includes its own gas inlet and contains a fluidized bed of particles. The gas inlet for chamber (8) is the main stream of hot gas (A), which fluidizes the layer of particles in the drying chamber (8). The gas stream (N) for the chamber (9) has a lower temperature than the stream (A), and the stream (P) has an even lower temperature. As the particles move from the chamber (8) to the chamber (9) and then to the chamber (10), they cool. The final SAE-CD composition is collected from the chamber (10) and sent to the container (4) through the pipeline (F). Small particles present in the chambers (9) and (10) are sent through the pipeline (G) to the cyclone (3). The gas leaving the cyclone is directed through a conduit (H) to the filter unit (5) to collect any particles that are not otherwise returned by the cyclone to the drying chamber. Particles collected in the filter unit are loaded into the collection container (6) for possible reprocessing. Gas exits the filter unit and is routed through condenser (s) (7), which remove moisture from the gas. Finally, the gas is either removed or returned back to the drying chamber through a conduit (L) and / or gas flows (A, N or P).

Figure 3 shows another illustrative fluidized-bed dryer apparatus that can be used to produce the SAE-CD composition of the invention. This device is similar to the device shown in figure 2; however, it excludes chambers (9-10), particle return pipe (G), and capacitor (s) (7). In addition, the cyclone returns fine particles to the drying chamber through a conduit (C) and, subsequently, a conduit (C1) and / or a conduit (C2). When small particles are introduced into the drying chamber through a conduit (C1), they are introduced as a co-flow with the feed stream sprayed into the drying chamber. When small particles are introduced into the drying chamber through a conduit (C2), small particles are introduced in a direction that is tangential or perpendicular to the gas stream (A) introduced into the drying chamber and / or the gas inlet (L). It should be noted that this illustrative device does not return gas from the filtration unit back to the drying chamber; however, it can be modified to carry out this operation.

Most particles in such fluidized bed chambers usually do not reach the height of a cloud of sprayed feed fluid. However, particles formed during the process that return back to the drying chamber can be introduced into a position adjacent to the spray gun of the feed liquid, or into the position between the spray gun and the fluidized bed.

During operation of any device, the gas flow can be controlled at various positions within the device to modify the fluidized bed, the drying rate, the classification of fine particles and / or the feed rate of small particles into the drying chamber. The method of spray drying in a fluidized bed includes:

the provision of a supplied liquid (solution, suspension or slurry), including a liquid carrier and, optionally, SAE-CD;

providing, in a fluidized-bed drying chamber, SAE-CD particles having a first average particle diameter size, where the layer is fluidized by a stream of hot gas flowing in the first direction;

spraying the supplied fluid into the fluidized bed in the drying chamber to form a particulate SAE-CD composition comprising agglomerated particles having a larger second average particle diameter, where spraying is carried out in the second direction, and most of the liquid carrier has been removed from the particulate composition ; and

collecting the particulate composition to form an SAE-CD composition.

Certain embodiments of the methods include those in which: 1) the method further comprises recycling a portion of the smaller particles in the particulate composition back into the drying chamber; 2) the portion of particles to be recycled is introduced into the drying chamber in a position adjacent to the point of introduction of the supplied liquid; 3) a portion of particles to be recycled is introduced into the drying chamber in a direction tangential or perpendicular to the direction of introduction of the feed liquid into the drying chamber; 4) a portion of particles to be recycled is introduced into the drying chamber in a position adjacent to the diffuser of the drying chamber; 5) the method is carried out in the form of a joint stream; 7) the method is carried out in the form of a mixed stream; 8) the composition in the form of particles includes less than 18 wt.% A liquid carrier; 9) the liquid carrier is aqueous; 10) the supplied fluid includes SAE-CD; 11) an SAE-CD composition has a combination of physical properties as described herein; and 12) spray drying in a fluidized bed has a cylindrical and / or conical drying chamber.

In the method of spray drying in a fluidized bed in a joint stream, the direction of flow of the sprayed feed liquid in the drying chamber is the same as the direction of the flow of hot air used to fluidize the particle layer. The atomizer may be a spray nozzle or a rotary atomizer (for example, a rotating disk). The air flow can be controlled so that mainly laminar or turbulent flow occurs.

In the spray drying method in a fluidized bed in counterflow, the hot air used to fluidize the bed moves through the drying chamber in the opposite direction to the sprayed feed fluid.

In the method of spray drying in a fluidized bed in a mixed stream, the particles move through the drying chamber in the co-flow and countercurrent phases. This type requires the use of a spray gun in the form of a nozzle spraying upward into the incoming air stream, or a spray gun spraying droplets downward in the direction of the integrated liquid layer, where the air inlet and outlet are located in the upper part of the drying chamber. Additional air inlets will direct upward flow to fluidize the particle bed.

Small or small particles used to form a fluidized bed in a drying chamber can be obtained separately, for example, by spray drying, crushing, grinding, other abrasion, sieving or other suitable means. Otherwise, small particles can be obtained in situ by operating equipment in the form of conventional spray drying, and subsequently by operating equipment in the form of spray drying in a fluidized bed. In one embodiment, small or small particles are obtained by separating these particles from material removed from the drying chamber and returning the small or small particles back to the drying chamber. The invention includes methods whereby fine particles are introduced into a drying chamber and generated in situ by drying a sprayed feed liquid.

The method according to the invention can be carried out in a continuous or semi-continuous manner, whereby a feed liquid containing SAE-CD feed is introduced continuously or semi-continuously into the drying chamber, and the SAE-CD composition is continuously or semi-continuously removed from the fluidized bed.

The aqueous liquid carrier used in the feed liquid, which may be a solution or suspension, may or may not contain other material, such as a by-product of the sulfoalkylation reaction and subsequent increase in basicity of the reaction medium. The liquid carrier used in the present invention is any aqueous medium used in pharmaceutical technology to agglomerate or granulate solids.

The solids content of the SAE-CD feed liquid can range from 0.1 to 80 wt.%, From 10 to 70 wt.%, From 30 to 70 wt.% Or from 40 to 60 wt.% Solids. Some embodiments of the supplied liquid include: 1) only sulfoalkyl ether cyclodextrin and water; or 2) only sulfoalkyl ether cyclodextrin, water and by-products of the synthesis method used to produce sulfoalkyl ether cyclodextrin. The sulfoalkyl ether cyclodextrin used in the feed liquid is sometimes referred to herein as the raw material sulfoalkyl ether cyclodextrin.

The supplied liquid can be cooled or heated before being introduced into the drying chamber. Temperature can be used to control the viscosity of the fluid being supplied: the higher the temperature, the lower the viscosity. The temperature of the liquid supplied can be from 0 ° C to 100 ° C, or an ambient temperature of up to 70 ° C.

The gas used to carry particles through the device is generally a gas such as air, helium or nitrogen. The device may include a gas charging unit for loading gas for operation, purging, and addition.

The inlet gas temperature can be used to control the particle drying rate, production rate, degree of agglomeration, water content in the SAE-CD composition and / or type of agglomeration. The temperature may vary from about 100 ° C to about 300 ° C, from about 130 ° C to about 180 ° C, from about 150 ° C to about 170 ° C, or from about 210 ° C to about 250 ° C.

The SAE-CD composition has a minimum hole diameter of the gravitational flow in the range of from about 3-7 mm or 4-6 mm, or less than about 10 mm, or less than about 20 mm. The term "minimum hole diameter of the gravitational flow" means the minimum diameter of the hole through which the SAE-CD composition will provide an acceptable volumetric flow. The following example further defines this term. This parameter is determined according to the method of Example 5 where the FLOWDEX instrument (Hanson Reserach Corp., Northridge, CA) is used. Applicants have been successful in preparing a SAE-CD composition that has a substantially different minimum bore diameter than that obtained by conventional spray drying.

The SAE-CD composition has a Carr index less than or equal to approximately compressibility of approximately 24%, or less than or equal to approximately compressibility of approximately 18%, or less than or equal to approximately compressibility of approximately 16%. Used in this regard, the term "compressibility" refers to the relative percentage reduction to which a certain density will be subjected, during the determination of the density after compaction by tapping the container. The Carr Index is a measure of the compressibility of a SAE-CD composition. It is based on the bulk density and density of the material after compaction as a result of tapping the container. The Carr Index was determined as described in Example 8 below. Applicants have been successful in producing spray agglomerated SAE-CD composition having a Carr index substantially different from other SAE-CD compositions obtained by spray drying, lyophilization or spray agglomeration.

SAE-CD has an actual density in the range of from about 1.25 to 1.35 g / cm ³ , or from 1.1 to 1.5 g / cm ³ , or from 1.29 to 1.32 g / cm ³ . The actual density was determined in accordance with Example 8 below. The SAE-CD composition of the invention has an actual density substantially different from the spray dried SAE-CD composition.

The SAE-CD composition of the invention has a bulk density of from about 0.55 to 0.66 g / cm ³ , from about 0.38 to less than 0.55 g / cm ^3, or from about 0.38 to about 0.66 g / cm ³ . The SAE-CD composition made in accordance with the spray agglomeration method of the invention has a higher bulk density than the bulk density of the SAE-CD composition made by another spray drying agglomeration method.

The SAE-CD composition has a density after shrinkage by tapping on the container (density after tapping) from about 0.66 to 0.75 g / cm ³ , or from about 0.49 to 0.66 g / cm ³ , or from about 0.49 to about 0.75 g / cm ³ when performed in accordance with method 1 of the US Pharmacopoeia <616>. The SAE-CD composition made in accordance with the spray agglomeration method of the invention has a higher density after tapping than the density after tapping the SAE-CD composition made by spray drying.

Since the solid composition SAE-CD can be used for the manufacture of tablets, in particular compressed tablets, its crush resistance was determined at various levels of maximum compression pressure for SAE-CD compositions having different moisture contents. The method of example 7 was used to determine this relationship. The behavior of the SAE-CD composition was compared (FIG. 4) with the behavior of Avicel PH-200, lactose and Dical, which are 3 excipients commonly used in the manufacture of tablet formulations. The SAE-CD composition of the invention has great advantages since its compression behavior can be improved by changing the moisture content, particle size and / or particle shape.

The tablet hardness or tablet crush resistance in units of kilopond (kp) depending on the maximum compression pressure (Pmax) in units of megapascals (MPa) is presented for the sample composition SAE-CD (SBE7-β-CD) of the present invention, "as such", those. as obtained as a result of the spray drying method in a fluidized bed, and balanced (B3 Eq and B4 Eq) over saturated magnesium nitrate. The behavior of these samples was compared with the behavior of available bulk fillers in direct compression, for example, microcrystalline cellulose or MCC (Avicel PH 200, FMC), lactose monohydrate (SuperTab, The Lactose Co. Of New Zealand), dibasic calcium dihydrogen phosphate (Encompress, Penwest Pharm Co .). For the tools used in this study, 100 MPa wounds approximately 6 kilonewtons (kN) of force. As such, the water content in the SAE-CD composition of the present invention was 2.77% and 2.36% for B3 and B4, respectively, according to the loss after drying (LOD) at 110 ° C. using the 2000XL comparative model (Arizona Instruments , Tempe, AZ). The water content after equilibration, according to the LOD determination, was 5.46% and 5.50% respectively for B3 Eq and B4 Eq.

At lower moisture levels, for example, in the range of from about 2 to about 3 wt.% (As determined by LOD conducted at a temperature of 104 ° C. to 110 ° C.), the SAE-CD composition had crush resistance in the range of approximately 1 to about 20 kp (kilopond) when pressed into a tablet using Pmax (maximum compression pressure) in the range of from about 30 to about 275 MPa (megapascals). At higher moisture levels, for example in the range of from about 5 to about 6 wt.% (As determined by the LOD), the SAE-CD composition had crush resistance in the range of from about 0.5 to about 11 kP when compressed into a tablet using Pmax in the range of from about 15 to about 70 MPa. The average particle diameter, particle size distribution, and morphology of the SAE-CD composition are readily modified to match the wide variety of characteristics of the milled drug in a micron colloid mill, which are presented in the formulation guide in this area. An advantage of the present invention is the ability of a person skilled in the art to modulate the physicochemical properties of the SAE-CD composition to match or complement the formulation or manufacturing methods, drug properties or excipient properties, thereby leading to an optimal product.

The dosage form of the invention can be used to administer a wide range of active agents. Active agents generally include physiologically or pharmacologically active substances that have a systemic or localized effect or effects in animals and humans. Active agents also include pesticides, herbicides, insecticides, antioxidants, plant growth stimulants, sterilization agents, catalysts, chemicals, food products, nutrients, cosmetics, vitamins, minerals, food additives, sterility inhibitors, fertility stimulants, microorganisms, flavoring agents , sweetening agents, cleaning products and other such compounds for pharmacological, veterinary, horticultural, household, food, culinary, with agricultural, cosmetic, industrial, cleansing, confectionery and flavoring applications.

In each case, the active agent can be independently selected from pharmaceutically active agents, such as an antibiotic, antihistamine, decongestant, anti-inflammatory agent, antiparasitic agent, antiviral agent, local anesthetic, antifungal agent, antibacterial agent, amoebicidal agent, trichamocidal agent, analgesic agent , anti-arthritis agent, anti-asthma agent, anticoagulant, anticonvulsant, antidepressant ssant, antidiabetic agent, antineoplastic agent, antipsychotic agent, antipsychotic agent, antihypertensive drug, sleeping pill, sedative, anxiolytic energizing agent, anti-Parkinson’s disease, anti-Alzheimer's disease, muscle relaxant, antimalarial, hormonal, contraceptive agent, hypoglycemic agent, antihyperglyceridemic agent, antilipidemic agent, med during which reduces cholesterol absorption inhibitor of bile acids, antilipemic agent, ophthalmic agent, electrolytic agent, diagnostic agent, prokinetic agent, an agent inhibiting gastric acid secretion, anti-incontinence, cardiovascular agent, corticosteroid agonist, In ₂ adrenergic receptors, dopamine D ₂ receptor agonist, anticholinergic agent, IL-5 inhibitor, IL-5 antisense modulators, milrinonlactate, tryptase inhibitor, tachykinin receptor antagonist, an leukotriene receptor agonist, 5-lipoxygenase inhibitor, anti-IgE antibody, protease inhibitor, or combinations thereof.

Other specific active agents that can be used in accordance with the invention include pentamidine dinethiouat, albuterol sulfate, metaprotorenol sulfate, flunisolide, cromolyn sodium, cromoglycate sodium, ergotamine tartrate, levalbuterol, terbutaline, reproterol, salbutamol, brometeroluleruberolotoleroloteroluroloteroleterolotoleroloterolumerolotoleroloteroleterolotolerolotol , epinephrine, isoprenaline or hexoprenaline, an anticholinergic agent such as tiotropium, ipratropium, oxytropium or glycopyrronium; a leukotriene antagonist such as andolast, iralucast, pranlucast, imitrodast, seratrodast, zileuton, zafirlukast or montelukast; a phosphodiesterase inhibitor such as filaminast or picamilast; platelet aggregation factor inhibitor such as apaphanthus, forapafant or israpafant; a calcium channel opening agent such as amiloride or furosemide; an anesthetic such as morphine, fentanyl, pentazocine, buprenorphine, pethidine, thymidine, methadone or heroin; a potency enhancer such as sildenafil, alprostadil or phentolamine; a peptide or protein, such as insulin, erythropoietin, gonadotropin or vasopressin; calcitonin, factor IX, granulocyte colony stimulating factor, macrophage granulocyte colony stimulating factor, growth hormone, heparin, heparin (low molecular weight), interferon alpha, interferon beta, interferon gamma, interleukin-2, hormone releasing luteinizing hormone, somatostatin analog, amylin, ciliary neurotropic factor, growth hormone releasing factor, insulin-like growth factor, insulinotropin, receptor antagonist interleukin-1, interleukin-3, interleukin-4, interleukin-6, stimulating factor macrophage colony (m-csf), nerve growth factor, parathyroid hormone, thymosin alpha-1, iib / iiia inhibitor, alpha-1 antitrypsin, anti-respiratory syncytial virus antibody, cystr transmembrane regulator gene (cftr), deoxyribonuclease, D permeability-enhancing bactericidal protein (ards), anti-cytomegalovirus antibody, interleukin-1 receptor, or a pharmaceutically acceptable derivative or salt of these compounds.

The list of active agents (drugs) presented in this document should not be considered exhaustive, and it only illustrates many of the options for implementation, which are considered included in the scope of the invention. Many other agents can be administered with the composition of the present invention. Suitable drugs are selected from the list of drugs included in this document, as well as from any other drugs taken by U.S.F.D.A. (United States Medicines and Food Administration), or other similarly recognized legislature in Canada (Health Canada), Mexico (Mexico Department of Health), Europe (European Medicines Agency (EAEA)), South America (particularly in Argentina (Adminstracion Nacional de Medicamentos, Alimentos y Technologia Medica (ANMAT) and Brazil (Ministerio da Saude)), Australia (Department of Health and Aging), Africa (particularly South Africa (Department of Health) and Zimbabwe (Ministry of Health and Welfare conditions of children) or Asia (particularly Japan (Ministry of Health, Labor and Welfare), Taiwan (Executive Youth Department of Health) and China (Ministry of Health of the People's Republic of China) as suitable for administration to humans and animals. Some embodiments of the invention include where the active substance is pharmacologically or biologically active, or where the environment of use is the gastrointestinal tract of a mammal.

The active agent may be present in its neutral, ionic, salt, basic, acidic, natural, synthetic, diastereomeric, epimeric, isomeric, enantiomerically pure, racemic, solvate, hydrated, anhydrous forms, in the form of a chelate, derivative, analogue, in esterified, not esterified or other usual form. When an active agent is indicated in this document, it implies all of its available forms.

The active agent contained in the formulation of the present invention may be present in the form of its pharmaceutically acceptable salt or salt-free form. As used herein, the term “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds, wherein the active agent is modified by reacting it with an acid or base, as necessary to form an ionically coupled pair. Examples of pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic salts. Suitable non-toxic salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and other acids known to those of ordinary skill in the art. Salts derived from organic acids, such as amino acids, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydromaleic, phenylacetic, glutamic, benzoic, salicylic, sulphanibenzoic, 2 fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic and other acids known to those of ordinary skill in the art. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent active agent that contains a basic or acidic moiety by conventional chemical methods. Lists of other suitable salts can be found in Remington's Pharmaceutical Sciences. 17 ^th ed., Mack Publishing Company, Easton, PA, 1985, the relevant description of which is incorporated herein by reference.

The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms that are within the scope of sound medical judgment suitable for use in contact with tissues of humans and animals, without excessive toxicity, irritation, allergic reactions or other problems or complications commensurate with the appropriate benefit / risk ratio.

As used herein, the term “patient” or “subject” is used to mean warm-blooded animals such as mammals such as cats, dogs, mice, guinea pigs, horses, bulls and cows, sheep and humans.

The formulation of the invention may include an active agent present in an effective amount. By the term “effective amount” is meant an amount or content of an active agent that is sufficient to elicit a desired or desired reaction, or, in other words, an amount that is sufficient to elicit a detectable biological response when administered to a subject.

The formulation of the invention can be used to deliver one or more different active agents. Specific combinations of active agents may be provided by the present formulation. Some combinations of active agents include: 1) a first drug from the first therapeutic class and another second drug from the same therapeutic class; 2) the first drug from the first therapeutic class and another second drug from another therapeutic class; 3) a first drug having a first type of biological activity and another second drug having approximately the same biological activity; 4) a first drug having a first type of biological activity, and another second drug having a different second type of biological activity. Illustrative combinations of active agents are described herein.

When combinations of active agents are used, one or both of the active agents may be present in a subtherapeutic amount. As used herein, the term “subtherapeutic amount” is that amount of a first drug that provides a less than normal therapeutic response in a patient to whom the first drug is administered in the absence of a second combination drug. In other words, the first and second drugs can together provide an enhanced, improved, additive or synergistic therapeutic effect compared to the administration of each drug separately, i.e. in the absence of another drug.

Once prepared, the SAE-CD composition may be included in any known pharmaceutical formulation or dosage form. The compositions and formulations of the invention are suitable for administration to a subject by means used in the pharmaceutical industry. Illustrative methods of administration include, but are not limited to, endobronchial (intrapulmonary, intratracheal, intraalveolar), oral, oral, ophthalmic, ophthalmic, aural, sublingual, buccal, transdermal, mucosal, rectal, vaginal, uterine, urethral, subsolar , intraperitoneal, intramuscular and subcutaneous administration.

The dosage form is in the form of one or a plurality of dosage forms containing, among other substances, a certain amount of the active ingredient and an SAE-CD composition, said amount being such that one or more predetermined units of the dosage form are usually required for a single therapeutic administration. In the case of multiple dosage forms, such as a notched tablet, the specified unit will be a single fraction, such as half or quarter of a multiple dosage form. It should be understood that the specific dose level for any patient will depend on a variety of factors, including the indication being treated, the active agent used, the activity of the active agent, the severity of the indication, health status, age, gender, body weight, diet and the patient’s pharmacological reaction, the particular used dosage form and other such factors.

After receiving the composition of the FAE-CD, it can be used to obtain a formulation, where the composition of the FAE-CD forms a complex or does not form a complex with the active agent. By the term “forms a complex” is meant “to be part of a clathrate or inclusion complex with,” i.e. the active agent included in the complex is part of a clathrate or inclusion complex with a cyclodextrin derivative.

By an active agent / CD complex is generally meant a clathrate or inclusion complex of a cyclodextrin derivative and active agent. The ratio of active agent to CD present in the molecular complex may vary and may range from about 10 to about 0.1 on a molar basis. Thus, the CD as a whole will, but should not, be present in excess relative to the active agent. The amount of excess will be determined by the endogenous solubility of the agent, the expected dose of the agent, and the binding constant for the formation of inclusion complexes between the specific drug (agent) and the particular derivative CD used. It should be noted that the cyclodextrin derivative may be present in a form not included in the complex and therefore in an amount significantly exceeding the amount of active agent present. The mass ratio or molar ratio of the altered cyclodextrin to the active agent may exceed 100, 1000 or even more.

Under the same conditions, SAE-CD compositions can form one or more ionic bonds with a positively charged acid-ionizable compound. Therefore, the compound can form a complex in the form of an inclusion complex with an altered cyclodextrin, and not for covalent, but ionic binding with an altered cyclodextrin.

Even though the SAE-CD composition may be the only carrier or excipient in the formulation, other carriers may be added to the formulation to further improve functioning.

The SAE-CD composition may be included in any formulation requiring an altered cyclodextrin. The active agent included in the formulation can be delivered in the form of a rapid, immediate, pulsating, timed, targeted, delayed and / or sustained release formulation.

By "immediate release" is meant the release of the active agent into the medium over a period of a few seconds to more than about 30 minutes after the start of the release, and the release starts no more than about 2 minutes after the introduction. Immediate release does not show a significant delay in drug release.

By "quick release" is meant the release of the active agent into the medium over a period of 1-59 minutes or from 0.1 minute to 3 hours after the release has begun, and the release may begin within a few minutes after administration or after the delay period ( delay time) after administration.

A sustained release formulation containing an SAE-CD composition will release a drug over an extended period. The mechanisms used for such delivery may include a pH dependent or pH independent release of the active agent; controlled by diffusion or dissolution; pseudo-zero order (approaching the release of zero order), zero order, pseudo-first order (approaching the release of first order) or first order; or fast, slow, delayed, timed release, or sustained release or release, otherwise controlled. The release profile of the active agent may also be sigmoidal in form, where the release profile includes an initial slow release rate followed by an average, faster release rate and a final slow release rate of the active agent. As used herein, the term “sustained release” refers to a definition that is widely recognized in the pharmaceutical art. A sustained release dosage form will release a drug at a substantially constant rate over an extended period of time, or a substantially constant amount of the drug will be released in parts over an extended period of time. The term "sustained release" in relation to the release of a drug includes the terms "controlled release", "delayed release", "prolonged release" or "slow release", as these terms are used in pharmaceutical technologies. Controlled release may begin within a few minutes after administration or after a delay period (delay time) after administration. Sustained release may begin within a few minutes after administration or after the expiration of the grace period (delay time) after administration.

By "controlled release" is meant the release of the active agent into the medium over a period of from about 8 hours to about 12 hours, 16 hours, 18 hours, 20 hours, 24 hours or more than 24 hours. "Sustained release" means the sustained release of the active agent for maintaining a constant level of the drug in the blood or target tissue of the subject to whom the drug is administered. Controlled release may begin within a few minutes after administration or after a delay period (delay time) after administration.

A timed release dosage form is one that begins to release the drug after a predetermined period of time, measured from the moment it was first contacted with the environment of use.

A slow release dosage form is one that provides a slow release rate of the drug so that the drug is released slowly and approximately continuously, for example, over a period of 3 hours, 6 hours, 12 hours, 18 hours, days, 2 or more days 1 week or 2 or more weeks.

A targeted release dosage form generally refers to an oral dosage form that is intended to deliver a drug to a specific part of a subject's gastrointestinal tract. An illustrative targeted dosage form is an enteric-coated dosage form that delivers the drug to the middle or lower part of the small intestine, but not the stomach or oral cavity of the subject. Other targeted dosage forms can be delivered to other parts of the gastrointestinal tract, such as the stomach, jejunum, ileum, duodenum, cecum, colon, small intestine, colon, or rectum.

The pulsatile release dosage form is one which provides pulses of a high concentration of the active ingredient, between which "concavities" of low concentration are inserted. A pulsating profile containing 2 peaks can be described as “bimodal”.

The pseudo-first-order release profile is a profile that approaches the first-order release profile. The first-order release profile characterizes the release profile of the dosage form, which releases a constant percentage of the initial charge of the drug per unit time.

The pseudo-zero order release profile is a profile that approaches the zero-order release profile. The zero-order release profile characterizes the release profile of the dosage form, which releases a constant amount of the drug per unit time.

Sustained release dosage forms can be prepared in accordance with the procedures described herein or in Biorelated Polymers and Gels: Controlled Release and Applications in Biomedical Engineering (ed. Teruo Okano; 1998); Encyclopedia of Controlled Drug Delivery (ed. Edith Mathiowitz; 1999); Future Strategies for Drag Delivery with Particulate Systems (ed. I.E. Diederichs; 1998); Controlled Release Series (ed. J. M. Anderson; 1987); Controlled Drug Delivery Series (Ed. S.D. Brack; 1983); Controlled Release of Drags Series (ed. M. Rosoff; 1989); Controlled Release Technology: Pharmaceutical Applications (ACS Symposium Series No. 348) (eds. P. I. Lee and W. R. Good; 1987); Extended Release Dosage Forms (ed. L. Krowczynski; 1987); Handbook of Pharmaceutical Controlled Release Technology (ed. D.L. Wise; 2000); Intelligent Materials for Controlled Release (ed. S.M.Dinh; 1999); Multicomponent Transport in Polymer Systems for Controlled Release (Polymer Science and Engineering Monograph Series) (ed. A. Polishchuk; 1997); Pharmaceutical Technology: Controlled Drag Release (ed. M. Rubenstein; 1987); Polymers for Controlled Drag Delivery (ed. P. J. J. Archa; 1991); Tailored Polymeric Materials for Controlled Delivery Systems (ACS Symposium Series No. 709) (ed. I. McCulloch; 1998); Oral Colon-Specific Drag Delivery (ed. D.R. Friend, 1992); and other publications known to those of ordinary skill in the art, the references of which are fully incorporated herein by reference.

The sustained release layer may be a composition controlled by diffusion, erosion, dissolution or matrix destruction, comprising a drug and one or more excipients that control the rate of release, and other optional excipients.

By "delayed release" is meant that the initial release of the drug from the corresponding drug-containing layer occurs after an approximate period of delay (or delay) has elapsed. For example, if drug release from this layer begins about 2 hours after the administration of a multilayer tablet to the subject. In general, delayed release is the opposite of immediate release, where drug release does not begin more than a few minutes after administration. Accordingly, the release profile of a drug from a particular layer may be a delayed-sustained release or a delayed-rapid release. A “delayed-prolonged” release profile is a profile where the sustained release of a drug begins after the expiration of the initial delay period. The “delayed-quick” release profile is a profile where the rapid release of a drug begins after the expiration of the initial delay period.

Although not necessary, the formulation of the present invention may include antioxidants, acidifying agents, alkaline agents, buffering agents, solubility enhancers, permeation enhancers, electrolytes, perfumes, glucose, glidants, stabilizers, fillers, cryoprotectants, plasticizers, flavors, sweeteners, surface tension modifiers, density modifiers, volatility modifiers, hydrophilic polymers, preservatives, antibacterial agents, dyes, antifungal stems agents, agents that enhance the formation of complexes, solvents, salt water, tonicity modifiers, anti-foaming agents, oil, penetration enhancers and other excipients known to those of ordinary skill in the art for use in pharmaceutical formulations, or a combination thereof. In each case, these materials may be independently incorporated into the active agent-containing particles or into the carrier particles. For example, the carrier may include one or more of these materials, and the active agent-containing particles may also include one or more of these materials.

As used herein, the term “sliding” is intended to mean an agent used to promote the flow of dry powder. Such compounds, by way of example and without limitation, include magnesium stearate, sodium dodecyl sulfate, colloidal silicon dioxide, corn starch, talc, calcium silicate, magnesium silicate, colloidal silicone, silicone hydrogel and other materials known to those of ordinary skill in the art.

As used herein, the term “antioxidant” is intended to mean an agent that inhibits oxidation and is thus used to prevent spoilage of drugs by the oxidative process. Such compounds include, by way of example and without limitation, acetone, potassium metabisulfite, potassium sulfite, ascorbic acid, ascorbyl palmitate, citric acid, butylated hydroxyanisole, butylated hydroxytoluene, hydroxyphosphoric acid, monothioglycerol, sodium propyl gallate, sodium sulfate, sodium citrate, sodium citrate sodium bisulfite, sodium formaldehyde sulfoxylate, thioglycolic acid, EDTA (ethylenediaminetetraacetic acid), sodium pentetate and metabisulfite, and others known to those of ordinary skill in the art art.

As used herein, the term “alkaline agent” is intended to mean a compound used to provide an alkaline environment when the dry powder of the invention is contacted with water. Such compounds include, by way of example and without limitation, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine, diethanolamine, organic amine base, alkaline amino acids and trolamine, and others known secondary specialists in this field.

As used herein, the term “acidifying agent” is intended to mean a compound used to provide an acidic environment when the dry powder of the invention is contacted with water. Such compounds include, by way of example and without limitation, acetic acid, acidic amino acids, citric acid, fumaric acid and other alpha hydroxy acids, hydrochloric acid, ascorbic acid, phosphoric acid, sulfuric acid, tartaric acid and nitric acid and others known to those of ordinary skill in the art. area.

As used herein, the term “buffering agent” is intended to mean a compound used to resist a change in pH upon contact with a medium with a different pH. Buffers are used in the present compositions to adjust the pH to a range of from about 2 to about 8, from about 3 to about 7, or from about 4 to about 5. By adjusting the pH of the dry powder, airway irritation can be minimized. Such compounds include, by way of example and without limitation, acetic acid, sodium acetate, adipic acid, benzoic acid, sodium benzoate, boric acid, sodium borate, citric acid, glycine, maleic acid, monobasic sodium phosphate, dibasic sodium phosphate, HEPES, lactic acid , tartaric acid, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, sodium bicarbonate, tris (hydroxymethylaminomethane), sodium tartrate and anhydrous sodium citrate and dihydrate, and others known to those of ordinary skill in the art. Other buffers include citric acid / phosphate, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, Mcllvain, phosphate, Prideaux-Ward, succinate, citrate-phosphate borate (Teorell-Stanhagen), veronalacetate, MES (2- (N-morpholino) ethanesulfonic acid), BIS-TRIS (bis (2-hydroxyethyl) imino-tris- (hydroxymethyl) methane), ADA (N- (2-acetamido) -2-iminodiacetic acid) , ACES (N- (carbamoylmethyl) -2-aminoethanesulfonic acid), PIPES (piperazine-N, N'-bis (2-ethanesulfonic acid)), MOPSO (3- (N-morpholino) -2-hydroxypropanesulfonic acid), BIS -TRIS PROPANE (1,3-bis (Tris (hydroxyme il) methylamino) propane), BES (N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid), MOPS (3- (N-morpholino) propanesulfonic acid), TES (N-Tris (hydroxymethyl) methyl-2 aminoethanesulfonic acid), HEPES (N- (2-hydroxyethyl) piperazine-N '- (2-ethanesulfonic acid), DIPSO (3- (N, N-bis (2-hydroxyethyl) amino) -2-hydroxypropanesulfonic acid), MOBS (4- (N-morpholine) butanesulfonic acid), TAPSO (3- (N-Tris (hydroxymethyl) methylamino) -2-hydroxypropanesulfonic acid), TRIZMA ^TM (Tris (hydroxymethylaminomethane), HEPPSO (N- (2-hydroxyethyl) piperazine-N '- (2-hydroxypropanesulfonic acid), POPSO (piperazine-N, N'-bis (2-hydroxypropanesulfonic acid)), TEA (triethanolamine), EPPS (N- (2-hydroxyethyl) piperazine-N '- (3-propanesulfonic acid), TRICINE (N-tris ( hydroxymethyl) methylglycine), GLY-GLY (glycylglycine), BICINE (N, N-bis (2-hydroxyethyl) glycine), BICINE (N, N-bis (2-hydroxyethyl) glycine), HEPBS (N- (2-hydroxyethyl ) piperazine-N '- (4-butanesulfonic acid)), TAPS (N-Tris (hydroxymethyl) methyl-3-aminopropanesulfonic acid), AMPD (2-amino-2-methyl-1,3-propanediol), and / or any other buffers known to those skilled in the art.

An agent that enhances the formation of complexes is a compound, or a compound that enhances (enhances) the formation of complexes of an active agent with an altered cyclodextrin. When an agent that enhances the formation of complexes is present, it may be necessary to modify it so that less modified cyclodextrin is required. Suitable complexing agents include one or more pharmacologically inert, water soluble polymers, hydroxyacids and other organic compounds commonly used in liquid formulations to enhance the formation of complexes of a particular agent with cyclodextrins. Suitable water soluble polymers include water soluble natural polymers, water soluble semi-synthetic polymers (such as water soluble cellulose derivatives) and water soluble synthetic polymers. Natural polymers include polysaccharides such as inulin, pectin, derivatives of algin and agar, and polypeptides such as casein and gelatin. Semi-synthetic polymers include cellulose derivatives, such as methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, their mixed ethers, such as hydroxypropyl methyl cellulose, and other mixed ethers, such as hydroxyethyl ethyl cellulose, hydroxypropyl ethyl cellulose and its hydroxymethyl cellulose hydroxymethylmethyl cellulose hydroxymethylmethyl cellulose and carboxymethylmethyl cellulose hydroxymethylmethyl cellulose methyl carboxymethyl cellulose methyl carboxymethyl cellulose methyl hydroxymethylmethyl; Synthetic polymers include polyoxyethylene derivatives (polyethylene glycols) and polyvinyl derivatives (polyvinyl alcohol, polyvinyl pyrrolidone and polystyrene sulfate) and various acrylic acid copolymers (e.g. carbomer). Suitable hydroxy acids include, by way of example and without limitation, citric acid, malic acid, lactic acid, tartaric acid, and others known to those of ordinary skill in the art.

As used herein, the term “preservative” is intended to mean a compound used to prevent the growth of microorganisms. Such compounds include, by way of example and without limitation, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, cetyl pyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenyl mercury acetate, thimerosal, metacresol, gamma-benzyl potassium chloride, potassium nitrate, potassium chloride, , sodium propionate, sorbic acid, thymol and methyl, ethyl, propyl or butyl parabens and others known to those of ordinary skill in the art.

As used herein, the term “colorant” is intended to mean a compound used to color pharmaceutical preparations. Such compounds include, by way of example and without limitation, FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, baked sugar and oxide iron (black, red, yellow), other FD&C dyes and natural coloring agents, such as grape skin extract, beetroot red powder, beta-carotene, annatto, carmine, long turmeric, sweet pepper, combinations thereof and other such materials known secondary specialists in this field.

As used herein, the term “tonicity modifier” is intended to mean a compound that can be used to control the tonicity of a liquid formulation. Suitable tonicity modifiers include glycerin, lactose, mannitol, dextrose, sodium chloride, sodium sulfate, sorbitol, trehalose, and others known to those of ordinary skill in the art.

As used herein, the term “anti-foaming agent” is intended to mean a compound or compounds that prevents or reduces the amount of foam that forms on the surface of a filler composition. Suitable anti-foaming agents include, by way of example and without limitation, dimethicone, simethicone, octoxin, and others known to those of ordinary skill in the art.

Hydrophilic polymers can be used to improve the function of formulations containing cyclodextrin. Loftsson (US Patent Nos. 5324718 and 5472954) has described a number of polymers suitable for combined use with cyclodextrin (unchanged or modified) to enhance the function and / or properties of cyclodextrin. Suitable polymers are disclosed in Pharmazie (2001), 56 (9), 746-747; International Journal of Pharmaceutics (2001), 212 (1), 29-40; Cyclodextrin: From Basic Research to Market, International Cyclodextrin Symposium, 10th, Ann Arbor, MI, United States, May 21-24, 2000 (2000), 10-15 (Wacker Biochem Corp .: Adrian, Mich.); PCT International Publication No. WO 9942111; Pharmazie, 53 (11), 733-740 (1998); Pharm. Technol. Eur., 9 (5), 26-34 (1997); J. Pharm. Sci. 85 (10), 1017-1025 (1996); European Patent Application EP0579435; Proceedings of the International Symposium on Cyclodextrins, 9th, Santiago de Comostela, Spain, May 31-June 3, 1998 (1999), 261-264 (Editor (s): Labandeira, JJTorres; Vila-Jato, JLKluwer Academic Publishers, Dordrecht, Neth); S.T.P. Pharma Sciences (1999), 9 (3), 237-242; ACS Symposium Series (1999), 737 (Polysaccharide Applications), 24-45; Pharmaceutical Research (1998), 15 (11), 1696-1701; Drug Development and Industrial Pharmacy (1998), 24 (4), 365-370; International Journal of Pharmaceutics (1998), 163 (1-2), 115-121; Book of Abstracts, 216th ACS National Meeting, Boston, August 23-27 (1998), CELL-016, American Chemical Society; Journal of Controlled Release, (1997), 44/1 (95-99); Pharm. Res. (1997) 14 (11), S203; Investigative Ophthalmology & Visual Science, (1996), 37 (6), 1199-1203; Proceedings of the International Symposium on Controlled Release of Bioactive Materials (1996), 23rd, 453-454; Drug Development and Industrial Pharmacy (1996), 22 (5), 401-405; Proceedings of the International Symposium on Cyclodextrins, 8th, Budapest, Mar. 31-Apr. 2, (1996), 373-376. (Editor (s): Szeytli, J .; Szente, L. Kluwer: Dordrecht, Neth.); Pharmaceutical Sciences (1996), 2 (6), 277-279; European Journal of Pharmaceutical Sciences, (1996) 4 (SUPPL.), SI44; Third European Congress of Pharmaceutical Sciences Edinburgh, Scotland, UK September 15-17, 1996; Pharmazie, (1996), 51 (1), 39-42; Eur. J. Pharm. Sci. (1996), 4 (SuppL), S143; U.S. Patents No. 5472954 and No. 5,324,718; International Journal of Pharmaceutics (Netherlands), (Dec. 29, 1995) 126, 73-78; Abstracts of Papers of the American Chemical Society, (02 APR 1995) 209 (1), 33-CELL; European Journal of Pharmaceutical Sciences, (1994) 2, 297-301; Pharmaceutical Research (New York), (1994) 11 (10), S225; International Journal of Pharmaceutics (Netherlands), (Apr 11, 1994) 104, 181-184; and International Journal of Pharmaceutics (1994), 110 (2), 169-77, the descriptions of which are fully incorporated herein by reference.

Other suitable polymers are well-known excipients commonly used in pharmaceutical formulations and are included, for example, in Remington's Pharmaceutical Sciences, 18th Edition, Alfonso R. Gennaro (editor), Mack Publishing Company, Easton, PA, 1990, pp. 291 -294; Alfred Martin, James Swarbrick and Arthur Commarata, Physical Pharmacy. Physical Chemical Principles in Pharmaceutical Sciences, 3rd edition (Lea & Febinger, Philadelphia, PA, 1983, pp. 592-638); ATFlorence and D. Altwood, (Physicochemical Principles of Pharmacy, 2nd Edition, MacMillan Press, London, 1988, pp. 281-334, the disclosures of which are incorporated herein by reference in their entirety. Still other suitable polymers include water soluble natural polymers, water soluble semi-synthetic polymers (such as water soluble cellulose derivatives) and water soluble synthetic polymers. Natural polymers include polysaccharides such as inulin, pectin, algin derivatives (eg sodium alginate) and agar, and polypeptides such like casein and gelatin. lusynthetic polymers include cellulose derivatives such as methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, their mixed ethers, such as hydroxypropyl methyl cellulose, and other mixed ethers such as hydroxyethyl ethyl cellulose, hydroxypropyl ethyl cellulose and its hydroxymethyl cellulose hydroxymethylmethyl cellulose and particular hydroxymethyl cellulose and carboxymethyl cellulose hydroxymethylmethyl cellulose methyl carboxymethyl cellulose methyl carboxymethyl cellulose methyl carboxymethyl cellulose and Synthetic polymers include polyoxyethylene derivatives (polyethylene glycols) and polyvinyl derivatives (polyvinyl alcohol, polyvinyl pyrrolidone and polystyrene sulfate) and various acrylic acid copolymers (e.g. carbomer). Other natural, semi-synthetic, and synthetic polymers not mentioned herein that meet the criteria for water solubility, pharmaceutical acceptability, and pharmacological inertness are likewise considered to be within the scope of the present invention.

The solubility enhancing agent can be added to the formulation of the invention. A solubility enhancing agent is a compound, or a compound, that enhances (enhances) the solubility of an active agent in an aqueous or humid environment, such as a lining of the airways. Suitable solubility enhancing agents include one or more organic solvents, detergents, soaps, surfactants and other organic compounds commonly used in parenteral formulations to enhance the solubility of a particular agent. Suitable organic solvents include, for example, ethanol, glycerol, poly (ethylene glycols), propylene glycol, poly (propylene glycols), poloxamers, and others known to those of ordinary skill in the art.

As used herein, the term “cryoprotectant” is intended to mean a compound used to protect an active agent from physical or chemical degradation during lyophilization. Such compositions include, by way of example and without limitation, dimethyl sulfoxide, glycerin, trehalose, propylene glycol, polyethylene glycol and others known to those of ordinary skill in the art.

Plasticizers can also be included in the preparations according to the invention to modify their properties and characteristics. As used herein, the term “plasticizer” includes all compounds capable of plasticizing or softening the polymer or binding agent used in the invention. The plasticizer should be able to lower the melting point or glass transition temperature (softening point temperature) of the polymer or binding agent. Plasticizers, such as low molecular weight PEG (polyethylene glycol), generally expand the average molecular density of the polymer into which they are incorporated, thereby lowering their glass transition temperature or softening point. Plasticizers also generally reduce the viscosity of the polymer. It is possible that the plasticizer will affect some particularly advantageous physical properties of the osmotic device of the invention.

The plasticizers used in the invention include, by way of example and without limitation, polymers, oligomers, low molecular weight copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester type plasticizers, poly (propylene glycol), multi-block polymers, single-block polymers, low molecular weight poly (ethylene glycol), plasticizers such as ester citrate, triacetin, propylene glycol and glycerin. Such plasticizers may also include ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other poly (ethylene glycol) compounds, monopropylene glycol mono-isopropyl ether, ethylene ether, mono-ethyl ether, mono-ethyl ether diethylene glycol monoethyl ether, sorbitolactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl likolat. All such plasticizers are commercially available from sources such as Aldrich or Sigma Co. It is also contemplated and within the scope of the invention that in the formulation of the invention a combination of plasticizers can be used. PEG based plasticizers are commercially available or can be manufactured in a variety of ways, such as disclosed in Poly (ethylene glycol) Chemistry: Biotechnical and Biomedical Applications (JM Harris, Ed .; Plenum Press, NY), the disclosure of which is incorporated herein by as a link to it.

As used herein, the term “perfume” is intended to mean a compound used to give a pharmaceutical preparation a pleasant taste and often odor. Illustrative flavoring agents or flavoring agents include synthetic aromatic oils and aromatic substances and / or natural oils, extracts from plants, leaves, flowers, fruits, etc. and their combinations. They may also include cinnamon oil, peanut oil, peppermint oil, onion oil, laurel oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, nutmeg oil, sage oil, bitter almond and cassia oil. Other fragrances used include vanilla, citrus oil, including lemon, orange, grapes, lime and grapefruit, and fruit essences, including apple, pear, peach, strawberries, cherries, plums, pineapple, apricots, etc. Fragrances that have been found to be particularly useful include commercially available orange, grape, cherry, and chewing gum fragrances and mixtures thereof. The amount of flavoring agents may depend on a number of factors, including the desired organoleptic effect. Fragrances will be present in any amount desired by those of ordinary skill in the art. Certain fragrances are grape and cherry flavors and citrus flavors, such as orange flavors.

As used herein, the term “sweetening agent” is intended to mean a compound used to impart a sweet taste to the preparation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, sodium saccharin, sorbitol, fructose, high fructose corn syrup, maltodextrin, sucralose, and other materials known to those of ordinary skill in the art and combinations thereof .

As used herein, a “penetration enhancer” is an agent or combination of agents that can be included in the formulation of the invention, and include, by way of example and without limitation, calcium chelating agents such as EDTA, methylated P-cyclodextrin, and polycarboxylic acids; surfactants such as sodium latsuryl sulfate, sodium dodecyl sulfate, carnitine, carnitine esters and tween; bile salts such as sodium taurocholate; fatty acids such as oleic and linoleic acid; and non-surfactants such as AZONE ^™ and dialkyl sulfoxides; effluent inhibitors such as AV171 (AyMax, Inc., South San Francisco, CA), D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), and peppermint oil; chitosan and chitosan derivatives such as N-methylchitosan, N-trimethylchitosan, mono-N-carboxymethylchitosan, quaternary chitosan derivatives; SNAC (N- (8- (2-hydroxybenzoyl) amino) caprylate) and SNAD (N- (10- (2-hydroxybenzoyl) amino) decanoate) (Emisphere Technologies, Inc., Tarrytown, NY); N-acylated non-alpha amino acids; HEMISPHERE variety delivery agents; Gelucire 44/14 or Vitamin E TPGS; CARBOPOL® 934P; others known to those of ordinary skill in the art; and their combinations.

The flavoring agent used herein is a relatively volatile substance or combination of substances that creates a perceptible aroma, smell or perception. Illustrative flavors include those generally accepted as FD&C (FDA Act).

A “surface tension modifier” is a material or combination of materials capable of modifying the surface properties of a composition in accordance with the invention. The surface tension modifier may include a surfactant, detergent or soap. It can be incorporated into carrier particles, particles containing an active agent, or in both types of particles.

A “density modifier” is a material or combination of materials that is included in a composition of the invention to increase or decrease its density. It can be incorporated into carrier particles, particles containing an active agent, or in both types of particles. The density modifier can be used to increase or decrease (if necessary) the density of the carrier to increase the dispersion of the active agent from the carrier. Similarly, the density modifier can be used, respectively, to decrease or increase (if necessary) the density of particles containing the active agent.

A “volatility modifier” is a material or combination of materials added to modify the volatility of an active agent. In one embodiment, the volatility modifier increases the volatility of the active agent. In another embodiment, the volatility modifier reduces the volatility of the active agent.

As used herein, the term “stabilizer” is intended to mean a compound used to stabilize a therapeutic agent against a physical, chemical or biochemical process that could reduce the therapeutic activity of the agent. Suitable stabilizers include, but are not limited to, albumin, sialic acid, acid and other amino acids, niacinamide, sodium acetyl tryptophonate, zinc oxide, sucrose, glucose, lactose, sorbitol, mannitol, glycerin, polyethylene glycols, sodium caprylate and sodium saccharin and others known to those of ordinary skill in the art.

As used herein, the term “excipient” is intended to mean a compound used to increase the volume of a lyophilized product and / or to help regulate the properties of the formulation during lyophilization. Such compounds include, by way of example and without limitation, dextran, trehalose, sucrose, polyvinylpyrrolidone, lactose, inositol, sorbitol, dimethyl sulfoxide, glycerin, albumin, calcium lactobionate, and others known to those of ordinary skill in the art.

It should be understood that the compounds used in the field of pharmaceutical formulations generally serve a variety of functions or purposes. So, if a compound named in this document is mentioned only once or is used in this document to define more than one term, its purpose or function should not be construed as limited solely by these named purposes or functions.

In connection with the above description and the examples below, the average person skilled in the art will be able to carry out the claimed invention without unnecessary experimentation. The foregoing will be better understood with reference to the following examples, which describe in detail certain procedures for preparing compositions and formulations in accordance with the present invention. All references to these examples are for illustrative purposes. The following examples should not be construed as exhaustive, but merely illustrating only a few of the many embodiments contemplated by the present invention.

Example 1

Illustrative formulations were made in accordance with the following general procedures.

Method A. Solid Formulation in a Mixture

The solid composition containing cyclodextrin is mixed until uniform with the solid composition containing the active agent. Compositions containing cyclodextrin and containing an active agent contain less than about 20 wt.% Water. Mixing the two compositions may also include mixing them at the same time, or abrasion can be performed as a separate process step. For example, each of the composition containing cyclodextrin and the composition containing the active agent is abraded before mixing. One or more additional excipients may be included in the SAE-CD composition and / or the active agent composition.

Method B. Liquid Formulation

The SAE-CD composition is mixed with a liquid carrier, optionally containing an active agent. The SAE-CD composition can be mixed with a liquid carrier before, after, or during the addition of the active agent, if present. One or more other excipients may be included in the formulation. If necessary, heating may be performed to facilitate mixing or dissolution.

Example 2

Obtaining solid compositions SAE-CD.

In methods A and B described below, SAE-CD starting material was provided in an aqueous liquid carrier, and SAE-CD starting material was prepared according to a method known from the literature. Certain embodiments have included SAE-CD starting material dissolved in water. The concentration of SAE-CD in the liquid carrier was changed as necessary to provide the liquid feed material of the desired viscosity or solids content.

Method A. Spray Fluid Bed Drying

SAE-CD media were prepared by spray agglomeration in a spray dryer FSD-16 fluid (GEA Inc., Columbia MD) as follows. Several solutions of sulfobutyl ether cyclodextrin (degree of substitution ~ 7, SBE7-BCD) at 20.1-49.8% solids were agglomerated in FSD-16 using a Spraying Systems top-mounted pressure spray nozzle at a spray pressure of 1,500-2,000 pounds / inch ² and a feed temperature of ~ 25 ° C. The conditions of the method were as follows: inlet / outlet temperature 210-250 / 83-100 ° C, the temperature at the inlet to the liquid layer 80-100 ° C and the temperature of the layer of the liquid product 57-87 ° C. The return of the smallest particles at the nozzle of the atomizer and at the diffuser of the chamber was investigated during individual cycles. The drying gas streams are heated electrically.

Served solutions containing SAE-CD were prepared by adding powdered ingredients to the required amount of water by heating and stirring in a feed tank.

Method B. Spray Fluid Bed Drying

The composition SAE-CD was obtained by spray agglomeration in a spray dryer FSD-16 fluid (GEA Inc., Columbia MD) with an attached 3-chamber fluidization layer. The chamber of the inner layer of liquid (chamber 1) was directly opened into the drying chamber and was used for final agglomeration, drying of agglomerates and dedusting. Chambers 2 and 3 of the outer annular liquid layer are connected in series with chamber 1, so that the product moves from chamber 1 to chamber 2 to chamber 3 under the control of the process conditions. Chamber 3 was used for cooling and final dedusting. The final product was recovered from chamber 3. The drying gas streams (N ₂ ) were electrically heated, and the main drying gas was introduced into the drying chamber through a ceiling air disperser. The drying gas in the three chambers of the liquid layer was evenly distributed through the perforated plates. The drying gas flows were separately regulated for various chambers of the liquid layer.

Beta-cyclodextrin sulfobutyl ether solutions (degree of substitution ~ 7, SBE7-BCD) at 48-52 wt.% Solids were agglomerated in FSD-12.5 using a Spraying Systems top-mounted nozzle for pressure spraying at a spray pressure of 10-50 bar and a solution temperature of 45-55 ° C. The conditions of the method were as follows: inlet / outlet temperature 150-170 / 70-90 ° C, the temperature at the inlet into the liquid layer of the chamber 1 100-150 ° C and the temperature of the product layer in the chamber 1 60-100 ° C. The smallest particles returned to the area adjacent to the nozzle of the atomizer.

Example 3

The particle diameter distribution (size) of several SAE-CD compositions (sulfobutyl ether beta-cyclodextrin, degree of substitution ~ 7) was determined by a laser diffraction device (Malvern Instruments Inc., Model 2000, South Borough, MA) equipped with a dry powder feeder. Curve was the particle size of the dispersion pressure, which was based on a dispersion pressure of 60 pounds / ^in2. Powder samples were taken using 500 detector scans for statistical significance. Turbidity values were monitored to ensure that adequate data were obtained. A detector lens with a focal length of 300 mm was used, providing a size range from 5.8 to 564 μm.

Analysis of particle size data for illustrative compositions of SAE-CD beta-cyclodextrin simple sulfobutyl ether with an average degree of substitution of ~ 7, SBE7-BCD, is included in the table below. Data for each composition indicate particle diameters in μm corresponding to the average diameter of De Brouckere (D [4,3]) or particle size cut-offs for 10%, 50%, or 90% of the cumulative volume fractions (μm stands for micron).

Lot SAE-CD Average diameter Particle size cutoff at indicated percentiles of volume distribution (D [4,3]) 10% fifty% 90% Size (μm) D [v, 0,1] D [v, 0.5] D [v, 0.9] * B3 78.7 28.7 67.9 138.1 B4 86.9 30,2 79.1 154.1 B5 83.8 33.1 76.7 145.4 B9 104.9 34.9 96.5 184.9 ** A1 175 A2 194 A3 119 A4 125 A5 92 A6 187 A7 164 * "B #" refers to an SAE-CD composition made in accordance with Example 2, Method B, where "#" indicates the lot number of the sample. ** "A #" refers to an SAE-CD composition made in accordance with Example 2, Method A, where "#" indicates the lot number of the sample.

Example 4

The moisture content of the SAE-CD compositions was measured by the Karl Fisher method (USP Method Ia <921>) or the moisture balance method.

Moisture balance method

A moisture balance measuring device Computrac Model 200 XL (Arizona Instruments, Tempe, AZ) was used to determine the mass loss of the selected powder samples over time when the powder was exposed to infrared heating. The powders were weighed (approximately 1 g of each sample), heated at 110 ° C. until a change in weight was observed, and the percentage weight loss was calculated.

Example 5

The fluidity of solid compositions SAE-CD was determined by a testing device (Flodex ^TM , Hanson Research Corp., Northridge, California), having:

- Stainless steel cylinder with an approximate capacity of 200 ml.

- A series of stainless steel discs. Moreover, each disk has a precision hole in the center in a graduated series, differing in diameter by 1-2 mm, which is easy to attach to form the bottom of the cylinder.

- A damper that covers the hole and which can be quickly removed without vibration to allow the powder to flow through the selected hole.

- An adjustable funnel for loading the sample cylinder by free fall of the test powder.

- A suitable container for collecting powder that flows through the unit.

The funnel was mounted above the cylinder so that the lower part of the funnel was near, but did not touch the surface of the powder after it was loaded into the cylinder. The disk was inserted into the bottom of the cylinder and the hole in the disk was closed. Then a powder loading of 50 g was poured through a funnel into the middle of the cylinder. The powder was allowed to settle in the cylinder for at least 30 s, then the hole in the disk was quickly and without vibration opened. Then, the flow through the hole of the disk was observed. A positive result was when the powder flowed through the hole, leaving a cavity having a shape similar to an inverted truncated cone in 3 out of 3 tests, and the powder that fell involved the entire height of the powder (not less than 60 mm).

A negative result was noted when the powder dropped sharply through the hole, forming a cylindrical cavity in the remaining powder.

If the result was positive, then the procedure was repeated with discs having holes of a smaller diameter until a hole of the smallest diameter was determined, which nevertheless gave a positive result in 3 of 3 tests.

If the result was negative, then the procedure was repeated with disks having holes of a larger diameter until a hole of the smallest diameter was determined, giving a positive result in 3 of 3 tests.

The measurement results for compositions SAE-CD (sulfobutyl ether beta-cyclodextrin with a degree of substitution of ~ 7, SBE7-B-CD) are presented below.

Lot SBE7-B-CD Minimum hole diameter (mm) B4 6 B9 6 A1 9 A2 8 A3 5 A4 four A5 10 A6 12 A7 10

Example 6

The average dissolution time of compositions SAE-CD (sulfobutyl ether beta-cyclodextrin with a degree of substitution of ~ 7, SBE7-B-CD) was determined by a flow-through device for determining dissolution, including a glass filter holder (Millipore Corp., Billerica, MA) attached to the pump and a water tank. The filter holder consisted of a ~ 300 ml funnel and a fritted glass base held together by a metal clip.

The test was carried out by placing 2.5 g of a powder sample on a filter with a diameter of 47 mm with a pore size of 10 μm, installed between the departments of the filter holder. Water was pumped at a temperature of ~ 25 ° C at a rate of 100 ml / min through the bottom of the device so that water rose through the filter into the tank. A sample was observed to determine the time required to dissolve all solids. If the sample floated and required more than 2.5 minutes to dissolve, then the pump was stopped after 250 ml.

Representative data for sulfobutyl ester of beta-cyclodextrin with a degree of substitution of ~ 7 (SBE7-B-CD) are included in the table below.

Dissolution Time (min) Composition SBE7-B-CD Cycle 1 Cycle 2 average value B3 3.0 3,5 3.25 B4 2.0 2.25 2.13 B5 2.0 2.0 2.0 B6 2.5 2.5 2.5 B8 2.0 2.5 2.25 B10 2.25 2.0 2.13 A5 2.0 2.0 2.0

Example 7

Compositions of SAE-CDs were compared in compression studies with samples of commercially available powders often used to prepare tablets, for example, microcrystalline cellulose (Avicel 200), US Pharmacopeia lactose, and dibasic calcium dihydrogen phosphate (DiCal).

The powders were pressed on a Colton single-unit measuring press, operating at a rate of 15 tablets / min. The press had a measurable compression and displacement force of the upper and lower dies. The mass of the sample was 200 mg, and the samples were extruded to 3 different tablet hardnesses of approximately 5, 10 and 15 kP using strains with a flat surface and a diameter of 0.345 inches. Force and displacement data were collected using a 4-channel, 12-bit digital oscilloscope (Model # 420, Nicolet Instrument Corp., Madison, WI, USA); samples were collected every 1 ms simultaneously for each of the four channels. The extruder head was lubricated with 10% (w / v) emulsion of magnesium stearate in acetone applied with a cotton swab. To maintain integrity from tablet to tablet, a standardized procedure has been developed for swab application and drying of the emulsion on the wall of the extruder head. The coating of the wall of the extruder head was also checked by visual inspection. To reduce signal noise, a fast Fourier transform (FFT) was performed according to the upper and lower stamp using the Igor Pro program version 3.1 (Wavemetrics, Inc., Oregon). Igor Pro was also used to find Pmax on the average tableting pressure curve (i.e. maximum die pressure) after performing FFT; the software algorithm found the minimum using the derivative of the curve.

The compressive strength of the tablets was measured with a KEY® HT-300 hardness tester (Englishtown, NJ). A dial indicator was used to measure the height of the tablets after compression. Typically, 5 tablets were compressed and tested for hardness at each of the three target hardness levels.

Example 8

The density and compressibility of the SAE-CD compositions was determined by the following methods:

Method A. Bulk Density

The bulk density of the SAE-CD compositions was determined in accordance with method I USP <616> using a graduated cylinder with a capacity of 100 ml.

Method B. Density after tapping

The density after compaction by tapping the SAE-CD compositions was determined in accordance with method I USP <616> using a graduated cylinder with a capacity of 100 ml.

Method C. Carr Compressibility Index

The Carr compressibility index of the SAE-CD compositions was calculated according to the formula:

Method D. Absolute Density

The absolute density of SAE-CD compositions was determined by a multivolume pycnometer (Micromeritics Instrument Corp., Model 1305, Norcross, GA) in accordance with method I USP <699>. For all measurements, a sample holder having a volume of 1 cm ^{3 was used} .

The measurement results for compositions SAE-CD (sulfobutyl ether beta-cyclodextrin with a degree of substitution of ~ 7, SBE7-B-CD) are presented below in the table.

Sample SBE7-B-CD Bulk density (g / cm ³ ) Density after compaction by tapping (g / cm ³ ) Carra Index (%) Absolute Density (g / cm ³ ) B3 0.610 0.731 16.6 1.29 B4 0.594 0.701 15.3 1.30 B5 0.601 0.708 15.1 1.30 B6 0.604 0.692 12.8 B8 0.573 0.670 14.6 B9 1.28 B10 0.595 0.694 14.2 A1 0.429 0.564 23.9 A2 0.410 0.539 23.9 A3 0.549 0.670 18.1 A4 0.549 0.661 16.9 A5 0.481 0.574 16,0 A6 0.433 0.528 18.0 A7 0.381 0.495 23.0

Example 9

A dry powder formulation suitable for administration by a DPI device includes one or more active agents, a carrier in the form of an SAE-CD composition, and optionally one or more excipients selected from the group consisting of an antioxidant, an acidifying agent, an alkaline agent, a buffering agent , solubility enhancing agent, penetration enhancer, electrolyte, perfume, glucose, moving, stabilizer, volume increasing agent, cryoprotectant, plasticizer, flavoring agents, sweetening agents, potassium modifier rhnostnogo tension, density modifier, volatility modifier, or a combination thereof. An SAE-CD carrier contains approximately 50-99.9% by weight of the formulation and has an average particle diameter of less than 420 microns. Particles containing the active agent have a median particle diameter of from about 0.1 to 10 microns. The carrier has a range of particle diameters ranging from about 1.5 to 2.9 μm, and the carrier was made in accordance with the invention and, optionally, by abrading a solid to form a particulate carrier. The SAE-CD used in the carrier has an average DS (degree of substitution) in the range of about 1 to 12.

Example 10

A compressed quick release tablet comprising beta-cyclodextrin sulfobutyl ether with a degree of substitution of ~ 4, (SBE4-β-CD, composition SAE-CD), and piroxicam are prepared according to the following formula and procedure.

Ingredient Amount (mg) 1: piroxicam 10 1: SBE4-β-CD 77 2: sorbitol 45 2: dextrose fifty 2: citric acid 10 2: xylitol 47.5 2: PEG 3350 9 3: magnesium stearate 1,5 3: flame hydrolyzed silica 1,5 3: croscarmellose sodium 5.5 Total 257

The above ingredients are used to make 257 mg of a tablet core having a quick release profile. The numbers for the ingredients indicate the general order of addition. After adding each group of ingredients, the mixture is dry mixed for 5-10 minutes. Magnesium stearate, flame hydrolyzed silica (CABOSIL ^™ M5P), and croscarmellose sodium are added separately (step 3) from the other ingredients, and an additional dry mixing step of 5 minutes is added to the general procedure.

The powder is then pressed into tablet form with a hardness of approximately 8-10 kg.

Example 11

A controlled release tablet comprising the composition SAE-CD, sulfobutyl ether beta-cyclodextrin with an average degree of substitution of 7, (SBE7-β-CD), and prednisone, receive in accordance with the following formula and procedure.

Ingredient Amount (mg) Prednisone fifteen SBE7-β-CD 210 Hydroxypropyl methylcellulose (HPMC K100M) 75 Total 300

The above ingredients are used to make 300 mg of a tablet core having a controlled release profile. The ingredients are mixed by hand and individual tablets are obtained on a cutting press under a pressure of 1 ton for 7 seconds. Tablets are made using a standard cup concave technological nozzle.

Example 12

An immediate-release oral dispersible tablet comprising a composition of SAE-CD, medium-displacement beta-cyclodextrin sulfobutyl ether, 7 (SBE7-β-CD), and zaleplon, are prepared according to the following formula and procedure.

Ingredient Amount per tablet (mg) Zaleplon 5 Croscarmellose sodium (Ac-Di-Sol) 24 SBE7-γ-CD 118 Microcrystalline Cellulose (Avicel PH102) 150 Colloidal Silicon Dioxide (Cab-O-Sil) 1,5 Magnesium stearate 1,5 Total 300

All tablet ingredients are sieved through a 400 mesh sieve (US Standard) before weighing, and then all ingredients except magnesium stearate (Mg) are mixed in a glass vial using a geometric dilution technique. The powder mixture is then passed twice through a 40 mesh sieve to facilitate uniform mixing of all ingredients. Before mechanical pressing, Mg stearate is added and then mixed for another 1 min. Finally, the final mixture is compressed into tablets with a 7 mm concave process nozzle using a rotary tablet press to obtain a tablet hardness of approximately 3.0 kilopond (cp).

Example 13

The formulated powder formulation of lamotrigine and the composition of SAE-CD, a sulfobutyl ether beta-cyclodextrin with an average degree of substitution of 7, (SBE7-β-CD), are obtained in accordance with the following formula and procedure.

Ingredient Amount (g) Lamotrigine 7.50 SBE7-β-CD 37.5 USP Citric Acid 3.75 Xylitol 300 Saccharin Sodium 0.75 Benzoic acid 1.28 Strawberry fragrance 1.4 Xanthan gum 1,5 Total 353.68

Saccharin sodium, benzoic acid, strawberry flavoring, citric acid and xanthan gum are combined together and thoroughly mixed. Lamotrigine is added to the mixture with further mixing, then SBE7-β-CD is added and mixing is continued. Then, xylitol is added to the obtained powder during geometric dilution and further mixing.

The powder can then be structured with water to obtain a final volume of 750 ml.

The following terms are described in detail below.

Term Definition Agglomerate An accumulation of particles that are fused together and act as a larger particle. Bulk density The mass of the poured powder divided by the bulk volume Carra Index A measure of the properties of a volumetric flow of powders. CD Cyclodextrin DPI Dry powder inhaler Kf Karl Fisher Analysis MDI Metered dose inhaler, or more correctly, metered dose inhaler, driven by a propellant monodisperse In terms of particle size, refers to a population of particles that have a uniform particle size NC Nanocoulomb, measure of charge Nd Not determined pMDI Metered dose inhaler Sem Scanning Electron Microscope Absolute density Bulk powder mass divided by the volume of compacted powder (after compaction of the powder by vertical tapping)

As used herein, the term “approximately” means ± 10% of the indicated value.

The following is a detailed description of specific embodiments of the invention. It should be understood that, although certain embodiments of the invention have been described herein for illustration purposes, various modifications may be made to it without departing from the spirit and scope of the invention. Accordingly, the invention is not limited except by the attached claims. All embodiments disclosed and claimed herein can be obtained and executed without undue experimentation in the light of the present description. A description of any patent or other publication cited herein is incorporated by reference.

Claims (21)

1. The composition of simple sulfoalkyl ether cyclodextrin for use in dosage forms containing
a) sulfoalkyl ether cyclodextrin;
b) not more than approximately 20 wt.% moisture;
c) bulk density in the range from about 0.38 to about 0.66 g / cm ³ ; and
d) the density after compaction by tapping in the range of from about 0.49 g / cm ³ to about 0.75 g / cm ³ , the density after compaction by tapping is higher than bulk density,
e) the minimum diameter of the hole of the gravitational flow is from about 3 mm to about 12 mm;
where the composition contains particles. 2. The composition according to claim 1, where the simple sulfoalkyl ether cyclodextrin is a compound or mixture of compounds of formula I

where n = 4, 5 or 6;
each R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are independently —O— or a group —O— (C ₂ -C ₆ alkylene) —SO ₃ ^- where at least one of R ₁ -R ₉ independently represents a group —O— (C ₂ -C ₆ alkylene) —SO ₃ ^- , a group —O- (CH ₂ ) _m SO ₃ ^- , where m = 2-6, -OCH ₂ CH ₂ CH ₂ SO ₃ ^- or -OCH ₂ CH ₂ CH ₂ CH ₂ SO ₃ ^- ;
and each S ₁ , S ₂ , S ₃ , S ₄ , S ₅ , S ₆ , S ₇ , S ₈ and S ₉ is independently a pharmaceutically acceptable cation. 3. The composition according to claim 1, where the bulk density is in the range from about 0.55 g / cm ³ to about 0.66 g / cm ³ , and the density after compaction by tapping in the range from about 0.66 g / cm ³ to approximately 0.75 g / cm ³ . 4. The composition according to claim 1, where the bulk density is in the range from about 0.38 g / cm ³ to about 0.55 g / cm ³ , and the density after sealing by tapping in the range from about 0.49 g / cm ³ to approximately 0.66 g / cm ³ . 5. The composition according to claim 1, where the minimum diameter of the hole of the gravitational flow of 10 mm or less. 6. The composition according to claim 1, where the composition has an absolute density in the range from about 1.1 g / cm ³ to 1.5 g / cm ³ . 7. The composition according to claim 1, where the composition has a Kara index of from about 12% to about 24%. 8. The composition according to claim 1, where the composition contains particles with an average diameter of from about 79 microns to about 200 microns. 9. The composition of claim 8, wherein at least 90% of the particle volume of the sulfoalkyl ether composition includes particles having calculated diameter values greater than or equal to about 25 microns. 10. The composition according to claim 1, where the composition has a moisture content in the range of from about 2 to about 3 wt.% And crush resistance in the range of from about 1.0 to about 20 kP, when pressed into a tablet using Pmax in the range of from about 30 to approximately 275 MPa. 11. The composition according to claim 1, where the composition has a moisture content in the range of about 5-6 wt.% And crush resistance in the range of about 0.5 to 11 kP, when pressed into a tablet using Pmax in the range of about 15-70 MPa . 12. The composition according to claim 1, where 2.5 g of the composition of simple sulfoalkyl ether has an average dissolution time when placed in water from about 2 minutes to about 4.5 minutes 13. The composition according to claim 1, where the composition includes agglomerated particles. 14. A pharmaceutical composition comprising the composition of claim 1 and an active agent. 15. A pharmaceutical dosage form containing a sulfoalkyl ether cyclodextrin composition according to claim 1 and an excipient, wherein the dosage form is selected from the group consisting of tablets, liquids, suspensions, emulsions, films, layered structures, pellets, powder, beads, granules, suppositories, ointments, creams, capsules, formulated powder, dry powder inhaler, sachets, lozenges, and lozenges. 16. The drug according to clause 15, in which the drug is in the form of a powder. 17. The drug according to clause 16, in which the powder contains abradable particles of the composition of simple sulfoalkyl ether cyclodextrin with an average particle diameter of from about 0.1 to about 10 microns. 18. The drug according to clause 15, in which the drug is in the form of tablets. 19. The medicament of claim 18, wherein the tablet is selected from the group consisting of a controlled release tablet, a sustained release tablet, a compressed tablet, a quick release compressed tablet, and an immediate release tablet disintegrating in the mouth. 20. A method of obtaining a composition of simple sulfoalkyl ether cyclodextrin, including
a) providing in the drying chamber of the spray drying apparatus from a fluidized bed of sulfoalkyl ether cyclodextrin particles having a first average particle diameter, where the layer is fluidized by a stream of heated gas flowing in the first direction;
b) spraying a supplied liquid containing water and a sulfoalkyl ether cyclodextrin with a spray onto a fluidized bed in a drying chamber to form a sulfoalkyl ether cyclodextrin ether composition comprising particles having a second average particle diameter greater than the first average particle diameter, where spraying is carried out in a second direction, and most of the liquid carrier is removed from the composition; and
c) collecting a sulfoalkyl ether cyclodextrin composition containing
1) sulfoalkyl ether cyclodextrin;
2) not more than approximately 20 wt.% Moisture;
3) bulk density in the range from about 0.38 to about 0.66 g / cm ³ ; and
4) the density after compaction by tapping in the range from about 0.49 g / cm ³ to about 0.75 g / cm ³
moreover, the density after compaction by tapping is higher than the bulk density, and
5) the minimum diameter of the hole of the gravitational flow is from about 3 mm to about 12 mm;
where the composition contains particles and where the conditions of the method are as follows:
spray pressure 1500-2000 pounds / ^in2; feed temperature ~ 25 ° C; inlet temperature 210-250 ° C; exhaust temperature 83-100 ° C; the temperature at the inlet to the liquid layer is 80-100 ° C; and the temperature of the liquid product layer is 67-87 ° C. 21. A method of obtaining a composition of simple sulfoalkyl ether cyclodextrin, including
a) providing, in a drying chamber, a spray drying apparatus from a fluidized bed with an attached 3-chamber fluidization layer of sulfoalkyl ether cyclodextrin particles having a first average particle diameter, where the layer is fluidized by a stream of heated gas flowing in the first direction;
b) spraying a supplied liquid containing water and a sulfoalkyl ether cyclodextrin with a spray onto a fluidized bed in a drying chamber to form a sulfoalkyl ether cyclodextrin ether composition comprising particles having a second average particle diameter greater than the first average particle diameter, where spraying is carried out in a second direction, and most of the liquid carrier is removed from the composition; where the 3-chamber fluidization layer includes three consecutive chambers with a fluidization layer and where the particles of the composition move in a chamber with a third fluidization layer, and
c) collecting the sulfoalkyl ether cyclodextrin composition from the third fluidized bed chamber, wherein the composition contains
1) sulfoalkyl ether cyclodextrin;
2) not more than approximately 20 wt.% Moisture;
3) bulk density in the range from about 0.38 to about 0.66 g / cm ³ ; and
4) the density after compaction by tapping in the range from about 0.49 g / cm ³ to about 0.75 g / cm ³ , the density after compaction by tapping is higher than bulk density,
5) the minimum diameter of the hole of the gravitational flow is from about 3 mm to about 12 mm;
where the composition contains particles and where the process conditions are as follows: spray pressure 10-50 bar; solution temperature 45-55 ° C; inlet temperature 150-170 ° C; outlet temperature 70-90 ° C; the temperature at the inlet in the liquid layer of the first chamber of three consecutive chambers of 100-150 ° C; and the temperature of the product layer in the liquid layer of the first chamber of three successive chambers of 60-100 ° C,
moreover, the particles are cooled when they move from the first chamber with a liquid layer to the third chamber with a liquid layer.

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