TARGETED DELIVERY OF HYDROPHILIC DRUGS TO LUNG

Abstract

A pharmaceutical composition in form of an aqueous suspension up to a size of 200 μm comprises or consists of amphiphilic sulfonate and/or sulfate of a hydrophilic cancer drug having a solubility in water or aqueous body fluid of less than 0.1% by weight. Also disclosed are the particles in powderous form, methods for their production and for the production of the suspension, a method of treating cancer, bacterial or fungal infections in lung by administration of the pharmaceutical composition, and a method of designing a composition according to the invention.

Claims

1. A pharmaceutical composition in form of an aqueous suspension comprising solid particles of amphiphilic particulate sulfonate and/or sulfate, consisting of a pharmacologically active agent D comprising from 1 to 4 amino groups of which one or more is protonated, and of a corresponding number of sulfate or sulfonate anion of a hydrophilic drug, the particles having a solubility in water or aqueous body fluid of less than 0.1% by weight, and wherein 90% or more of the particles have a size in the interval of 5000 nm to 100 000 nm, wherein the amphiphilic particulate sulfonate or sulfate are represented by formulas (1) and (2), respectively:
D.sup.n+(R.sup.1SO.sub.3).sup.−.sub.n  (1);
D.sup.n+(R.sub.2OSO.sub.3).sup.−.sub.n  (2); wherein R.sup.1 is straight chain C.sub.10-C.sub.20 alkyl; R.sup.2 is straight chain C.sub.10-C.sub.20 alkyl; n is an integer from 1 to 4, and D is selected from the group consisting of anti cancer drugs, anti bacterial drugs and anti fungal drugs.

2. The composition of claim 1, further comprising buffer and/or pharmaceutically acceptable excipient.

3. The composition of claim 1, wherein R.sup.1 and R.sup.2 is straight chain C.sub.12-C.sub.18 alkyl.

4. A method of producing the pharmaceutical composition of claim 1, comprising: providing a first aqeuous solution of a salt of said drug with an inorganic or organic acid that is not amphiphilic; providing a second aqueous solution comprising an amount of a sodium or potassium salt of an alkyl sulfonate of the formula (Na or K).sup.+(R.sup.1SO.sub.3).sup.− or of an alkane sulfate of the formula (Na or K).sup.+(R.sup.2OSO.sub.3).sup.− equivalent to the amount of said salt; mixing said first and second solutions.

5. The method of claim 4, wherein R.sup.1 is straight chain C.sub.10-C.sub.20 alkyl; R.sup.2 is straight chain C.sub.10-C.sub.20 alkyl; n is an integer from 1 to 4.

6. The method of claim 5, wherein R.sup.1 and R.sup.2 is straight chain C.sub.12-C.sub.18 alkyl.

7. An amphiphilic particulate sulfonate or sulfate powder consisting of or comprising a pharmacologically active agent D comprising from 1 to 4 amino groups of which one or more is protonated and of a number of sulfate or sulfonate anion corresponding to the number of protonated amino groups, represented by formulas (1) and (2):
D.sup.n+(R.sup.1SO.sub.3).sup.−.sub.n  (1)
D.sup.n+(R.sup.2OSO.sub.3).sup.−.sub.n  (2) wherein R.sup.1 is straight chain C.sub.10-C.sub.20 alkyl; R.sup.2 is straight chain C.sub.10-C.sub.20 alkyl; n is an integer from 1 to 4.

8. The amphiphilic particulate sulfonate or sulfate powder of claim 7, wherein R.sup.1 and R.sup.2 is straight chain C.sub.12-C.sub.18 alkyl.

9. The amphiphilic particulate sulfonate or sulfate powder of claim 7, wherein the particle size is up to 100 μm.

10. The amphiphilic particulate sulfonate or sulfate powder of claim 7 wherein the particle size is within the range of 20 μm-90 μm, or 40 μm-80 μm.

11. The amphiphilic particulate sulfonate or sulfate powder of claim 7 comprising a re-suspension facilitating agent and/or sodium or potassium salt of hydrochloric or hydrobromic acid.

12. A method of designing a pharmaceutical composition for providing, during a predetermined period, a therapeutic target with a predetermined concentration of a sulfate or sulfonate of a pharmacologically active agent D comprising from 1 to 4 amino groups represented by formula (1) or (2) or a mixture of these agents:
D.sup.n+(R.sup.1SO.sub.3).sup.−.sub.n  (1)
D.sup.n+(R.sup.2OSO.sub.3).sup.−.sub.n  (2) wherein R.sup.1 is straight chain C.sub.10-C.sub.20 alkyl; R.sup.2 is straight chain C.sub.10-C.sub.20 alkyl; n is an integer from 1 to 4; wherein the method comprises: i) determining the solubility of D.sup.n+(R.sup.1SO.sub.3).sup.−.sub.n and/or D.sup.n+(R.sup.2OSO.sub.3).sup.−.sub.n for various carbon chain lengths X, Y in an aqueous solvent; ii) determining the correlation between the solubility of said sulfate or sulfonate of said pharmacologically active agent and the expected concentration of said pharmaceutically active agent D in the therapeutic target upon administration of said pharmacologically active agent D to the subject or animal; iii) defining a target solubility of said sulfate or sulfonate of said pharmacologically active agent in said solvent based on a desired concentration of said pharmaceutically active substance D in tissue of a lung; iv) determining the carbon chain length(s) X, Y corresponding to said target solubility; v) providing a sulfate or sulfonate of said pharmacologically active agent comprising the so determined carbon chain length(s) X, Y; vi) providing a fluid carrier; vii) combining said sulfate or sulfonate of said pharmacologically active agent comprising the so determined carbon chain length(s) X, Y with the fluid carrier in an amount capable of maintaining said concentration during said period.

13. The method of claim 12, wherein the solubility is determined in an aqueous organic solvent in particular aqueous ethanol in a concentration of from 5% to 50% (v/v).

14. The method of claim 12, wherein D is selected from the group consisting of doxorubicin, epirubicin, daunorubicin, idarubicin, mitoxantrone, viniblastine, vincristine, vinorelbine, amsacrine, topotecan, irinotecan.

15. The method of claim 12, wherein D is selected from the group consisting of aminoglycosides, ansamycins, carbapenems, cephalosporins, glycopeptides, daptomycin, macrolides, oxazolidinones, penicillins, quinolones, sulfonamides, doxycycline, tetracycline, minocycline, oxytetracycline, clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin, rifapentine, streptomycin, amphotericin B, candicidin, filipin, hamycin, natamycin, nystatin, echinocandins, imidazole, triazole, and thiazole.

16. A method of treating a lung disease in a person, comprising administrating to said person a therapeutically effective amount of a pharmaceutical composition in form of an aqueous suspension comprising solid particles of amphiphilic particulate sulfonate and/or sulfate, comprising a pharmacologically active agent D comprising from 1 to 4 amino groups of which one or more is protonated, and of a corresponding number of sulfate or sulfonate anion of a hydrophilic drug, the particles having a solubility in water or aqueous body fluid of less than 0.1% by weight, and wherein 90% or more of the particles have a size in the interval of 5000 nm to 100 000 nm, wherein the amphiphilic particulate sulfonate or sulfate are represented by formulas (1) and (2), respectively:
D.sup.n+(R.sup.1SO.sub.3).sup.−.sub.n  (1);
D.sup.n+(R.sup.2OSO.sub.3).sup.−.sub.n  (2); wherein R.sup.1 is straight chain C.sub.10-C.sub.20 alkyl; R.sup.2 is straight chain C.sub.10-C.sub.20 alkyl; n is an integer from 1 to 4, and D is selected from the group consisting of anti cancer drugs, anti bacterial drugs and anti fungal drugs or of a pharmaceutical composition comprising amphiphilic particulate sulfonate or sulfate powder of claim 7.

17. The method of claim 16, wherein administration is by perfusion, infusion or injection into a vein or artery.

18. The method of claim 16, wherein administration is to a solid tumour by infusion or injection into the peripheral circulation (i.e. intravenous injection), infusion or injection directly into the solid tumour, or by a bolus or by several boli.

19. The method of claim 18, wherein said solid tumour is a lung tumour, kidney tumour, liver tumour, pancreas tumour, breast tumour, or prostate tumour.

20. The composition of claim 2, wherein R.sup.1 and R.sup.2 is straight chain C.sub.12-C.sub.18 alkyl.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0060] FIG. 1 is a graph illustrating the dependence of the solubility of doxorubicin alkyl sulfate in 30% aqueous ethanol on alkyl chain length;

[0061] FIG. 2 is a graph illustrating the dependence of the solubility of doxorubicin alkane sulfonate in 30% aqueous ethanol on alkyl chain length;

[0062] FIG. 3 is a graph illustrating the dependence of the solubility of mitoxantrone alkyl sulfate in 30% aqueous ethanol on alkyl chain length;

[0063] FIG. 4 is a graph illustrating the dependence of the solubility of mitoxantrone alkane sulfonate in 30% aqueous ethanol on alkyl chain length;

[0064] FIG. 5 is a graph illustrating the dependence of the solubility of irinotecan alkane sulfonate in 10% aqueous ethanol on alkyl chain length;

[0065] FIG. 6 is a graph illustrating the dependence of the solubility of vinorelbine alkane sulfonate in 20% aqueous ethanol on alkyl chain length;

[0066] FIG. 7 is a graph illustrating the dependence of the solubility of doxycycline complex with alkane sulfonates in 20% aqueous ethanol on the length of alkyl chain of the alkane sulfonates.

[0067] FIG. 8 is a graph illustrating the dependence of the solubility of doxycycline complex with alkyl sulfates in 20% aqueous ethanol on the length of alkyl chain of the alkyl sulfates

[0068] FIG. 9 is a graph illustrating the dependence of the solubility of amphotericin B complex with alkane sulfonates in 30% aqueous ethanol on the length of alkyl chain of the alkane sulfonates

[0069] FIG. 10 is a graph illustrating the dependence of the concentration of doxorubicin in lung in Wistar rats on the solubility of complexes in 30% aqueous ethanol

[0070] FIG. 11 is a graph illustrating the dependence of the concentration of doxorubicin in lung in Californian rabbits on the solubility of complexes in 30% aqueous ethanol.

[0071] FIG. 12 is a graph illustrating the dependence of the concentration of doxycycline in lung in Wistar rats on the solubility of complexes in 20% aqueous ethanol.

[0072] FIG. 13 is a graph illustrating the dependence of the concentration of doxycycline in blood serum in Wistar rats on the solubility of complexes in 20% aqueous ethanol.

[0073] FIG. 14 is a graph showing the relationship between amount drug, i.e., doxorubicin measured in lung and average particle size of the complex.

[0074] Exponential (for FIG. 1-9) and logarithmic (for FIG. 10-13) trendlines and their equations were obtained with the use of Microsoft Excel software.

DETAILED DESCRIPTION

[0075] It is to be understood that this invention is not limited to the particular configurations, process steps, and materials disclosed herein as such configurations, process steps, and materials may vary somewhat. It is also to be understood that the terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting since the scope of the present invention will be limited only by the appended claims and equivalents thereof.

[0076] All references cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual publication or patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

[0077] The present invention is best understood by reference to the following definitions, the Figures and exemplary disclosure provided herein.

[0078] In this application, unless otherwise stated, the term “lung disease” comprises primary Acute Bronchitis, Acute Respiratory Distress Syndrome (ARDS), Asbestosis, Asthma, Bronchiectasis, Bronchiolitis, Bronchiolitis Obliterans Organizing Pneumonia (BOOP), Bronchopulmonary Dysplasia, Byssinosis, Chronic Bronchitis, Coccidioidomycosis (Cocci), Chronic Obstructive Pulmonary Disease (COPD), Cryptogenic Organizing Pneumonia (COP), Cystic Fibrosis, Emphysema, Hantavirus Pulmonary Syndrome, Histoplasmosis, Human Metapneumovirus, Hypersensitivity Pneumonitis, Influenza, Middle Eastern Respiratory Syndrome, Nontuberculosis Mycobacterium, Pertussis, Pneumoconiosis (Black Lung Disease), Pneumonia of different origin, Primary Ciliary Dyskinesia, Primary Pulmonary Hypertension, Pulmonary Arterial Hypertension, Pulmonary Fibrosis, Pulmonary Vascular Disease, Respiratory Syncytial Virus, Sarcoidosis, Severe Acute Respiratory Syndrome, Silicosis, Sleep Apnea, and Sudden Infant Death Syndrome.

[0079] For example doxycycline (DOX) is a broad-spectrum antibiotic of the tetracycline class that is useful for the treatment of a number of infections, including bacterial, protozoal and helminth.

[0080] Another example is an antifungal drug Amphotericin B (ampB) which is often used intravenously for pulmonary fungal infections. It is the only effective treatment for some fungal infections and it is well known for its severe and potentially lethal side effects.

[0081] In this application, unless otherwise stated, the term lung cancer comprises primary cancer such as non-small cell lung cancer, small cell lung cancer as well as secondary tumors in a lung, Lymphangiomatosis, Mesothelioma.

[0082] Materials and Methods

[0083] Solubility in aqueous ethanol was determined by centrifuging an adequate amount of freshly obtained colloid at 3000 rpm for 30-90 min, decanting the supernatant, adding 10 mL water and shaking the mixture, then repeating centrifugation, shaking and washing 3 times. The centrifugate from the final centrifugation was air dried for 72 h at room temperature followed by drying in vacuo for 24 h. A portion of the dried centrifugate (20 mg) was resuspended in 6 mL aqueous ethanol (EtOH) by stirring at room temperature for 24 h. The mixture was centrifuged at 3000 rpm for 10 min and the supernatant filtered through a 0.2 micrometer filter to remove aggregates of undissolved solid product. The solubility of the compound was determined by a UV method. Particle size analysis was accomplished by laser diffraction method.

[0084] The composition used for in vivo investigation was freshly prepared or obtained by dilution of concentrates. For in vivo investigation both rats and rabbits were used: female Wistar rats 60-75 days old weighing 300 g±30 g and Californian breed male rabbits 75-90 days old weighing 2000 g±250 g were selected. For every formulation tested at a particular time point, 4 rats or 3 rabbits were used. Different doxorubicin containing formulations with a total doxorubicin dose 5 mg/kg were administered via a single bolus injection into the tail for rats and via a slow flow of 1 ml/min in the marginal ear vein for rabbits. Immediately after sacrification, the animal organs and tissues were deep-frozen in liquid nitrogen.

[0085] Determination of the Bio-Distribution of Doxorubicin and Doxycycline in Lung Tissue.

[0086] Five or six pieces of lung tissue of a total weight of about 1 g were taken from different parts of a lung. The samples were homogenized with a solution of aqueous ethanol containing HCl for 20 s at 7000 rpm and for 10 s at 11000 rpm. The homogenate obtained was vortexed for 30 min and centrifuged at 3000 rpm for 30 min. The supernatant was treated with a solution of monochloroacetic acid and incubated for 1 hour followed by centrifugation of the mixture obtained at 15000 rpm for 15 min. Doxorubicin and doxycycline (DOC) concentration in the final supernatant was determined with fluorometric analysis and high-performance liquid chromatography respectively.

Example 1

[0087] Preparation of Suspension of Doxorubicin Alkyl Sulfate and Alkane Sulfonate

[0088] To a solution of doxorubicin hydrochloride (DOX Cl) (50 mL, 1 mg/mL) in 5% aqueous dextrose in an Erlenmeyer flask was added at room temperature a solution of a 5-10% molar excess of Na.sup.+(R.sup.1SO.sub.3).sup.− or Na.sup.−(R.sup.2OSO.sub.3).sup.− and in the same solvent as for doxorubicin hydrochloride. Instead of 5% aqueous dextrose can be used in this and the other examples Ringer solution or 0.9% saline or phosphate-buffered saline or another aqueous solution of an osmolality from 270 to 300 mOsm/L. The process of colloid formation was monitored visually. After completing of the addition the mixture was vortexed or shaken for an additional time period varying from 30 min to 7 days. The suspension obtained then was either directly used or placed for storage in a refrigerator. Concentration of doxorubicin in the compositions was determined by a UV method at 495 or 233 nm. For sampling, an aliquot of the colloid was diluted with methanol (excess of methanol>20:1).

Example 2

[0089] Preparation of Suspension of Mitoxantrone (MIT) Alkyl Sulfates and Alkane Sulfonates

[0090] To a vigorously stirred solution of mitoxantrone dihydrochloride (40 mL, 0.2 mg/mL) in 5% dextrose in water in an Erlenmeyer flask was added at room temperature a solution containing 0.03 mmol of Na.sup.+(R.sup.1SO.sub.3).sup.− or Na.sup.+(R.sup.2OSO.sub.3).sup.− in the same solvent as for mitoxantrone dihydrochloride. The formation of a black colloid was monitored visually. The colloid slowly disintegrated into a black precipitate and a pale supernatant. After completing of the addition the mixture obtained stirred for additional time (from 1 to 7 days). The suspension composition was either used directly or stored in a refrigerator for later use. The concentration of mitoxantrone in the colloid was determined by a UV method at 662, 611 or 242 nm. For sampling an aliquot of the colloid was diluted with methanol to >20:1.

Example 3

[0091] Preparation of Suspension of Irinotecan (IRI) Alkyl Sulfates and Alkane Sulfonates

[0092] To a vigorously solution of irinotecan hydrochloride trihydrate (5 mL, 4 mg/mL) in deionized water was added at room temperature a solution containing Na.sup.+(R.sup.1SO.sub.3).sup.− or Na.sup.+(R.sup.2OSO.sub.3).sup.− in deionized water. The formation of a colloid was monitored visually. After completing of the addition the mixture obtained stirred for 2 days and the mixture was centrifuged 10 min at 3000 rpm. On standing the white colloid slowly disintegrated into a white precipitate and a nearly colourless supernatant. The supernatant was replaced by 5% aqeuous dextrose. The precipitate was resuspended in water by vortexing for 10 min. The composition obtained then was either directly used or stored in a refrigerator for future use. The concentration of irinotecane in the colloid or suspension was determined by a UV method at 360, 255 or 220 nm. For sampling, an aliquot of the product was diluted with methanol (excess of methanol>20:1).

Example 4

[0093] Preparation of Suspension of Vinorelbine (VIN) Alkyl Sulfates and Alkane Sulfonates

[0094] To a vigorously stirred solution of vinorelbine tartrate (2 mL, 5 mg/mL) in 5% aqueous dextrose in an Erlenmeyer flask was added at room temperature a solution of one equivalent of Na.sup.+(R.sup.1SO.sub.3).sup.− or Na.sup.+(R.sup.2OSO.sub.3).sup.− in the same solvent as for vinorelbine tartrate. The formation of a colloid was monitored visually. After completing of the addition the mixture obtained was vortexed or shaken for 7 days. On standing the colloid slowly disintegrated into a precipitate and a clear supernatant. The suspension was either used directly or stored in a refrigerator for future use. The concentration of vinorelbine in the suspension was determined by a UV method at 268 or 212 nm. For sampling, an aliquot of the colloid was diluted with methanol (excess of methanol>20:1).

Example 5

[0095] Preparation of Suspension of Doxycycline (DOC) Alkyl Sulfates and Alkane Sulfonates

[0096] To a solution of doxycycline hyclate (50 mL, 1 mg/mL) in 5% aqueous dextrose in an Erlenmeyer flask was added at room temperature a solution of a 5-10% molar excess of Na.sup.+(R.sup.1SO.sub.3).sup.− or Na.sup.+(R.sup.2OSO.sub.3).sup.− and in the same solvent as for doxycycline hyclate hydrochloride. Instead of 5% aqueous dextrose can be used in this and the other examples Ringer solution or 0.9% saline or phosphate-buffered saline or another aqueous solution of an osmolality from 270 to 300 mOsm/L. The process of colloid formation was monitored visually. After completing of the addition the mixture was vortexed or shaken for an additional time period varying from 30 min to 7 days. The suspension obtained then was either directly used or placed for storage in a refrigerator. Concentration of doxycycline in the compositions was determined by a UV method at 273 and 345 nm. For sampling, an aliquot of the colloid was diluted with methanol (excess of methanol>20:1).

Example 6

[0097] Preparation of Suspension of Amphotericin B (ampB) Alkyl Sulfates and Alkane Sulfonates

[0098] To a solution of amphotericin B (2 mL, conc 0.5 mg/mL) in 5% aqueous dextrose in an Erlenmeyer flask was added at room temperature a solution of a 5-10% molar excess of Na.sup.+(R.sup.1SO.sub.3).sup.− or Na.sup.+(R.sup.2OSO.sub.3).sup.− and in the same solvent as for amphotericin. Instead of 5% aqueous dextrose can be used in this and the other examples Ringer solution or 0.9% saline or phosphate-buffered saline or another aqueous solution of an osmolality from 270 to 300 mOsm/L. The process of colloid formation was monitored visually. After completing of the addition the mixture was vortexed or shaken for an additional time period varying from 30 min to 3 days. The suspension obtained then was either directly used or placed for storage in a refrigerator. Concentration of amphotericin in the compositions was determined by a UV method at 410 or 385 nm. For sampling, an aliquot of the colloid was diluted with methanol (excess of methanol>20:1).

Example 7

[0099] Solubility of Suspension of Doxorubicin (DOX) Alkyl Sulfates and Alkane Sulfonates in 30% Aqueous Ethanol

[0100] Solubility was determined in accordance with the general method described under Materials and Methods. The results are summarized in Table 1 and presented in FIGS. 1 and 2.

TABLE-US-00001 TABLE 1 Solubility of suspension of doxorubicin alkyl sulfates and alkane sufonates in 30% ethanol (v/v). Generic formula Alkyl chain Solubility, of anion length, n mg/mL C.sub.nH.sub.2n+1OSO.sub.3.sup.− 10 0.50769 12 0.20560 14 0.03281 16 0.00729 18 0.00260 C.sub.nH.sub.2n+1SO.sub.3.sup.− 10 1.06429 12 0.23953 14 0.04596 16 0.01194 18 0.00279

Example 8

[0101] Solubility of Suspension of Mitoxantrone Alkyl Sulfates and Alkane Sulfonates in 30% Aqueous Ethanol

[0102] The solubility was determined in accordance with the general method described under Materials and Methods. The results are summarized in Table 2 and presented in FIGS. 3 and 4.

TABLE-US-00002 TABLE 2 Solubility of suspension of mitoxantrone alkyl sulfates and alkane sufonates in 30% ethanol (v/v). Generic formula Alkyl chain Solubility of anion length (n) (mg/mL) C.sub.nH.sub.2n+1OSO.sub.3.sup.−  8 0.78058 10 0.17582 12 0.06484 14 0.00720 C.sub.nH.sub.2n+1SO.sub.3.sup.−  8 1.34798 10 0.29487 12 0.68313 14 0.00203

Example 9

[0103] Solubility of Irinotecan (IRI) Alkane Sulfonates in 10% Aqueous Ethanol

[0104] The solubility was determined in accordance with the general method described under Materials and Methods. The results are summarized in Table 3.

TABLE-US-00003 TABLE 3 Solubility of suspension of irinotecan alkane sufonates in 30% ethanol (v/v). Alkyl chain Solubility, length, n mg/mL 10 0.83483 12 0.15453 14 0.07064 16 0.01476

Example 10

[0105] Solubility of Suspension of Vinorelbine Alkane Sulfonates (VIN) in 20% Aqueous Ethanol.

[0106] The solubility was determined in accordance with the general method described under Materials and Methods. The results are summarized in Table 4 and visualized in FIG. 6.

TABLE-US-00004 TABLE 4 Solubility of suspension of vinorelbine alkane sulfonates in 20% aqueous ethanol. Alkyl chain Solubility, length, n mg/mL 10 1.11868 12 0.25692 14 0.06731 16 0.01977

Example 11

[0107] Solubility of Suspension of Doxycycline (DOC) Alkane Sulfonates and Alkyl Sulfates in 20% Aqueous Ethanol

[0108] The solubility was determined in accordance with the general method described under Materials and Methods. The results are summarized in Table 5.

Example 12

[0109] Solubility of Suspension of Amphotericin B (ampB) Alkane Sulfonates in 30% Aqueous Ethanol

[0110] The solubility was determined in accordance with the general method described under Materials and Methods. The results are summarized in Table 6 and illustrated in FIG. 9.

TABLE-US-00005 TABLE 5 Solubility of suspension of doxycycline (DOC) alkane sulfonates and alkyl sulfates in 20% aqueous ethanol. Generic formula Length of C Solubility, of anion chain, n mg/mL C.sub.nH.sub.2n+1OSO.sub.3.sup.− 10 3.77651 12 0.98191 14 0.11776 16 0.03199 18 0.00523 C.sub.nH.sub.2n+1SO.sub.3.sup.− 10 3.16529 12 0.32034 14 0.05510 16 0.01034 18 0.00181

TABLE-US-00006 TABLE 6 Generic formula Length of Solubility, of anion a chain, n mg/mL C.sub.nH.sub.2n+1OSO.sub.3.sup.− 10 0.50769 12 0.20560 14 0.03281 16 0.00729 18 0.00260

Example 13 and 14

[0111] In Vivo Analysis of Distribution of Doxorubicin (DOX) in Lung in Wistar Rats

[0112] Relationship Between Solubility of of Doxorubicin Sulfonates in 30% Aqueous Ethanol and Increase of Doxorubicin Concentration in Lung in Wistar Rats after 4 Hours after Intravenous Single Bolus Injection, (See FIG. 10).

[0113] An aqueous solution of doxorubicin hydrochloride, an aqueous suspension of doxorubicin alkane sulfate and an aqueous suspension of doxorubicin alkyl sulfonate were administered via a single bolus injection into the tail Animals were sacrificed after 4 hours after administered via a single bolus injection into the tail; total doxorubicin dose 5 mg/kg. The concentration of doxorubicin in a lung was determined according to the procedure described above. The results are summarized in Table 7 and illustrated in FIG. 10. As it is seen from the table the concentration of doxorubicin determined in blood serum does not depend on the nature of doxorubicin salt.

TABLE-US-00007 TABLE 7 The amount of Doxorubicin (DOX) is expressed in μg/kg ± SD, and the difference is expressed relative to the control CI-DOX (1).EXAMPLE 14 Anion of Lung tissue Blood serum Solubility doxorubicin Relative Relative in 30% salt DOX difference DOX difference ethanol CI (DOX) 0.71 ± 0.05 (1) 0.019 ± 0.004 (1) — C.sub.12H.sub.25OSO.sub.3 0.77 ± 0.19 1.08 0.021 ± 0.007 1.12 0.206 C.sub.14H.sub.29OSO.sub.3 3.17 ± 0.33 4.46 0.023 ± 0.009 1.21 0.033 C.sub.12H.sub.25SO.sub.3 0.88 ± 0.09 1.24 0.014 ± 0.003 0.75 0.240 C.sub.16H.sub.33SO.sub.3 6.11 ± 0.75 8.61 0.019 ± 0.007 1.04 0.012

Example 15

[0114] In Vivo Analysis of Distribution of Doxorubicin (DOX) in Lung in Californian Rabbits

[0115] Suspension of complexes of doxorubicin and doxorubicin hydrochloride were administered via a slow flow of 1 ml/min to rabbits in the marginal ear vein with a total doxorubicin dose 1.25 mg/kg. Animals were sacrificed after 4 hours after administration. Concentration of doxorubicin in lung and femoral muscle was determined in accordance to the procedure described above. The results are summarized in Table 8 and FIG. 11. As it is seen from table 8 the concentration of doxorubicin in femoral muscle as a representation of a system concentration is not increased for complexes compared with doxorubicin hydrochloride.

TABLE-US-00008 TABLE 8 The amount of Doxorubicin (DOX) is expressed in μg/kg ± SD, and the difference is expressed relative to the control CI-DOX (1). Lung tissue Femoral muscle Solubility Anion of Relative Relative in 30% DOX salt DOX difference DOX difference ethanol CI (DOX)  0.83 ± 0.05 (1) 0.23 ± 0.02 (1) — C.sub.12H.sub.25OSO.sub.3  1.61 ± 0.25  1.94 0.20 ± 0.02 0.87 0.2056 C.sub.14H.sub.29OSO.sub.3  6.14 ± 0.53  7.40 0.06 ± 0.01 0.26 0.0328 C.sub.16H.sub.33SO.sub.3 10.70 ± 0.77 12.89 0.12 ± 0.06 0.52 0.0119

Example 16

[0116] Illustrates the relationship between solubility of non-covalent complexes of doxorubicin in 30% aqueous ethanol and increase of doxorubicin concentration in lung of Californian rabbits after 4 hours after intravenous injection, See FIG. 11.

Example 17

[0117] In Vivo Analysis of Distribution of Doxycycline (DOX) in Lung and Blood Serum in Wistar Rats

[0118] Suspension of complexes of doxycycline and doxycycline hyclate were administered via a single bolus injection into the tail with a total doxycycline dose 3 mg/kg. Animals were sacrificed after 30 min after administration. Concentration of doxycycline in a lung and blood serum was determined in accordance to the procedure described above. The results are summarized in a Table 9. As it is seen from the table the concentration of doxycycline in a blood serum is decreased for non-covalent complexes compared to doxycycline hyclate.

Example 18

[0119] Shows an illustration of relationship between solubility of complexes of doxycycline (DOC) in 20% aqueous ethanol and increase of doxycycline concentration in lung of Wistar rats after 30 min after intravenous single bolus injection, see FIG. 12.

Example 19

[0120] Illustrates the relationship between solubility of complexes of doxycycline in 20% aqueous ethanol and decrease of doxycycline concentration in blood serum of Wistar rats after 30 min after intravenous single bolus injection, see FIG. 13.

TABLE-US-00009 TABLE 9 The amount of Doxorubicin (DOX) is expressed in ng/ml ± SD, and the difference is expressed reative to the control CI-DOX (1). Solubility Anion of Lung tissue Blood serum in 20% DOX salt DOX Difference DOX Difference ethanol CI (Dox) 172 ± 18 (1) 115 ± 12 (1) — C.sub.12H.sub.25OSO.sub.3  551 ± 185  3.20 127 ± 22 1.10 0.9819 C.sub.14H.sub.29OSO.sub.3 1582 ± 101  9.20 45 ± 1 0.39 0.1178 C.sub.12H.sub.25SO.sub.3  943 ± 600  5.48 61 ± 7 0.53 0.3203 C.sub.16H.sub.33SO.sub.3 2020 ± 117 11.74 25 ± 2 0.22 0.0103

Example 20

[0121] Preparation of a colloid non-covalent complex of doxorubicin (DOX) with desired solubility in 30% aqueous ethanol (EtoH).

[0122] This example illustrates preparation of non-covalent complexes with defined solubility in a special solvent.

[0123] The task: to prepare a colloid non-covalent complex of doxorubicin with a use of alkane sulfonates with even number of carbon atoms in 30% aqueous ethanol with solubility 0.1 mg/mL.

[0124] We assume that an impact of the number of carbon atoms in alkane sulfonate radical is additive. We suppose also a continuous function for solubility y in 30% aqueous ethanol

[0125] Following function (f1), which was obtained in example 5 (see FIG. 2) represents relationship between number of carbon atoms x and solubility y.

y=f1(x)=1754.71710 exp(−0.74429x)  (eq. 1)

[0126] Using following function (f2) it is possible to perform reverse calculation, i.e. calculate number of carbon atoms X from a given solubility Y:

x=f2(y)=−1/0.7442855697 ln(y/1754.71709855)  (eq 2)

[0127] For the solubility of y=0.1 mg/mL the function f2 returns x equal to 13.20628. Taking the assumption of an additive behaviour of carbon atoms in the radicals we can calculate a ratio of C12 and C14 sulfonates (the adjacent sulfonates with closest solubility) to provide the suggested C13.20628 radical: [0128] 1 equivalent of C13.20628 is equal to a mixture of 0.397 equivalents of C.sub.12 and 0.603 equivalents of C.sub.14.

[0129] A colloid complex with the determined ratio of C.sub.12 and C.sub.14 sulfonates was prepared in accordance the typical method described in example 1. The solubility of the complex was determined in accordance with the general method which is described above and was found 0.098713 mg/mL.

Example 21

[0130] Relationship between detected amount doxorubicin (μg/kg) in lung of Wistar rats and particle size of suspensions. Aqueous suspensions of complex comprising doxorubicin and sulfate having 14 carbons i.e., C.sub.14H.sub.29OSO.sub.3Na-complex with a different particle size were administered via a single bolus injection into the tail. Animals were sacrificed 4 hours after administration; total amount of doxorubicin was 5 mg/kg. The concentration of doxorubicin in lung was determined according to the procedure described above. The results are summarized in FIG. 14 and Table 10. The results show that a particle size of about 40-90 μm is particularly advantageous in targeting lung tissue.

TABLE-US-00010 TABLE 10 Average size of 0.475 10.87 63.24 189 particles (μm) Doxorubicin in 710 ± 0.0 620 ± 0.1 3170 ± 0.3 49 ± 0.2 lung (μg/kg)