WO1996019230A1 - Soluble 2-chloro-2'-deoxyadenosine formulations - Google Patents

Soluble 2-chloro-2'-deoxyadenosine formulations Download PDF

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Publication number
WO1996019230A1
WO1996019230A1 PCT/US1995/016418 US9516418W WO9619230A1 WO 1996019230 A1 WO1996019230 A1 WO 1996019230A1 US 9516418 W US9516418 W US 9516418W WO 9619230 A1 WO9619230 A1 WO 9619230A1
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Prior art keywords
cda
solution
benzyl alcohol
propylene glycol
formulations
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PCT/US1995/016418
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French (fr)
Inventor
Michael Bornstein
Rosemary Rozman
Kevin Francis Long
George Kaon Wong
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Ortho Pharmaceutical Corp
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Ortho Pharmaceutical Corp
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Priority to DK95943134T priority Critical patent/DK0801571T3/en
Priority to PL95321431A priority patent/PL321431A1/en
Priority to EP95943134A priority patent/EP0801571B1/en
Priority to CA002208484A priority patent/CA2208484C/en
Priority to JP8519914A priority patent/JPH10512549A/en
Priority to AT95943134T priority patent/ATE223221T1/en
Priority to CZ971942A priority patent/CZ194297A3/en
Priority to AU44251/96A priority patent/AU4425196A/en
Priority to SI9530619T priority patent/SI0801571T1/en
Priority to DE69528080T priority patent/DE69528080T2/en
Publication of WO1996019230A1 publication Critical patent/WO1996019230A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • This invention relates to pharmaceutically useful and soluble formulations of 2-chloro-2'-deoxyadenos ⁇ ne (2-CdA) in water. More particularly, this invention relates to soluble formulations of 2-CdA in water with certain solubilizers and optionally certain preservatives and buffers which are injectable in humans and have a improved shelf-life.
  • the compound 2-CdA has the following formula:
  • 2-CdA is known as an antileukemic agent, i.e., in treating leukemias, such as, hairy cell leukemia and L 1210 leukemia, and as an immunosuppressive agent (D. A. Carson, D. Bruce Wasson, and Ernst Beutler, Proc Soc Acad. Sci. USA, Vol. 81 , pp 2232- 2236, 1984). More recently, 2-CdA has been has been disclosed as effective in the treatment of rheumatoid arthritis and multiple sclerosis, U.S. Pat. No. 5,310,732.
  • 2-CdA has been administered by intravenous injection of saline solutions presenting two problems for subtaneous or intramuscular injection.
  • 2-CdA is slightly soluble in water which requires a large volume of material to be injected subscutaneously or intramuscularly to achieve the required dose. Dilute solutions are acceptable for intravenous injection, but may create pain or inflammatory difficulties tor subcutaneous or intramuscular injection.
  • 2-CdA has limited stability in simple saline solutions. Longer shelf-life is beneficial for extended storaqe at refrigerated or room temperature conditions.
  • a non-buffered solution containing 1.0 mg/mL of 2-CdA in 9.0 mg/mL Sodium Chloride Injection, USP.
  • Figure 1 is the concentration of 2-CdA versus time in water and with 1 % benzyl alcohol as a cosolvent.
  • Figure 2 is the concentration of 2-CdA versus time with 10% propylene glycol as a cosolvent.
  • Figure 3 is the concentration fo 2-CdA versus time with various levels of benzyl alcohol and a single combination of benzyl alcohol and propylene gylcol as shown.
  • a solubilizmg agent selected from the group consisting of from about 5 to about 30 mg/mL of benzyl alcohol and from about 50 to about 400 mg/mL of propylene glycol.
  • the solution contains from a ⁇ out 2 to about 7 mg/mL of 2- CdA. Most preferably the solution contains from about 3 to about 5 mg/mL of 2-CdA.
  • Benzyl alcohol is known generally as a preservative in pharmaceutical formulations based on its antibacterial action and as a solubilizmg agent for certain pharmaceutical compounds.
  • benzyl alcohol is present in the solutions of the present invention from about 8 to about 20 mg/mL benzyl alcohol and most preferrably from about 10 to about 15 mg/mL
  • Propylene glycol is a known solubilizmg agent for a variety of pharmaceuticals.
  • both benzyl alcohol and propylene glycol be present within the prescribed ranges to obtain optimum solubility of 2-CdA in water.
  • the other may be present in less that the pres ⁇ bed minimum amount.
  • sodium chloride might be added to render the solution isotonic. Where employed, it might constitute from about 2 to about 6 mg/mL of the solution.
  • the m-cresol is known generally as a preservative in pharmaceutical formulations based on its antibactenal action. In preferred solutions herein there might be added from about 1.5 to about 2.5 mg/mL of m-cresol and most preferrably about 2 mg/mL.
  • Suitable buffers are any of those available for pha ⁇ p £?r?j ⁇ -;al application and which are capable of stabilizing pH for the instant solutions between 5.5 and 8.5.
  • Such buffers include but are not 'im " - *o c.r-o_Dhate, citrate, acetate, borate and tns.
  • the preferred buffer for LS ? ⁇ re n is sodium pnospnate buffer.
  • a preferred pH range for the snelf stable solutions herein is between about 6.0 and about 7.0.
  • the ratio of the sodium phophate monobasic. NaH P ⁇ 4 -H 2 0. and the sodium phosphate dibasic, Na2HP0 4 *7H 0, are adjusted to achieve the pH desired.
  • This buffer is generally useful to achieve a pH in the range of from 4.5 to 8.5. Of course, sufficient buffer should be employed not only to obtain the desired pH but to stabilize the pH at that value. For solutions herein there might be employed a weight ratio from about 2 to 1 to about 1 to 1 of the sodium phosphate monobasic to the sodium phosphate dibasic.
  • Table 1 The formulation of Table 1 was prepared and found suitable for use as an injectable and pharmaceutically useful solution. This solution is pH 6.5. All figures shown are in mg/mL. The following abbreviations are employed in Table 1 and elsewhere herein: propylene glycol, USP, (PG), benzyl alcohol, NF, (BA), m-cresol, (MC), sodium phosphate monobasic, monohydrate, USP, (SPMM) and sodium phosphate dibasic, heptahydrate, USP, (SPDH). Water for injection, USP (WFI), was added to 1.0 mL.
  • 2-CdA may be administered to a patient in need of the same in a daily dose of 0.05 to about 0.15 mg/Kg.
  • a more desirable daily dose would be from 0.07 to about 0.1 mg/Kg.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Hematology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Shelf stable formulations of 2-CdA in water are disclosed which contain benzyl alcohol and/or propylene glycol and a buffer system.

Description

SOLURL F g-CHLORO-2'-DEOXYADENOSINE FORMULATIONS
This invention relates to pharmaceutically useful and soluble formulations of 2-chloro-2'-deoxyadenosιne (2-CdA) in water. More particularly, this invention relates to soluble formulations of 2-CdA in water with certain solubilizers and optionally certain preservatives and buffers which are injectable in humans and have a improved shelf-life.
BACKGROUND OF THE INVENTION
The compound 2-CdA has the following formula:
Figure imgf000003_0001
2-CdA is known as an antileukemic agent, i.e., in treating leukemias, such as, hairy cell leukemia and L 1210 leukemia, and as an immunosuppressive agent (D. A. Carson, D. Bruce Wasson, and Ernst Beutler, Proc Soc Acad. Sci. USA, Vol. 81 , pp 2232- 2236, 1984). More recently, 2-CdA has been has been disclosed as effective in the treatment of rheumatoid arthritis and multiple sclerosis, U.S. Pat. No. 5,310,732.
To date, 2-CdA has been administered by intravenous injection of saline solutions presenting two problems for subtaneous or intramuscular injection. First, 2-CdA is slightly soluble in water which requires a large volume of material to be injected subscutaneously or intramuscularly to achieve the required dose. Dilute solutions are acceptable for intravenous injection, but may create pain or inflammatory difficulties tor subcutaneous or intramuscular injection. Secondly, 2-CdA has limited stability in simple saline solutions. Longer shelf-life is beneficial for extended storaqe at refrigerated or room temperature conditions. U.S. Pat. No. 5.310,732. col. 8. teacnes a 0.1 mg/mL isotonic saline solution of 2-CdA. There has been marketed a non-buffered solution containing 1.0 mg/mL of 2-CdA in 9.0 mg/mL Sodium Chloride Injection, USP.
BRIFF DESCRIPTION OF THE DRAWINGS
Figure 1 is the concentration of 2-CdA versus time in water and with 1 % benzyl alcohol as a cosolvent. Figure 2 is the concentration of 2-CdA versus time with 10% propylene glycol as a cosolvent. Figure 3 is the concentration fo 2-CdA versus time with various levels of benzyl alcohol and a single combination of benzyl alcohol and propylene gylcol as shown.
SUMMARY OF THE INVENTION
There is provided by the present invention a solution of 2-CdA in water comprising:
a) from about 1 to about 8 mg/mL of 2-CdA; and
b) a solubilizmg agent selected from the group consisting of from about 5 to about 30 mg/mL of benzyl alcohol and from about 50 to about 400 mg/mL of propylene glycol.
DETAILED DESCRIPTION OF THF INVENTION
Processes for preparing 2-CdA are known. European Patent Application No. 173,059 A2 and Robins et al., J. Am. Chem. Soc, 106, 6379 (1984) disclose the preparation or 2-CdA. The preparation consists of the glycosilation of 2,6-dιchloropunne with 1 -chloro-2'-deoxy-3\5'-dι-0-p-toluoyl-b- D-erythropentofuranose to yield the N-9 glycosilated puπne, 2,6-dιchloro-9-(2- deoxy-3,5-di-0-p-toluoyl-b-D-erythropentofuranosyl)-puπne, which is subsequently reacted with ammonia to yield 2-CdA. n alternative method to manufacture 2-CdA is taught in U.S. Pat. No. 5,208,327 by Robert H. K. Chen. Preferably, the solution contains from aσout 2 to about 7 mg/mL of 2- CdA. Most preferably the solution contains from about 3 to about 5 mg/mL of 2-CdA.
Benzyl alcohol is known generally as a preservative in pharmaceutical formulations based on its antibacterial action and as a solubilizmg agent for certain pharmaceutical compounds. Preferably, in the solutions of the present invention there is present from about 8 to about 20 mg/mL benzyl alcohol and most preferrably from about 10 to about 15 mg/mL
Propylene glycol is a known solubilizmg agent for a variety of pharmaceuticals. Preferably in the solution of the present invention there is from about 75 to about 200 mg/mL of propylene glycol and most preferrably from about 100 to about 150 mg/mL.
It is preferred that both benzyl alcohol and propylene glycol be present within the prescribed ranges to obtain optimum solubility of 2-CdA in water. Of course, where one of either benzyl alcohol or propylene glycol it is contemplated within the present invention that the other may be present in less that the presαbed minimum amount.
To provide for useful solutions of 2-CdA which may be injected to achieve the desired pharmaceutical effect, it may be necessary or desirable to include further compounds in the formulation
In the absence of propylene glycol, sodium chloride might be added to render the solution isotonic. Where employed, it might constitute from about 2 to about 6 mg/mL of the solution.
The m-cresol is known generally as a preservative in pharmaceutical formulations based on its antibactenal action. In preferred solutions herein there might be added from about 1.5 to about 2.5 mg/mL of m-cresol and most preferrably about 2 mg/mL.
Suitable buffers are any of those available for phaτp£?r?jτ-;al application and which are capable of stabilizing pH for the instant solutions between 5.5 and 8.5. Such buffers include but are not 'im " - *o c.r-o_Dhate, citrate, acetate, borate and tns. The preferred buffer for LS ? ^÷re n is sodium pnospnate buffer. A preferred pH range for the snelf stable solutions herein is between about 6.0 and about 7.0. The ratio of the sodium phophate monobasic. NaH Pθ4-H20. and the sodium phosphate dibasic, Na2HP04*7H 0, are adjusted to achieve the pH desired. This buffer is generally useful to achieve a pH in the range of from 4.5 to 8.5. Of course, sufficient buffer should be employed not only to obtain the desired pH but to stabilize the pH at that value. For solutions herein there might be employed a weight ratio from about 2 to 1 to about 1 to 1 of the sodium phosphate monobasic to the sodium phosphate dibasic.
The formulation of Table 1 was prepared and found suitable for use as an injectable and pharmaceutically useful solution. This solution is pH 6.5. All figures shown are in mg/mL. The following abbreviations are employed in Table 1 and elsewhere herein: propylene glycol, USP, (PG), benzyl alcohol, NF, (BA), m-cresol, (MC), sodium phosphate monobasic, monohydrate, USP, (SPMM) and sodium phosphate dibasic, heptahydrate, USP, (SPDH). Water for injection, USP (WFI), was added to 1.0 mL.
TABLE 1
Formulation 1
2-CdA 5.0
PG 100.0
BA 10.0
MC 2.0
SPMM 1.816
SPDH 0.941
2-CdA may be administered to a patient in need of the same in a daily dose of 0.05 to about 0.15 mg/Kg. A more desirable daily dose would be from 0.07 to about 0.1 mg/Kg.
The invention is illustrated, but in no way limited, by the following examples. EXAMPLE
The following solutions were prepared with water for injection to make a total volume of 1.0 mL. All figures are in mg/mL
TAPLE 2
Formulation 2-CdA fiA P£
Control 10.0
1 10.0 100.0
2 10.0 5.0
3 10.0 10.0
4 10.0 15.0
5 1 100..00 20.0
6 10.0 25.0
7 10.0 30.0
8 10.0 10.0 100.0
The formulations of Table 2 were stored in a darkened container at room temperature and tested periodically for the amount of 2-CdA in solution. The reported figure is 2-CdA in solution in mg/mL.
TAB E 3
Da s Formulation
Control
0 (target) 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 3 10.1 7.65
4 8.29 9.97 9.80 10.1 9.99 9.67
6 4.71
10 9.54 7.30
17 4.66 2.21 22 2.94
24 4.25 2.26
32 2.61 4.42 6.25 6.85 7 92 4 71
38 3.64 2.09 9 3.63 2.15 4 2.66
102 2.85
11 1 3.7 2.24
It is evident from the data above, that the solubility of 2-CdA in water is greatly increased by the addition of either propylene glycol or benzyl alcohol. Nowhere are co-solvents having such a marked effect on the solubility of 2- CdA taught or suggested in the prior art.

Claims

WHAT IS CLAIMED IS:
1. A solution of 2-CdA in water comprising: '
a) from about 1 to aDOut 8 mg/mL 2-CdA: and
b) a solubilizing agent selected from the group consisting of from about 5 to about 30 mg/mL of benzyl alcohol and from about 50 to about 400 mg/mL of propylene glycol.
2. The solution of claim 1 comprising from about 2 to about 7 mg/mL of 2- CdA.
3. The solution of claim 1 compπsing from about 3 to about 5 mg/mL of 2- CdA.
4. The solution of claim 1 wherein the solubilizing agent is propylene glycol.
5. The solution of claim 1 wherein the solubilizing agent is benzyl alcohol.
6. The solution of claim 1 wherein the solubilizing agent selected from the group consisting of from about 8 to about 20 mg/mL of benzyl alcohol and from about 75 to about 200 mg/mL of propylene glycol.
7. The solution of claim 1 wherein the solubilizing agent selected from the group consisting of from about 10 to about 15 mg/mL of benzyl alcohol and from about 100 to about 150 nmg/mL of propylene glycol.
PCT/US1995/016418 1994-12-22 1995-12-15 Soluble 2-chloro-2'-deoxyadenosine formulations Ceased WO1996019230A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
DK95943134T DK0801571T3 (en) 1994-12-22 1995-12-15 Soluble 2'-chloro-2'-deoxyadenosion formulations
PL95321431A PL321431A1 (en) 1994-12-22 1995-12-15 Soluble 2-chloro-2'deoxyadenosine compositions
EP95943134A EP0801571B1 (en) 1994-12-22 1995-12-15 Soluble 2-chloro-2'-deoxyadenosine formulations
CA002208484A CA2208484C (en) 1994-12-22 1995-12-15 Soluble 2-chloro-2'-deoxyadenosine formulations
JP8519914A JPH10512549A (en) 1994-12-22 1995-12-15 Soluble 2-chloro-2'-deoxyadenosine formulation
AT95943134T ATE223221T1 (en) 1994-12-22 1995-12-15 SOLUBLE MEDICINAL COMPOSITIONS CONTAINING 2-CHLORO-2'-DEOXYADENOSINE
CZ971942A CZ194297A3 (en) 1994-12-22 1995-12-15 Solution of 2-chloro-2-deoxyadenosine in water
AU44251/96A AU4425196A (en) 1994-12-22 1995-12-15 Soluble 2-chloro-2'-deoxyadenosine formulations
SI9530619T SI0801571T1 (en) 1994-12-22 1995-12-15 Soluble 2-chloro-2'-deoxyadenosine formulations
DE69528080T DE69528080T2 (en) 1994-12-22 1995-12-15 SOLUBLE MEDICAL COMPOSITIONS CONTAINING 2-CHLORO-2'-DEOXYADENOSINE

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US36208394A 1994-12-22 1994-12-22
US08/362,083 1994-12-22

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US (1) US5681822A (en)
EP (1) EP0801571B1 (en)
JP (1) JPH10512549A (en)
AT (1) ATE223221T1 (en)
CA (1) CA2208484C (en)
CZ (1) CZ194297A3 (en)
DE (1) DE69528080T2 (en)
DK (1) DK0801571T3 (en)
ES (1) ES2182920T3 (en)
HU (1) HUT77928A (en)
IL (1) IL116469A0 (en)
PL (1) PL321431A1 (en)
PT (1) PT801571E (en)
WO (1) WO1996019230A1 (en)
ZA (1) ZA9510924B (en)

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WO2006067141A1 (en) 2004-12-22 2006-06-29 Laboratoires Serono S.A. Cladribine regimen for treating multiple sclerosis
WO2007135172A2 (en) 2006-05-24 2007-11-29 Laboratoires Serono S.A. Cladribine regimen for treating multiple sclerosis
EP2343074A1 (en) 2009-12-23 2011-07-13 Merck Serono S.A. Use of purine analogues for treating airway diseases
WO2019101960A1 (en) 2017-11-24 2019-05-31 Merck Patent Gmbh Cladribine regimen for use intreating progressive forms of multiple sclerosis
WO2022053608A1 (en) 2020-09-10 2022-03-17 Merck Patent Gmbh Novel treatment regimen for the treatment of autoimmune disorders
WO2022184867A1 (en) 2021-03-03 2022-09-09 Merck Patent Gmbh Improved treatment methods using dmds for the treatment of autoimmune diseases, and biomarker for predicting and/or optimising said treatment methods

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US6194395B1 (en) * 1999-02-25 2001-02-27 Orthro-Mcneil Pharmaceutical, Inc. Cyclodextrin cladribine formulations
CA2518903C (en) * 2003-04-02 2013-02-05 Ares Trading S.A. Liquid pharmaceutical formulations of fsh and lh together with a non-ionic surfactant
WO2004112826A1 (en) * 2003-06-20 2004-12-29 Ares Trading Sa Freeze-dried fsh / lh formulations
FR2873695A1 (en) * 2004-07-30 2006-02-03 Palumed Sa HYBRID MOLECULES QA OR Q IS AMINOQUINOLINE AND A IS AN ANTIBIOTIC OR A RESISTANCE INHIBITOR), THEIR SYNTHESIS AND USES THEREOF AS ANTIBACTERIAL AGENT

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WO1993023058A1 (en) * 1992-05-19 1993-11-25 The Scripps Research Institute Use of 2-halo adenine derivatives as therapeutic agents against chronic myelogenous leukemia
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US4908441A (en) * 1988-07-19 1990-03-13 Warner-Lambert Company Deoxyadenosine compounds and methods of making and using the same
US5208327A (en) * 1991-12-18 1993-05-04 Ortho Pharmaceutical Corporation Intermediates useful in a synthesis of 2-chloro-2'-deoxyadenosine

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
EP0190726A2 (en) * 1985-02-05 1986-08-13 Warner-Lambert Company Novel deoxyadenosine phosphate compounds and methods of making and using the same
US5310732A (en) * 1986-02-03 1994-05-10 The Scripps Research Institute 2-halo-2'-deoxyadenosines in the treatment of rheumatoid arthritis
WO1993023058A1 (en) * 1992-05-19 1993-11-25 The Scripps Research Institute Use of 2-halo adenine derivatives as therapeutic agents against chronic myelogenous leukemia

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WO2006067141A1 (en) 2004-12-22 2006-06-29 Laboratoires Serono S.A. Cladribine regimen for treating multiple sclerosis
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WO2007135172A2 (en) 2006-05-24 2007-11-29 Laboratoires Serono S.A. Cladribine regimen for treating multiple sclerosis
US9925151B2 (en) 2006-05-24 2018-03-27 Merck Serono Sa Cladribine regimen for treating multiple sclerosis
US10555913B2 (en) 2006-05-24 2020-02-11 Merck Serono Sa Cladribine regimen for treating multiple sclerosis
US12377056B2 (en) 2006-05-24 2025-08-05 Merck Serono Sa Cladribine regimen for treating multiple sclerosis
EP2343074A1 (en) 2009-12-23 2011-07-13 Merck Serono S.A. Use of purine analogues for treating airway diseases
WO2019101960A1 (en) 2017-11-24 2019-05-31 Merck Patent Gmbh Cladribine regimen for use intreating progressive forms of multiple sclerosis
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PT801571E (en) 2002-12-31
HUT77928A (en) 1998-11-30
DK0801571T3 (en) 2003-01-06
DE69528080D1 (en) 2002-10-10
CA2208484C (en) 2008-09-23
DE69528080T2 (en) 2003-06-05
PL321431A1 (en) 1997-12-08
ES2182920T3 (en) 2003-03-16
EP0801571A1 (en) 1997-10-22
CA2208484A1 (en) 1996-06-27
EP0801571B1 (en) 2002-09-04
US5681822A (en) 1997-10-28
IL116469A0 (en) 1996-03-31
CZ194297A3 (en) 1997-10-15
JPH10512549A (en) 1998-12-02
ATE223221T1 (en) 2002-09-15
ZA9510924B (en) 1997-06-23

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