- Novel drug delivery of dual acting prodrugs of hydroxychloroquine with aryl acetic acid NSAIDs: Design, kinetics and pharmacological study
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Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by restricted movements of joints of hand, feet, elbow, knees and neck but principally the synovial joints. Though etiopathology is not exactly known, treatment paradigms are evolving to provide a tighter control over symptoms and disease progression. Current trend is introduction of disease modifying anti-rheumatoid drugs (DMARDs) at early stages. Hydroxychloroquine (HCQ) and nonsteroidal anti-inflammatory drugs (NSAIDs) are two mechanistically different categories widely used in the management of RA where the first arrests the disease progression while the latter offers symptomatic relief. Present work aims at minimizing problems of slow onset and accumulation of HCQ in non-targeted sites and local gastric intolerance to NSAIDs by designing their mutual ester prodrugs. Synthesis of prodrugs was achieved by CDI coupling and structures were confirmed by IR, 1H–NMR, 13C–NMR, mass spectroscopy and elemental analysis. Prodrugs resisted hydrolysis in acidic environment of the stomach but exhibited significant release in small intestine. Upon oral administration of prodrugs to rats, 40.5–49% HCQ and 53.4–66.8% of NSAIDs were recovered in 8.5–10?h in blood. Urine and feces samples pooled over a period of 24?h exhibited 2.3–3.5% and 0.75–0.9% of HCQ, respectively, without any presence of intact prodrugs or NSAIDs. Prodrugs were pharmacologically evaluated for analgesic and anti-inflammatory activities using standard animal models. Among all, prodrugs of HCQ with licofelone (HL) and aceclofenac (HA) produced superior analgesia, improved weight gain, normalization of joint diameter/paw volume than HCQ and physical mixtures of HCQ and NSAIDs. Hematological and biochemical studies indicated significant step up in RBC, Hb, platelet count, total protein nutrient (TPN) levels and step down in WBC, serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) by the treatment with HL and HA. Through these novel codrugs, problems of slow onset and accumulation of HCQ in non-targeted sites and local gastric intolerance to NSAIDs were well addressed. These dual acting mutual prodrugs of two mechanistically different anti-arthritic agents could be explored further as promising strategy for effective management of RA.
- Poorvashree, Joshi,Suneela, Dhaneshwar
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- Chloroquine-Modified Hydroxyethyl Starch as a Polymeric Drug for Cancer Therapy
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Hydroxyethyl starch (HES) is a clinically used polysaccharide colloidal plasma volume expander. The goal of this study was to synthesize HES modified with hydroxychloroquine (HCQ) as a novel polymeric drug with the ability to inhibit the invasive character of pancreatic cancer (PC) cells. HES was conjugated with HCQ using a simple carbonyldiimidazole coupling to prepare Chloroquine-modified HES (CQ-HES). CQ-HES with various degrees of HCQ substitution were synthesized and characterized. Atomic force microscopy was used to demonstrate a pH-dependent assembly of CQ-HES into well-defined nanoparticles. In vitro studies in multiple PC cell lines showed CQ-HES to have a similar toxicity profile as HCQ. Confocal microscopy revealed the propensity of CQ-HES to localize to lysosomes and mechanistic studies confirmed the ability of CQ-HES to inhibit autophagy in PC cells. Further studies demonstrated a greatly enhanced ability of CQ-HES to inhibit the migration and invasion of PC cells when compared with HCQ. The enhanced inhibitory actions of CQ-HES compared to HCQ appeared to arise in part from the increased inhibition of ERK and Akt phosphorylation. We found no significant HCQ release from CQ-HES, which confirmed that the observed activity was due to the action of CQ-HES as a polymeric drug. Due to its promising ability to block cancer cell invasion and the ability to form nanoparticles, CQ-HES has the potential as a drug delivery platform suitable for future development with chemotherapeutics to establish novel antimetastatic treatments.
- Sleightholm, Richard,Yang, Bin,Yu, Fei,Xie, Ying,Oupicky, David
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- High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine
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Numerous synthetic methods for the continuous preparation of fine chemicals and active pharmaceutical ingredients (API's) have been reported in recent years resulting in a dramatic improvement in process efficiencies. Herein we report a highly efficient continuous synthesis of the antimalarial drug hydroxychloroquine (HCQ). Key improvements in the new process include the elimination of protecting groups with an overall yield improvement of 52% over the current commercial process. The continuous process employs a combination of packed bed reactors with continuous stirred tank reactors for the direct conversion of the starting materials to the product. This high-yielding, multigram-scale continuous synthesis provides an opportunity to achieve increase global access to hydroxychloroquine for treatment of malaria.
- Yu, Eric,Mangunuru, Hari P.R.,Telang, Nakul S.,Kong, Caleb J.,Verghese, Jenson,Gilliland, Stanley E.,Ahmad, Saeed,Dominey, Raymond N.,Gupton, B. Frank
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- CRYSTALS OF HYDROXYCHLOROQUINE SULFATE
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Two crystals of (S)-(+)-hydroxychloroquine sulfate. One crystal features diffraction peaks at 12.3±0.1°, 13.1±0.1°, 17.9±0.1°, 22.8±0.1°, 23.4±0.1°, 25.1±0.1°, and 26.3±0.1° as 2θ angles in a powder X-ray diffraction pattern. The other crystal features diffraction peaks at 12.8±0.1°, 14.5±0.1°, 16.7±0.1°, 17.6±0.1°, 20.2±0.1°, 21.4±0.1°, 23.8±0.1°, 25.7±0.1°, and 26.0±0.1° as 2θ angles in a powder X-ray diffraction pattern. Also disclosed are methods of preparing crystals of (S)-(+)-hydroxychloroquine sulfate.
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Paragraph 0040-0041
(2021/10/22)
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- Preparation method of hydroxychloroquine
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The invention relates to a preparation method of hydroxychloroquine, which comprises the following steps: protecting hydroxyl of 5-(N-ethyl-N-ethoxyl)-2-aminopentane through a silanization reagent, removing amino protons from tetrahydrofuran or toluene by using a bis(trimethylsilyl lithium amide) solution to form amino anions, and carrying out a substitution reaction with 4.7 dichloroquinoline to generate hydroxychloroquine. The hydroxychloroquine and sulfuric acid are salified in an alcoholic solution to generate hydroxychloroquine sulfate, and the hydroxychloroquine sulfate preparation method provided by the invention has the characteristics of low toxicity, low pollution, high purity, low reaction temperature, short reaction time, high yield and the like, and is suitable for industrialization.
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Paragraph 0022; 0034-0039
(2021/05/05)
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- Refining method of hydroxychloroquine crude product
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The present invention provides a refining method of a hydroxychloroquine crude product. The refining method comprises two refining processes. In the first refining process, by controlling the use amount of a derivatization reagent and the derivatization reaction temperature, an impurity III is converted into a new impurity easy to remove, the new impurity is removed through a recrystallization mode, the active ingredient hydroxychloroquine hardly participates in the derivatization reaction, the primary refining of the crude hydroxychloroquine product is realized, almost no impurity III exists in the primary refined product, the loss of hydroxychloroquine is low, the yield reaches 90% or above, and the purity reaches 99.5% or above. In the second refining process, a simple recrystallization mode is adopted, the yield of the hydroxychloroquine is high, the yield reaches about 95%, and the purity reaches 99.9%.
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Paragraph 0047-0075
(2021/07/24)
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- Hydroxychloroquine sulfate and preparation method thereof
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The invention discloses hydroxychloroquine sulfate and a preparation method thereof, and relates to the technical field of medicinal chemistry. The preparation method comprises the steps of mixing 4, 7-dichloroquinoline with a hydroxychloroquine side chain, carrying out heating condensation in the presence of an organic base catalyst, adding water and liquid, and carrying out cooling crystallization to obtain hydroxychloroquine; and dissolving hydroxychloroquine in an ethyl acetate and ethanol aqueous solution, heating, dissolving and clarifying, dropwise adding concentrated sulfuric acid, cooling, crystallizing, filtering and drying to obtain hydroxychloroquine sulfate. The method has the beneficial effects that a solvent-free reaction is used, and a catalyst is added, so that high pollution is avoided, the reaction process is accelerated, and the operation is simple; and meanwhile, the HPLC purity of the obtained hydroxychloroquine refined product is not less than 96.50%, the maximum single impurity content is less than 0.10%, the yield can reach 85%, the HPLC purity of hydroxychloroquine sulfate is not less than 98.00%, the maximum single impurity content is less than 0.10%, and the yield can reach 90%.
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Paragraph 0039-0041; 0044-0046; 0049-0051; 0054-0056; ...
(2021/07/31)
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- Preparation method of hydroxychloroquine
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The invention relates to the field of medicinal chemistry, in particular to a preparation method of hydroxychloroquine. According to the method, the nucleophilic reaction is promoted by adding the organic amine, the reaction time is shortened, the reaction conversion rate is increased, the impurity content is reduced, the product quality is improved, other organic solvents and catalysts are not used, the high-pressure reaction condition is avoided, and the method is mild in reaction condition, simple in post-treatment, high in process controllability and suitable for industrial production. The preparation method of hydroxychloroquine comprises the following step: reacting 4, 7-dichloroquinoline and 2-[(4-amino amyl) (ethyl) amino] ethanol in triethanolamine to prepare hydroxychloroquine.
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Paragraph 0032-0046
(2021/10/20)
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- Preparation method of hydroxychloroquine sulfate
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The invention provides a preparation method of hydroxychloroquine sulfate, specifically a preparation method of hydroxychloroquine sulfate. The method comprises the following steps: (1) preparation of hydroxychloroquine: (1.1) in a first solvent, in the presence of KI and an antioxidant, reacting 4, 7-dichloroquinoline (formula I) with an amino side chain as shown in a formula II to obtain a reaction mixture containing hydroxychloroquine (formula III); and (1.2) separating the hydroxychloroquine from the reaction mixture containing the hydroxychloroquine; and (2) preparation of hydroxychloroquine sulfate: (2.1) in a second inert solvent, reacting the hydroxychloroquine obtained in the step (1) with sulfuric acid to form a salt so as to obtain the hydroxychloroquine sulfate (formula IV).
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Paragraph 0099; 0151-0158; 0165-0172; 0179-0185; 0192; ...
(2021/07/08)
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- Industrial preparation method of hydroxychloroquine sulfate with high purity and high yield
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The invention discloses an industrial preparation method of hydroxychloroquine sulfate with high purity and high yield. The method is mild in reaction condition, an alcohol organic solvent is adopted,reaction is carried out at the temperature of 80-100 DEG C, the reaction temperature is not higher than 100 DEG C, nitrogen protection is not needed, the method is suitable for industrial production,the yield of hydroxychloroquine prepared through the method is larger than or equal to 85%, the purity of hydroxychloroquine is larger than or equal to 99.70%, and the maximum single impurity is smaller than 0.10%. The prepared hydroxychloroquine can be further salified, the purity of the prepared salt is greater than or equal to 99.8%, and the maximum single impurity is less than 0.1%.
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Paragraph 0013-0015; 0019
(2020/09/12)
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- Preparation method of hydroxychloroquine sulfate
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The invention relates to a preparation method of hydroxychloroquine sulfate, and belongs to the technical field of medicine synthesis. According to the preparation method of hydroxychloroquine sulfate, 7-chloro-4-fluoroquinoline and 5-(N-ethyl-N-2-hydroxyethyl amine)-2-pentylamine are subjected to a reaction to prepare hydroxychloroquine, and then hydroxychloroquine and sulfuric acid are salifiedto prepare hydroxychloroquine sulfate. The 7-chloro-4-fluoroquinoline is prepared from 4,7-dichloroquinoline through a halogen exchange reaction. The preparation method of hydroxychloroquine sulfate has the advantages of low reaction temperature, short reaction time, fewer byproducts, simple technique and favorable reproducibility, and is beneficial to industrial production.
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Paragraph 0062; 0065
(2020/07/28)
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- Chiral chloroquine, hydroxychloroquine and derivatives thereof as well as preparation method and application of chiral chloroquine, hydroxychloroquine and derivatives thereof
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The invention belongs to the field of drug synthesis, and discloses a compound with a structure as shown in a formula I (See the specification) and pharmaceutically acceptable salt, tautomer, polymorphic substance, isomer and solvate thereof. Secondly, the invention discloses a method for preparing chiral chloroquine and hydroxychloroquine through chiral high performance liquid chromatography. Finally, the invention discloses application of chiral chloroquine, hydroxychloroquine and salt derivatives thereof in preparation of drugs for treating novel coronavirus pneumonia.
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Paragraph 0178-0183
(2020/09/16)
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- Application of chiral chloroquine, hydroxychloroquine or salt of the chiral chloroquine and hydroxychloroquine as anti-coronavirus drug target 3CL hydrolase inhibitor for reducing cardiotoxicity
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The invention discloses an application of chiral chloroquine, hydroxychloroquine or pharmaceutically acceptable salts of the chiral chloroquine and hydroxychloroquine in preparation of drugs used forpreventing and/or treating coronavirus pneumonia by using a coronavirus key drug target 3CL hydrolase (Mpro) as an action target. The chiral chloroquine and hydroxychloroquine have high bonding strength with the Mpro causing inflammation of the lung and the like; the activity of the Mpro can be significantly inhibited; and the chiral chloroquine and hydroxychloroquine are indicated to have the effect of preventing and treating pneumonia caused by coronaviruses and be able to be used as anti-pneumonia drugs. Through evaluation on the inhibitory activity of an hERG potassium ion channel, the concentration at which the chloroquine, hydroxychloroquine and enantiomers of the chloroquine and hydroxychloroquine are likely to generate cardiotoxicity to the hERG potassium ion channel is provided. The chiral chloroquine and hydroxychloroquine are prepared through chiral high-performance liquid chromatography and chiral synthesis; S-configuration chloroquine, hydroxychloroquine or salts of the chloroquine and hydroxychloroquine can be selected as a drug independently, or form a pharmaceutical composition for treating diseases caused by the coronaviruses; and due to higher activity and low cardiotoxicity of the chloroquine, hydroxychloroquine or salts of the chloroquine and hydroxychloroquine, the administration dosage range is greatly widened.
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Paragraph 0092-0097
(2020/11/02)
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- A preparation method of the sulfuric acid hydroxy chloroquine
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The invention discloses a high purity sulfuric acid hydroxy chloroquine preparation method. The method to the 4, 7 - dichloro quinolinic and hydroxychloroqine side chain as raw materials for directly preparing hydrochloride hydroxychloroqine, then neutralized sodium alcoholate or polysiloxane, filtering the concentrated, beating, crystallization results in the hydroxy chloroquine is collapsed, finally a certain proportion of the pure water solution with sulfuric acid to form the salt obtained by the reaction of sulfuric acid hydroxy chloroquine. The method for production chloroquine process avoids the phenol or its use of the catalyst, the post-processing also avoids the extraction operation, high purity of the product, in the production process the basic waste water is not generated. The invention has simple operation, high yield, make sulfuric acid hydroxy chloroquine HPLC purity of ≥ 99.6%, the largest single impurity ≤ 0.1%, is more suitable for industrial production.
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Paragraph 0028-0042
(2019/02/10)
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- HIGH-YIELDING CONTINUOUS FLOW SYNTHESIS OF ANTIMALARIAL DRUG HYDROXYCHLOROQUINE
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Cost effective, semi-continuous flow methods and systems for synthesizing the antimalarial drug hydroxychloroquine (HCQ) in high yield are provided. The synthesis method that uses simple, inexpensive reagents to obtain the crucial intermediate 5-(ethyl(2-hydroxyethyl)- amino)pentan-2-one, vertical-integration of the starting material 5-iodopentan-2-one and the integration of continuous stirred tank reactors.
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- New preparation method of the sulfuric acid hydroxy chloroquine
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This invention relates to a preparation method of the sulfuric acid hydroxy chloroquine, characterized in that in order to mother nucleus of 4, 7 - dichloro quinolinic as the starting material, with the hydroxychloroqine side chain 5 - (N - ethyl - N - 2 - hydroxy serotonin reuptake) - 2 - pentylamine in presence of catalyst, condensation reaction to obtain hydroxychloroqine free base, with the sulfuric acid to form the salt obtained after the sulfuric acid hydroxy chloroquine. This invention has overcome the disadvantages of the prior art, a bit lies in: reduces the consumption of the side chain, the total yield ≥ 90%, sulfuric acid hydroxy chloroquine yield ≥ 96%, overall yield ≥ 86%, sulfuric acid hydroxy chloroquine purity is greater than 99.7%, [...] less than 0.1%, in accordance with the Pharmacopoeia requirements, reaction time is short, simple and convenient operation, pollution is small, low cost, and is suitable for industrial production.
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Paragraph 0003
(2019/03/28)
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- Hydroxychloroquine synthetic method
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The invention provides a hydroxychloroquine synthetic method, including the steps of mixing 4,7-dichloroquinoline, 2-[(4-aminopentyl)(ethyl)amino]ethanol and N,N-diisopropylethylamine, reacting under protective gas, and after the reaction, performing extraction, concentration and purification to obtain the hydroxychloroquine. By using the synthetic method provided by the invention, N,N-diisopropylethylamine is used as both an acid-binding and a solvent to promote smooth reaction, the amount is small (only theoretical amount), and the consumption is low; the reaction time is short, alkalization is not needed after treatment, the hydroxychloroquine can be obtained by just the operations of extraction and recrystallization, and the operation is simple; the extraction solvent and the recrystallization solvent may be the same solvent, which is beneficial to the recovery and utilization of the solvent, and the production cost is reduced; the total recovery is increased from 45.9% to 74.7%, the product quality is increased from 99.0% to 99.8% or above (HPLC purity), and single impurity being less than or equal to 0.1%.
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Paragraph 0045-0048
(2019/10/10)
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- Preparation method of hydroxychloroquine and sulfate thereof
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The invention discloses a preparation method of hydroxychloroquine and sulfate thereof. The preparation method of the hydroxychloroquine comprises the following steps of step (1), under the inert gasprotection atmosphere, enabling 4,7-dichloroquine and hydroxychloroquine side chain compounds to react at the temperature of 134 to 144 DEG C until the content of 4,7-dichloroquine is smaller than orequal to 10%, so as to obtain a crude product of the hydroxychloroquine, wherein the content of the hydroxychloroquine in the crude product of the hydroxychloroquine is greater than 92%; step (2), recrystallizing the obtained crude product of the hydroxychloroquine in step (1) in a mixed solvent of alcohol solvent and ester solvent, so as to obtain a refined product of the hydroxychloroquine. Thepurity of the refined product of the hydroxychloroquine can reach 99.9%, the maximum content of single impurity is controlled within 0.06%, and the total content of other impurities is smaller than 0.04%.
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Paragraph 0004; 0089-0092; 0099-0105; 0108-0110; 0113-0120
(2018/11/04)
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- Preparing and refining method for hydroxychloroquine and preparation method for sulfate of hydroxychloroquine
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The invention discloses a preparing and refining method for hydroxychloroquine and a preparation method for a sulfate of the hydroxychloroquine. The refining method for the hydroxychloroquine comprises the following steps: performing crystallization on a crude product of the hydroxychloroquine in a mixed solvent of a ketone solvent and an ester solvent to obtain a refined product of the hydroxychloroquine, wherein a content of the hydroxychloroquine in the crude product of the hydroxychloroquine is higher than 92%. According to the method disclosed by the invention, purity of the refined product of the hydroxychloroquine prepared by the method can reach 99.9%, a maximum content of a single impurity is controlled within 0.06%, and a total content of other impurities is lower than 0.04%; andpurity of the hydroxychloroquine sulfate prepared from the hydroxychloroquine can reach 99.8%, and a maximum content of a single impurity is controlled within 0.06%.
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Page/Page column 8-11
(2018/11/03)
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- Hydroxychloroquine sulfate crystal form A and preparation method thereof
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The invention discloses a hydroxychloroquine sulfate crystal form A and a preparation method thereof and uses means of XRPD, DSC and IR for representation. The hydroxychloroquine sulfate crystal formA provided by the invention improves the chemical stability of hydroxychloroquine sulfate, is simple in preparation method and easy in industrialized production and can provide a study foundation to development of more hydroxychloroquine sulfate dosage forms at the same time. In the preparation method provided by the invention, a sulfuric acid aqueous solution with the mass percentage being 40-60percent is used, the safety and the operability are improved, and the heat release risk generated by using concentrated sulfuric acid is effectively lowered.
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Paragraph 0039; 0040
(2018/11/22)
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- A method for preparing sulfuric acid hydroxy chloroquine
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The invention discloses a preparation method of hydroxychloroquine sulfate. The preparation method is characterized by comprising the following steps: condensing 4,7-dichloroquinoline serving as an initial raw material and a hydroxychloroquine side chain under the action of a catalyst, so as to obtain hydroxychloroquine; and reacting hydroxychloroquine with sulfuric acid, so as to prepare the hydroxychloroquine sulfate. According to the method disclosed by the invention, the defects in the prior art are overcome. The method has the advantages that the yield of the prepared hydroxychloroquine sulfate crude product is greater than or equal to 85%, the yield of hydroxychloroquine sulfate is greater than or equal to 94%; the total yield is greater than or equal to 80%; the purity of the prepared hydroxychloroquine sulfate HPLC is greater than or equal to 99.6%; the maximum single impurity is smaller than 0.1%; the method accords with the requirements of United States pharmacopeia, is short in reaction step, and simple in the whole technological operation; and the obtained product is high in quality, high in yield, and relatively suitable for industrial production.
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Paragraph 0015; 0033-0035; 0038-0040; 0052-0054; 0061-0063
(2018/11/03)
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- A sulfuric acid hydroxy chloroquinoline industrial preparation method
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The invention provides an industrial production method for hydroxychloroquine sulfate, which includes the following steps: enabling 4.7-dichloroquinoxaline and 5-(N-ethyl-N-ethoxyl)-2-amino pentane to react under gas shield for 13-24 h at a gradually increased temperature of 120-130 DEG C to obtain hydroxychloroquine; preparing the hydroxychloroquine sulfate after the reaction between the hydroxychloroquine and an alcohol sulfate solution at the temperature of 20-30 DEG C. According to the method, the yield of the obtained crude product of the hydroxychloroquine is not smaller than 85%, the yield of the obtained hydroxychloroquine sulfate is not smaller than 85%, the yield of the obtained hydroxychloroquine sulfate HPLC is not smaller than 99.5%, the yield of single impurity is not larger than 0.1%, so that requirements of United States Pharmacopeia is met; the novel method is simple in procedure, is environment-friendly and easy in industrial production.
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Paragraph 0017; 0033-0040
(2018/07/10)
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- Hydroxychloroqine flax ester and its synthetic method
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The invention discloses a structural formula of hydroxychloroquine linolenate and also provides a method for preparing hydroxychloroquine linolenate. The method comprises the following steps: preparing hydroxychloroquine from hydroxychloroquine sulfate and a sodium hydroxide liquid, and purifying by adding ethyl acetate; adding an organic solvent, a catalyst and a dewatering agent in linolenic acid, then adding the prepared hydroxychloroquine to carry out constant-temperature reaction for 12-24 hours, wherein the mole equivalence ratio of linolenic acid to hydroxychloroquine is (1:1)-(1:1.5); and finally, carrying out column chromatography separation to obtain high-purity hydroxychloroquine linolenate. After lots of hydroxychloroquine linolenate is absorbed by tumor cells, hydroxychloroquine linolenate is metabolized to form hydroxychloroquine, thereby increasing the concentration of focus medicine and reducing medicine dose.
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Paragraph 0028; 0029
(2017/02/23)
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- High molecular weight prodrug derivatives of antiinflammatory drugs
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Compounds of the formula 1, PS - O - A - (CH2)n- B - D (1), wherein PS-O represents an alkoxide residue of any of the free hydroxy groups of a polysaccharide (PS-OH) compound with molecular weight (Mw) of from 40,000 to 5,000,000 selected from dextran, carboxymethyl dextran, diethylaminoethyl dextran, starch, hydroxyet-hyl starch, alginates, glycogen, pullullan, agarose, cellulose, chitosan, chitin and carrageenan,A is a carbonyl group or absent,n is zero or a positive integer from 1 to 14,B is oxygen, a carbonyl group, NR wherein R is hydrogen or lower alkyl, or B is absent, and, D is (i) a group of the formula:, R1 - CO - (11), wherein R1-CO- represents the acyl residue of a carboxylic acid drug (R1-COOH) used in the treatment of inflammatory disorders; or (ii) a group of the formula:, R2 - O - (12), wherein R2-O- refers to the C-21 alkoxide residue of a known antiinflammatory steroid (R2-OH) or an alkoxide residue of any other drug or medicament containing a hydroxy functional group used in the treatment of inflammatory disorders; with the proviso that when A is absent, n is 0, and B is absent, then R1-CO- is different from the acyl residue of acetylsalicylic acid;, and non-toxic pharmaceutically acceptable acid addition salts thereof;, and non-toxic pharmaceutically acceptable cation salts thereof. Such compounds are biolabile prodrugs providing controlled release and prolonged duration of action of the parent active antiinflamma-tory agents locally at the administration site after intra-articular, intra-muscular, subcutaneous or extra-dural application while at the same time being highly stable in aqueous solution in the pH range 3--5. After oral administration of such prodrugs the parent drug is liberated selectively in the terminal ileum and the colon over an extended period of time.
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