WO1990013538A1 - Organic salts of cysteine derivatives - Google Patents

Organic salts of cysteine derivatives Download PDF

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Publication number
WO1990013538A1
WO1990013538A1 PCT/SE1990/000285 SE9000285W WO9013538A1 WO 1990013538 A1 WO1990013538 A1 WO 1990013538A1 SE 9000285 W SE9000285 W SE 9000285W WO 9013538 A1 WO9013538 A1 WO 9013538A1
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WIPO (PCT)
Prior art keywords
salt
cysteine
cysteine derivative
derivative
isobutyryl
Prior art date
Application number
PCT/SE1990/000285
Other languages
French (fr)
Inventor
Jan Anders Lindberg
Jan William Trofast
Original Assignee
Aktiebolaget Draco
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Publication of WO1990013538A1 publication Critical patent/WO1990013538A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton

Definitions

  • the present invention relates to organic salts of new ⁇ ysteine derivatives with anti-inflammatory effect and pharmaceutical compositions containing them and methods for their pharmacological use.
  • the object of the invention is to provide crystalline, non-hygroscopic and chemically stable salts of organic origin of cysteine derivatives useful for inhalation in the treatment of inflammatory diseases mainly in the respiratory tract.
  • N-acetyl-L-cysteine has been used as a therapeutic agent against e.g. chronic bronchitis for over 20 years.
  • a patent with the title "Decongestant Compositions comprising N-acetylated Sulfhydryl Compounds" (GB 954268) was published in 1964.
  • N-acetyl-L- cysteine has a number of applications in the field of medical treatment of humans primarily against obstructive lung disease like chronic bronchitis claimed to act as a mucolytic. The compound has been given both orally and as a nebulized aqueous solution for this purpose.
  • N-butyryl-cysteine is disclosed in DE 1208450 as an ingredient for a hair preparation.
  • EP 92287 describes a water-soluble N-acetylcysteine salt useful as mucolytic or as antidote against acute intoxication with paracetamol.
  • the high doses recommended (100 mg up to 10 g per day) are administrated orally or rectally.
  • US 3,647,834 provides improved compositions of N-acetyl-L- cysteine which are substantially odorless and tasteless and this is especially the case with the zinc mercaptide N-acet ⁇ lcysteine carboxylates. Only inorganic salts are exemplified.
  • Salt-forming agents are often chosen empirically. Choosing the appropriate salt, however, can be a very difficult task, since each salt imparts unique properties to the parent compound. No efficient screening techniques exist to facilitate selection of the salt most likely to exhibit the desired pharmacokinetic profile, solubility, stability and crystal properties necessary for a suitable formulation.
  • the present invention concerns a compound of the formula:
  • R is -CH(CH 3 ) 2 or -C(CH.,)- j and is a counterion of organic origin.
  • the organic salts are prepared from a cysteine derivative and an organic compound such as arginine, lysine, histidine, ethanolamine, diethanolamine, ethylenediamine, choline and the like in a salt-forming reaction. It was unexpected that these salts were non- amorphous and non-hygroscopic compared to the inorganic salts often used for N-acetyl-L-cysteine.
  • the salts of the organic compounds mentioned thus show the basic requirements for ease of crystallization, non- hygroscopicity, chemical stability and flowability of the resulting micronized cysteine derivative.
  • the new cysteine derivative according to formula I is much less efficiently metabolized. This leads to a superior bio- availability of the new cysteine derivative.
  • Amorphous inorganic salts of both N-acetyl-L-cysteine and N-isobutyryl-L-cysteine are useless in dry powder inhala ⁇ tion devices due to their hygroscopicity, instability and difficulties in preparation of suitable formulations. Many inorganic cations must be avoided because of physiological reasons.
  • the organic salts of the cysteine derivatives are generally prepared by mixing the cysteine derivative with the organic base dissolved or partly dissolved in a solvent or solvent mixture.
  • solvents used in these reactions are water, alcohols, glycols, ketones, dimethyl-formamide, dimethylsulfoxid or other polar solvents or mixtures thereof.
  • the salts are precipitated by adding a more lipophilic solvent or solvent mixture or by evaporation or lyophilization of the solvents used.
  • the reaction could be performed at temperatures from -5° to +100°C but preferably at 20° to 30°C and preferably in an inert atmosphere.
  • N-acetyl-L-cysteine Since the compounds of the formula I have similar or identical potentials as N-acetyl-L-cysteine to 1) break disulphide bridges, 2) act as antioxidants and 3) act as radical scavengers, local treatment with the new substances should be much more effective than N-acetyl-L- cysteine against diseases in the respiratory tract, provided that the disease is caused or maintained by some sort of oxidative stress.
  • the invention thus provides compounds and isomers thereof, which are useful in the therapeutic treatment of inflamma ⁇ tory lung disease, such as chronic bronchitis, and
  • lung injury diseases like septic shock, ARDS and bronchopulmonary dysplasia
  • R and M are the same as given above.
  • the compounds of the formula I as their organic salts will be administered by inhalation with or without a pharmaceutically acceptable carrier.
  • the medicament is inhaled from a pressurized metered dose inhaler, from a dry powder inhaler, e.g. Turbuhaler*- or from a dry powder inhaler utilizing gelatine, plastic or other capsules.
  • a diluent carrier generally being non- toxic and chemically inert to the medicament, e.g. lactose, trehalose, mannitol or glucose, can be added to the powdered medicament.
  • Suitable daily doses of the pharmacologically active compounds of the invention in therapeutical treatment of humans are 1 to 20 mg.
  • One object of the invention is to provide molecules which after inhalation would give high levels of free thiols in the target organ. Therefore, experiments were performed to investigate biological stability and bioavailability of the compounds of formula I, and to compare these with N-acetyl-L-cysteine.
  • N-acetyl-L-cysteine was rapidly hydrolyzed to yield L-cysteine in homogenates of liver, intestinal mucosa, and lung from rat.
  • N-isobutyryl-L-cysteine and N-pivaloyl-L- cysteine were not hydrolyzed to any measureable extent in vitro.
  • the particle size of the dry powder formulations are depending on the location of desired deposition in the respiratory tract.
  • the particle size mostly preferred is often below 10 ⁇ m, thereby making a micronization step necessary.
  • a pressurized metered dose inhaler (containing 10 ml) has the following composition:
  • the ethylenediamine salt of the cysteine derivatives was weighed into a 10 ml aluminium-container.
  • a chilled propellant mixture (propellant 11 and propellant 12) containing Span 85 was added to the container.
  • a 100 ⁇ l metering valve was immediately crimped on the container. To allow a good suspension of the solid the metered dose inhaler was put into a sonicating bath for a few minutes.
  • a combination, containing a carrier (here exemplified with lactose) , to be inhaled from a dry powder inhaler utilizing gelatine, plastic or other capsules has the following composition in each capsule:
  • the active drug and the carrier were mixed in a planetary or other stirring mixer and weighed into gelatine, plastic or other kind of capsules.
  • the pure nonhygroscopic salt of the new cysteine derivatives e.g. N-isobutyryl-L-cysteine is weighed into the substance magazine in a device like the Turbuhaler . Each dose is between 1 and 5 mg.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicinal Preparation (AREA)

Abstract

A salt of a cysteine derivative of formula (I), wherein R is -CH(CH3)2 or -C(CH3)3 or an optical isomer thereof and M is a counterion of organic origin useful for the treatment of inflammatory diseases mainly in the respiratory tract.

Description

ORGANIC SALTS OF CYSTKINE DERIVATIVES
Description of the invention
The present invention relates to organic salts of new σysteine derivatives with anti-inflammatory effect and pharmaceutical compositions containing them and methods for their pharmacological use.
The object of the invention is to provide crystalline, non-hygroscopic and chemically stable salts of organic origin of cysteine derivatives useful for inhalation in the treatment of inflammatory diseases mainly in the respiratory tract.
Background art
N-acetyl-L-cysteine has been used as a therapeutic agent against e.g. chronic bronchitis for over 20 years. A patent with the title "Decongestant Compositions comprising N-acetylated Sulfhydryl Compounds" (GB 954268) was published in 1964. N-acetyl-L- cysteine has a number of applications in the field of medical treatment of humans primarily against obstructive lung disease like chronic bronchitis claimed to act as a mucolytic. The compound has been given both orally and as a nebulized aqueous solution for this purpose.
N-butyryl-cysteine is disclosed in DE 1208450 as an ingredient for a hair preparation.
EP 92287 describes a water-soluble N-acetylcysteine salt useful as mucolytic or as antidote against acute intoxication with paracetamol. The high doses recommended (100 mg up to 10 g per day) are administrated orally or rectally.
US 3,647,834 provides improved compositions of N-acetyl-L- cysteine which are substantially odorless and tasteless and this is especially the case with the zinc mercaptide N-acetγlcysteine carboxylates. Only inorganic salts are exemplified.
Disclosure of the invention
Salt-forming agents are often chosen empirically. Choosing the appropriate salt, however, can be a very difficult task, since each salt imparts unique properties to the parent compound. No efficient screening techniques exist to facilitate selection of the salt most likely to exhibit the desired pharmacokinetic profile, solubility, stability and crystal properties necessary for a suitable formulation.
The present invention concerns a compound of the formula:
Figure imgf000004_0001
wherein R is -CH(CH3)2 or -C(CH.,)-j and is a counterion of organic origin. The organic salts are prepared from a cysteine derivative and an organic compound such as arginine, lysine, histidine, ethanolamine, diethanolamine, ethylenediamine, choline and the like in a salt-forming reaction. It was unexpected that these salts were non- amorphous and non-hygroscopic compared to the inorganic salts often used for N-acetyl-L-cysteine. The salts of the organic compounds mentioned thus show the basic requirements for ease of crystallization, non- hygroscopicity, chemical stability and flowability of the resulting micronized cysteine derivative. Compared to N- acetyl-L-cysteine the new cysteine derivative according to formula I is much less efficiently metabolized. This leads to a superior bio- availability of the new cysteine derivative. By high bio- avaliability combined with local administration directly to the respiratory tract a high local disposition is obtained using minimal doses and thereby reducing the systemic circulation. It is impossible to administer the cysteine derivative itself due to its strong acidity. Amorphous inorganic salts of both N-acetyl-L-cysteine and N-isobutyryl-L-cysteine are useless in dry powder inhala¬ tion devices due to their hygroscopicity, instability and difficulties in preparation of suitable formulations. Many inorganic cations must be avoided because of physiological reasons.
The organic salts of the cysteine derivatives are generally prepared by mixing the cysteine derivative with the organic base dissolved or partly dissolved in a solvent or solvent mixture. Example of solvents used in these reactions are water, alcohols, glycols, ketones, dimethyl-formamide, dimethylsulfoxid or other polar solvents or mixtures thereof.
After the reaction is complete the salts are precipitated by adding a more lipophilic solvent or solvent mixture or by evaporation or lyophilization of the solvents used.
The reaction could be performed at temperatures from -5° to +100°C but preferably at 20° to 30°C and preferably in an inert atmosphere.
Since the compounds of the formula I have similar or identical potentials as N-acetyl-L-cysteine to 1) break disulphide bridges, 2) act as antioxidants and 3) act as radical scavengers, local treatment with the new substances should be much more effective than N-acetyl-L- cysteine against diseases in the respiratory tract, provided that the disease is caused or maintained by some sort of oxidative stress.
It must also be pointed out, that another consequence of the biological stability of the compounds of formula I is that very little, if any, L-cysteine will be liberated. This means that these compounds will give rise to only very low levels of glutathione precursors. Therefore, the effects on the oxygen toxicity system described below are likely to be dependent on the synthetic thiols themselves, and not on glutathione biosynthesis.
The invention thus provides compounds and isomers thereof, which are useful in the therapeutic treatment of inflamma¬ tory lung disease, such as chronic bronchitis, and
1) other lung diseases complicated by viscous mucus like cystic fibrosis, asthma and emphysema,
2) lung injury diseases like septic shock, ARDS and bronchopulmonary dysplasia,
3) diseases caused by radiation like gamma ray induced pneumatitis and fibrosis, and
4) diseases in the lung parenchyma like sarcoidosis, fibrosis, granulomatosis, collagenosis.
The compounds of the formula I exist in two different optical forms, L and D isomers:
Figure imgf000006_0001
which both are included in this invention. R and M are the same as given above.
Pharmaceutical formulations
According to the present invention the compounds of the formula I as their organic salts will be administered by inhalation with or without a pharmaceutically acceptable carrier.
The medicament is inhaled from a pressurized metered dose inhaler, from a dry powder inhaler, e.g. Turbuhaler*- or from a dry powder inhaler utilizing gelatine, plastic or other capsules. A diluent carrier, generally being non- toxic and chemically inert to the medicament, e.g. lactose, trehalose, mannitol or glucose, can be added to the powdered medicament.
Suitable daily doses of the pharmacologically active compounds of the invention in therapeutical treatment of humans are 1 to 20 mg.
It has thus been possible to circumvent the problems of low stability and amorphous forms of prior art and to obtain a single, useful and effective preparation of salts of the new cysteine derivatives with high bioavailability that can be used in dry powder formulations in the treat¬ ment of different inflammatory diseases in the respiratory tract.
Metabolic Experiments
One object of the invention is to provide molecules which after inhalation would give high levels of free thiols in the target organ. Therefore, experiments were performed to investigate biological stability and bioavailability of the compounds of formula I, and to compare these with N-acetyl-L-cysteine.
N-acetyl-L-cysteine was rapidly hydrolyzed to yield L-cysteine in homogenates of liver, intestinal mucosa, and lung from rat. N-isobutyryl-L-cysteine and N-pivaloyl-L- cysteine were not hydrolyzed to any measureable extent in vitro.
Working examples
The invention is illustrated but not limited by the following examples:
Example 1
Preparation of lysine salt of N-isobutyryl-L-cysteine
To a stirred mixture of 1.64 g (10 mmole) lysine monohydrate and 12 ml water/methanol (2:8, v/v) was added 1.91 g (10 mmole) N-isobutyryl-L-cysteine. pH of the solution was 8. After stirring further for 1 hr, the solvent was evaporated to dryness: Recrystallization in water/ethanol (4:96) v/v) gave 1.8 g of the lysine salt of N-isobutyryl-L-cysteine.
NMR (δ, ppm; D20, ref. = sodium 3-trimethyl-silyl- tetradeuteropropionate) 1.12 (d,3H), 1.14 (d,3H), 3.01 (t,2H), 3.75 (lH,t), 4.37 (lH,t).
Example 2
Preparation of the ethylenediamine salt of N-isobutyryl-L- cysteine
To a stirred mixture of 9.55 g (50 mmole) N-isobutyryl-L- cysteine and water/ethanol (4:96, v/v) was added 1.5 g
(25 mmole) ethylenediamine. pH of the solution was 7. Work up procedure as in example 1 gave after recrystallization in acetonitrile 5.5 g of the ethylenediamine salt (1:2) of N-isobutyryl-L-cysteine.
NMR (6, ppm; D20, ref. = sodium 3-trimethγl-silyl- tetradeuteropropionate) 1.12 (3H,d),.1.14 (3H,d), 3.36 (2H,s), 4.37 (lH,t).
Example 3
Preparation of the diethanolamine salt of N-isobutyryl-L- cysteine
To a stirred mixture of 9.55 g (50 mmole) N-isobutyryl-L- cysteine in ethanol/water (96:4, v/v) was added 5.25 g (50 mmole) diethanolamine. After stirring further for 1 hr, the salt was precipitated by adding acetone, filtered and dried (6.5 g) .
NMR (δ, ppm; D20, ref. = sodium 3-trimethyl-silyl- tetradeuteropropionate) 1.14 (3H,d), 1.15 (3H,d), 3.25 (2H,m), 3.88 (2H,m), 4.39 (lH,t).
Examples of pharmaceutical preparations
The particle size of the dry powder formulations are depending on the location of desired deposition in the respiratory tract. The particle size mostly preferred is often below 10 μm, thereby making a micronization step necessary.
Example A
A pressurized metered dose inhaler (containing 10 ml) has the following composition:
Ethylenediamine salt (1:2) of N-isobutyryl- L-cysteine 10 mg/ml Span 85 (sorbitan trioleate) 7 mg/ml
Propellant 11 (CC13F)/Propellant 12
(CC12F) (15/85) q.s.
The ethylenediamine salt of the cysteine derivatives was weighed into a 10 ml aluminium-container. A chilled propellant mixture (propellant 11 and propellant 12) containing Span 85 was added to the container. A 100 μl metering valve was immediately crimped on the container. To allow a good suspension of the solid the metered dose inhaler was put into a sonicating bath for a few minutes.
Example B
A combination, containing a carrier (here exemplified with lactose) , to be inhaled from a dry powder inhaler utilizing gelatine, plastic or other capsules has the following composition in each capsule:
Ethylenediamine salt (1:2) of N-isobutyryl- L-cysteine 3 mg Lactose 12 mg
The active drug and the carrier were mixed in a planetary or other stirring mixer and weighed into gelatine, plastic or other kind of capsules.
Example C
The pure nonhygroscopic salt of the new cysteine derivatives e.g. N-isobutyryl-L-cysteine is weighed into the substance magazine in a device like the Turbuhaler . Each dose is between 1 and 5 mg.

Claims

1. A salt of a cysteine derivative characterized by the general formula
HS .COOM
CH2 CH
"^NHCO-R
wherein R is -CH(CH3)2 or -C(CH3)3 or an optical isomer' thereof and M is a counterion of organic origin.
2. A salt of a cysteine derivative as claimed in claim 1 characterized in that the group M is derived from arginine, lysine, histidine, ethanolamine, diethanolamine, ethylenediamine or choline.
3. A salt of a cysteine derivative as claimed in claim 1, characterized in that it is the lysine salt of N- isobutγryl-L-cysteine.
4. A salt of a cysteine derivative as claimed in claim 1 characterized in that it is the ethylenediamine salt of N-isobutyryl-L-cysteine.
5. A salt of a cysteine derivative as claimed in claim 1 characterized in that it is the diethanolamine salt of N- isobutyryl-L-cysteine.
6. A process for preparing a salt of a cysteine derivative as claimed in any of claims 1 to 5, characterized in that a cysteine derivative of the formula
Figure imgf000011_0001
or an optical isomer thereof and wherein R is defined as in claim 1, is mixed with a dissolved or partly dissolved organic base, such as arginine, lysine, histidine, ethanolamine, diethanolamine, ethylendiamine or choline, whereafter the salts are obtained by.precipitation.
7. A pharmaceutical composition comprising as active ingredient a salt of a cysteine derivative or an optical isomer thereof as claimed in any of claims 1 to 5.
8. A pharmaceutical composition as claimed in claim 7 characterized in that it is administered from a pressurized metered dose inhaler or from a dry powder inhaler.
9. A method for the treatment of inflammatory diseases in mammals, including man, characterized by the administration to a host in the need of such treatment of an effective amount a salt of a cysteine derivative or an optical isomer thereof as claimed in any of claims 1-5.
10. A salt of a cysteine derivative as claimed in any of claims 1-5 for use as a drug.
11. Use of a salt of a cysteine derivative as claimed in any of claims 1-5 for the preparation of medicaments with action against inflammatory diseases.
PCT/SE1990/000285 1989-05-02 1990-04-27 Organic salts of cysteine derivatives WO1990013538A1 (en)

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SE8901570A SE8901570D0 (en) 1989-05-02 1989-05-02 ORGANIC SALTS OF CYSTEINE DERIVATIVES

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017212249A1 (en) * 2016-06-07 2017-12-14 Novabiotics Limited Microparticles comprising a sulphur-containing compound
US10905660B2 (en) 2016-06-07 2021-02-02 Novabiotics Limited Microparticles
RU2780397C2 (en) * 2016-06-07 2022-09-22 НоваБиотикс Лимитед Microparticles containing sulfur-containing compounds
IL263540B1 (en) * 2016-06-07 2023-03-01 Novabiotics Ltd Microparticles comprising a sulphur-containing compound

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB954268A (en) * 1962-02-26 1964-04-02 Mead Johnson & Co Decongestant compositions comprising n-acylated sulphydryl compounds
DE1208450B (en) * 1963-08-13 1966-01-05 Mead Johnson & Co Preparations for shaping human hair
FR2503151A1 (en) * 1981-04-02 1982-10-08 Morelle Jean Compsns. contg. N-butyryl alpha-aminoacid(s) - for cosmetic, hygienic, therapeutic or agricultural use
EP0092287A2 (en) * 1982-04-19 1983-10-26 "PHARLYSE", Société Anonyme Acetylcysteine salts, their preparation and use
EP0304017A2 (en) * 1987-08-21 1989-02-22 Degussa Aktiengesellschaft Process for the preparation of N-acetyl cystein salts
EP0317540A1 (en) * 1987-11-19 1989-05-24 Aktiebolaget Draco Cysteine derivatives, processes for their preparation and their use

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB954268A (en) * 1962-02-26 1964-04-02 Mead Johnson & Co Decongestant compositions comprising n-acylated sulphydryl compounds
DE1208450B (en) * 1963-08-13 1966-01-05 Mead Johnson & Co Preparations for shaping human hair
FR2503151A1 (en) * 1981-04-02 1982-10-08 Morelle Jean Compsns. contg. N-butyryl alpha-aminoacid(s) - for cosmetic, hygienic, therapeutic or agricultural use
EP0092287A2 (en) * 1982-04-19 1983-10-26 "PHARLYSE", Société Anonyme Acetylcysteine salts, their preparation and use
EP0304017A2 (en) * 1987-08-21 1989-02-22 Degussa Aktiengesellschaft Process for the preparation of N-acetyl cystein salts
EP0317540A1 (en) * 1987-11-19 1989-05-24 Aktiebolaget Draco Cysteine derivatives, processes for their preparation and their use

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017212249A1 (en) * 2016-06-07 2017-12-14 Novabiotics Limited Microparticles comprising a sulphur-containing compound
CN109310654A (en) * 2016-06-07 2019-02-05 诺瓦生命科学有限公司 Particle comprising sulfur-containing compound
JP2019517541A (en) * 2016-06-07 2019-06-24 ノバビオティクス・リミテッドＮｏｖａｂｉｏｔｉｃｓ Ｌｉｍｉｔｅｄ Microparticles Containing Sulfur-Containing Compounds
US10905660B2 (en) 2016-06-07 2021-02-02 Novabiotics Limited Microparticles
US11369568B2 (en) 2016-06-07 2022-06-28 Novabiotics Limited Microparticles comprising a sulphur-containing compound
AU2017277897B2 (en) * 2016-06-07 2022-09-08 Novabiotics Limited Microparticles comprising a sulphur-containing compound
RU2780397C2 (en) * 2016-06-07 2022-09-22 НоваБиотикс Лимитед Microparticles containing sulfur-containing compounds
IL263540B1 (en) * 2016-06-07 2023-03-01 Novabiotics Ltd Microparticles comprising a sulphur-containing compound
IL263540B2 (en) * 2016-06-07 2023-07-01 Novabiotics Ltd Microparticles comprising a sulphur-containing compound

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