GB2552728A9 - Non-effervescent granulates containing N-acetylcysteine - Google Patents
Non-effervescent granulates containing N-acetylcysteine Download PDFInfo
- Publication number
- GB2552728A9 GB2552728A9 GB1701787.2A GB201701787A GB2552728A9 GB 2552728 A9 GB2552728 A9 GB 2552728A9 GB 201701787 A GB201701787 A GB 201701787A GB 2552728 A9 GB2552728 A9 GB 2552728A9
- Authority
- GB
- United Kingdom
- Prior art keywords
- weight
- acetylcysteine
- maltodextrin
- effervescent
- flavour
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
- 239000008187 granular material Substances 0.000 title claims abstract description 62
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 title claims abstract description 45
- 229960004308 acetylcysteine Drugs 0.000 title claims abstract description 34
- 239000000203 mixture Substances 0.000 claims abstract description 23
- 229920002774 Maltodextrin Polymers 0.000 claims abstract description 22
- 239000005913 Maltodextrin Substances 0.000 claims abstract description 22
- 229940035034 maltodextrin Drugs 0.000 claims abstract description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000000796 flavoring agent Substances 0.000 claims abstract description 18
- 239000004376 Sucralose Substances 0.000 claims abstract description 17
- 235000019408 sucralose Nutrition 0.000 claims abstract description 17
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims abstract description 17
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 10
- 229930195725 Mannitol Natural products 0.000 claims abstract description 10
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 10
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims abstract description 10
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 10
- 235000003599 food sweetener Nutrition 0.000 claims abstract description 10
- 239000000594 mannitol Substances 0.000 claims abstract description 10
- 235000010355 mannitol Nutrition 0.000 claims abstract description 10
- 239000003765 sweetening agent Substances 0.000 claims abstract description 10
- 150000005846 sugar alcohols Polymers 0.000 claims abstract description 5
- YTKBWWKAVMSYHE-OALUTQOASA-N (3s)-3-[3-(3-hydroxy-4-methoxyphenyl)propylamino]-4-[[(2s)-1-methoxy-1-oxo-3-phenylpropan-2-yl]amino]-4-oxobutanoic acid Chemical compound C([C@@H](C(=O)OC)NC(=O)[C@H](CC(O)=O)NCCCC=1C=C(O)C(OC)=CC=1)C1=CC=CC=C1 YTKBWWKAVMSYHE-OALUTQOASA-N 0.000 claims abstract description 3
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims abstract description 3
- 239000004394 Advantame Substances 0.000 claims abstract description 3
- 108010011485 Aspartame Proteins 0.000 claims abstract description 3
- 235000005979 Citrus limon Nutrition 0.000 claims abstract description 3
- 244000131522 Citrus pyriformis Species 0.000 claims abstract description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims abstract description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims abstract description 3
- 235000016623 Fragaria vesca Nutrition 0.000 claims abstract description 3
- 240000009088 Fragaria x ananassa Species 0.000 claims abstract description 3
- 235000011363 Fragaria x ananassa Nutrition 0.000 claims abstract description 3
- 235000007265 Myrrhis odorata Nutrition 0.000 claims abstract description 3
- 108010093901 N-(N-(3-(3-hydroxy-4-methoxyphenyl) propyl)-alpha-aspartyl)-L-phenylalanine 1-methyl ester Proteins 0.000 claims abstract description 3
- 239000004384 Neotame Substances 0.000 claims abstract description 3
- 240000004760 Pimpinella anisum Species 0.000 claims abstract description 3
- 235000012550 Pimpinella anisum Nutrition 0.000 claims abstract description 3
- 244000018633 Prunus armeniaca Species 0.000 claims abstract description 3
- 235000009827 Prunus armeniaca Nutrition 0.000 claims abstract description 3
- 244000228451 Stevia rebaudiana Species 0.000 claims abstract description 3
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims abstract description 3
- 235000010358 acesulfame potassium Nutrition 0.000 claims abstract description 3
- 229960004998 acesulfame potassium Drugs 0.000 claims abstract description 3
- 239000000619 acesulfame-K Substances 0.000 claims abstract description 3
- 235000019453 advantame Nutrition 0.000 claims abstract description 3
- 239000000605 aspartame Substances 0.000 claims abstract description 3
- 235000010357 aspartame Nutrition 0.000 claims abstract description 3
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims abstract description 3
- 229960003438 aspartame Drugs 0.000 claims abstract description 3
- 239000000832 lactitol Substances 0.000 claims abstract description 3
- 235000010448 lactitol Nutrition 0.000 claims abstract description 3
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 claims abstract description 3
- 229960003451 lactitol Drugs 0.000 claims abstract description 3
- 239000000845 maltitol Substances 0.000 claims abstract description 3
- 235000010449 maltitol Nutrition 0.000 claims abstract description 3
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims abstract description 3
- 229940035436 maltitol Drugs 0.000 claims abstract description 3
- 229960001855 mannitol Drugs 0.000 claims abstract description 3
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims abstract description 3
- 235000019412 neotame Nutrition 0.000 claims abstract description 3
- HLIAVLHNDJUHFG-HOTGVXAUSA-N neotame Chemical compound CC(C)(C)CCN[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 HLIAVLHNDJUHFG-HOTGVXAUSA-N 0.000 claims abstract description 3
- 108010070257 neotame Proteins 0.000 claims abstract description 3
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 claims abstract description 3
- 235000019204 saccharin Nutrition 0.000 claims abstract description 3
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229940081974 saccharin Drugs 0.000 claims abstract description 3
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 claims abstract description 3
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 3
- 239000000600 sorbitol Substances 0.000 claims abstract description 3
- 229960002920 sorbitol Drugs 0.000 claims abstract description 3
- 235000010356 sorbitol Nutrition 0.000 claims abstract description 3
- 239000000454 talc Substances 0.000 claims abstract description 3
- 229910052623 talc Inorganic materials 0.000 claims abstract description 3
- 239000000811 xylitol Substances 0.000 claims abstract description 3
- 235000010447 xylitol Nutrition 0.000 claims abstract description 3
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims abstract description 3
- 229960002675 xylitol Drugs 0.000 claims abstract description 3
- 239000007968 orange flavor Substances 0.000 claims description 15
- 235000019634 flavors Nutrition 0.000 claims description 8
- 235000021311 artificial sweeteners Nutrition 0.000 claims description 2
- 235000021096 natural sweeteners Nutrition 0.000 claims description 2
- 239000007967 peppermint flavor Substances 0.000 claims description 2
- 244000246386 Mentha pulegium Species 0.000 abstract 1
- 235000016257 Mentha pulegium Nutrition 0.000 abstract 1
- 235000004357 Mentha x piperita Nutrition 0.000 abstract 1
- 235000001050 hortel pimenta Nutrition 0.000 abstract 1
- -1 orange flavouring Substances 0.000 abstract 1
- 229920005862 polyol Polymers 0.000 abstract 1
- 150000003077 polyols Chemical class 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 229910002016 Aerosil® 200 Inorganic materials 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000001674 Agaricus brunnescens Nutrition 0.000 description 1
- 241000134916 Amanita Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 208000002064 Dental Plaque Diseases 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000005374 Poisoning Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000027032 Renal vascular disease Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000000510 mucolytic effect Effects 0.000 description 1
- 208000012237 paracetamol poisoning Diseases 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 208000015670 renal artery disease Diseases 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
Classifications
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/12—Mucolytics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Biophysics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Pulmonology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
A non-effervescent granulate containing N-acetylcysteine and maltodextrin is disclosed. The composition also comprises a gliding agent selected from fumed colloidal silicon dioxide, precipitated silica, and talc; a flavouring agent selected from orange, lemon, peppermint, anise, apricot or strawberry; and a sweetener chosen from aspartame, saccharin, acesulfame potassium, sucralose, stevia, advantame or neotame. A polyalcohol may also be included and is selected from sorbitol, xylitol, mannitol, maltitol and lactitol. In a preferred embodiment, the composition comprises at least 30 wt% N-acetylcysteine, at least 30 wt% maltodextrin, orange flavouring, sucralose (as sweetener), colloidal silicon dioxide (as gliding agent) and mannitol (as polyol).
Description
TITLE
Non-effervescent granulates containing N-acetylcysteine
DESCRIPTION
The present invention relates to a pharmaceutical composition in the form of a noneffervescent granulate containing N-acetylcysteine and, more in particular, a pharmaceutical composition in the form of a non-effervescent granulate containing N-acetylcysteine and maltodextrin.
N-acetylcysteine, commonly known as NAC, is a synthetic modified N-acetylated aminoacid, used for years as mucolytic active ingredient.
NAC is also used in different doses and formulations for treating paracetamol poisoning, amanita and other mushrooms poisoning, muco-viscidosis, dry eye syndrome, dental plaque, skin diseases and other pathologies.
EP 2 558 065 A1, in the name of the applicant, discloses stable effervescent formulations containing NAC and sucralose.
One of the main problem bound to the formulation of NAC, in particular as a granulate, is to provide a composition that is stable, both from a chemical and physical point of view.
The problem of stability is more evident when effervescent granulates of NAC are stored for a long time especially at high room temperatures, as often happens in summer, or in regions where the climate is constantly warm.
In fact, in effervescent granulates when heated over 40 °C, the sodium bicarbonate present in the formulation starts to react, releasing CO2 and water. In these conditions, the stabilities of the effervescent granulate and of NAC decrease.
Moreover, effervescent granulates contain a lot of sodium or potassium sourced from the carbonate or bicarbonate used for effervescence, that is not indicated for some patients affected by renal or cardiovascular diseases.
Another problem in the formulation of NAC as a granulate is to provide a granulate that has a good flowability and which is in particular free flowing, allowing to prepare sachets containing the granulate, showing a regularity of weight.
Moreover, there is the need of a granulate containing NAC having a reduced volume (i.e. bulk and tapped density), so as to be easily filled in sachets.
There is therefore the need of a stable granulate containing NAC that solves all the above mentioned technical problems.
-2The inventors of the present application have surprisingly found that noneffervescent granulates containing N-acetylcysteine and maltodextrin are very stable both from a physical and chemical point of view, have a good flowability and reduced volume and present therefore many advantages from a pharmaceutical technology formulation point of view.
It is therefore object of the present invention a non-effervescent granulate comprising:
- at least 30% by weight of N-acetylcysteine,
- at least 30% by weight of maltodextrin,
- a gliding agent,
- a sweetener,
- a flavouring agent, wherein the weight ratio between N-acetylcysteine and maltodextrin is from about 0.8 to about 1.2.
The non-effervescent granulates of the present invention can contain 600 mg of NAC with a total weight of about 1.3 - 2.0 g and have an increased stability compared to the effervescent granulates containing the same amount of NAC known in the art, as it can be appreciated in the experimental part.
The characterizing feature of the non-effervescent granulate according to the present invention is the weight ratio between N-acetylcysteine and maltodextrin which is from about 0.8 to about 1.2.
Preferably the weight ratio between N-acetylcysteine and maltodextrin is from about 0.9 to about 1 and it is more preferably 0.9.
A gliding agent according to the present invention can be fumed colloidal silicon dioxide, known with the trade name of Aerosil® 200, or precipitated silica known with the trade name of Syloid®, or talc, preferably the gliding agent is fumed colloidal silicon dioxide.
A sweetener according to the present invention can be any artificial or natural sweetener conventionally used in pharmaceutical technology, such as aspartame, saccharin, acesulfame potassium, sucralose, stevia, advantame, neotame, preferably the sweetener is sucralose.
A flavouring agent according to the present invention can be any flavouring agent conventionally used in pharmaceutical technology, such as orange flavour, lemon flavour, peppermint flavour, anise flavour, apricot flavour, strawberry flavour,
-3preferably the flavouring agent is orange flavour, in particular Orange flavor Sensient 00285.
According to another embodiment of the present invention, the non-effervescent granulate can optionally further comprise a polyalcohol preferably selected among sorbitol, xylitol, mannitol, maltitol, lactitol, more preferably mannitol.
According to a preferred embodiment of the present invention the non-effervescent granulate comprises N-acetylcysteine in an amount of about 30-45% by weight and maltodextrin in an amount of about 33-50% by weight.
A non-effervescent granulate comprising:
- 30-45% by weight of N-acetylcysteine,
- 33-50% by weight of maltodextrin,
- 0.1-0.5% by weight of a gliding agent,
- 2-6% by weight of a flavouring agent,
- 0.7-2% by weight of a sweetener is a further preferred object of the present invention.
The non-effervescent granulate according to the present invention can be prepared according to conventional techniques of granulation that will be illustrated in detail in the experimental section.
Specific examples of particularly preferred non-effervescent granulate have the following quantitative composition (in brackets percentages by weight):
| N-acetylcysteine 600 mg (44.78%) Maltodextrin 660 mg (49.25%) Orange flavour 60 mg (4.48%) Sucralose 18 mg (1.34%) Colloidal silicon dioxide 2 mg (0.15%) Total weight 1340 mg | |
| and | N-acetylcysteine 600 mg (30.00%) Maltodextrin 660 mg (33.00%) Mannitol 660 mg (33.00%) Orange flavour 60 mg (3.00%) Sucralose 18 mg (0.90%) Colloidal silicon dioxide 2 mg (0.10%) Total weight 2000 mg |
-4In order to better illustrate the invention, without however limiting it, the following examples are now given.
Example 1
Preparation of a non-effervescent granulate
| Components | Composition per sachet mg | Composition per batch of Kg 134 Kg |
| N-Acetylcysteine | 600 | 60 |
| Maltodextrin | 660 | 66 |
| Orange flavor Sensient 00285 | 60 | 6 |
| Sucralose | 18 | 1.8 |
| Aerosil 200 | 2 | 0.2 |
| Total weight | 1340 | 134 |
In a fluid bed granulator as Aeromatic S6 Kg 60 of N-acetylcysteine, Kg 66 of maltodextrin, Kg 1.8 of sucralose and Kg 6 of orange flavour were placed.
The mixture was granulated with Kg 6 of purified water and then dried at 60 °C until the granulate relative humidity (RH) was below 0.5%.
At the end of process, the granulate was blended for 15 minutes in a cube mixer as a Zanchetta bin blender together with Kg 0.2 of Aerosyl 200.
Using an industrial equipment as Marchesini RC 600 filing machine, sachets were filled with mg 1340 of granulate in order to get mg 600 of N-acetylcysteine in each sachet.
Non-effervescent granulate characteristics:
| Granulate appearance | White to yellowish granules without foreign bodies |
| Particle size | 90% less than 500 pm 50% less than 250 pm |
| Bulk density | 0.7 |
| Tapped density | 0.8 |
| Flowability as angle of repose | 34° |
-5Comparative example 2
Preparation of an effervescent granulate
| Components | Composition per sachet mg | Composition per batch of Kg 150 Kg |
| N-Acetylcysteine | 600 | 60 |
| Sodium Bicarbonate | 420 | 42 |
| Citric acid | 400 | 40 |
| Orange flavor Sensient 00285 | 70 | 7 |
| Sucralose | 10 | 1.0 |
| Total weight | 1500 | 150 |
In a fluid bed granulator Aeromatic S6, Kg 60 of N-acetylcysteine, Kg 40 of citric acid, Kg 42 of sodium bicarbonate, Kg 7 of orange flavour and Kg 1 of sucralose were placed.
The mixture was granulated with Kg 6 of purified water and then dried at 60 °C until the granulate relative humidity (RH) was below 0.5%.
At the end of process, the granulate was blended for 15 minutes in a cube mixer as a Zanchetta bin blender.
Using an industrial equipment as Marchesini RC 600 filing machine, sachets were filled with mg 1500 of granulate in order to get mg 600 of N-acetylcysteine in each sachet.
Effervescent granulate characteristics:
| Granulate appearance | White to yellowish granules without foreign bodies |
| Particle size | 90% less than 530 pm 50% less than 250 pm |
| Bulk density | 0.87 |
| Tapped density | 0.96 |
| Flowability as angle of repose | 34° |
-6Example 3
Preparation of a non-effervescent granulate
| Components | Composition per sachet mg | Composition per batch of Kg 134 Kg |
| N-Acetylcysteine | 600 | 60 |
| Maltodextrin | 660 | 66 |
| Mannitol | 660 | 66 |
| Orange flavor Sensient 00285 | 60 | 6 |
| Sucralose | 18 | 1.8 |
| Aerosil 200 | 2 | 0.2 |
| Total weight | 2000 | 200 |
In a fluid bed granulator Aeromatic S6, Kg 60 of N-acetylcysteine, Kg 66 of maltodextrin, Kg 66 of mannitol DC, 400 Kg 6 of orange flavour, Kg 1.8 of sucralose Kg 0.2 of Aerosyl 200 were placed.
The mixture was granulated with Kg 6 of purified water and then dried at 60 °C until the granulate relative humidity (RH) was below 0.5%.
At the end of process, the granulate was blended for 15 minutes in a cube mixer as a Zanchetta bin blender.
Using and industrial equipment as Marchesini RC 600 filing machine, sachets were filled with mg 2000 of granulate in order to get mg 600 of N-acetylcysteine in each sachet.
Non-effervescent granulate characteristics:
| Granulate appearance | White to yellowish granules without foreign bodies |
| Particle size | 90% less than 530 pm 50% less than 250 pm |
| Bulk density | 0.70 |
| Tapped density | 0.8 |
| Flowability as angle of repose | 35° |
-7Example 4
Comparison of the CV (variation coefficient) of the weight of the granulate filled in the sachets
| Example 1 | Comparative Example 2 | Example 3 | |
| Target weight mg | 1340 | 1500 | 2000 |
| CV | 1.2 | 1.3 | 1.5 |
The example 1, despite the reduced weight of sachets and the presence of more than 40 % of N-Acetylcysteine in the composition shows a regularity of the weight similar or superior to the other compositions.
Example 5
Stability comparison between Example 1, Comparative example 2 and Example 3
| Example 1 | Comparative example 2 | Example 3 | |
| Assay N-Acetylcysteine 3 months at 40°C-75%RH | 100% | 80% | 100% |
| Assay N-Acetylcysteine 6 months at 40°C-75%RH | 100% | 50% | 100% |
As it can be appreciated by the results reported above, the non-effervescent granulates of the present invention (examples 1 and 3) have:
- Lower bulk density compared to the effervescent granulate of comparative example 2;
- Lower tapped density compared to the effervescent granulate of comparative example 2;
- Lower coefficient of variation (in particular example 1) compared to the effervescent granulate of comparative example 2;
- Better stability (assay N-acetylcysteine) compared to the effervescent granulate of comparative example 2.
Claims (10)
1) A non-effervescent granulate comprising:
- at least 30% by weight of N-acetylcysteine,
- at least 30% by weight of maltodextrin,
- a gliding agent,
- a flavouring agent,
- a sweetener, wherein the weight ratio between N-acetylcysteine and maltodextrin is from about 0.8 to about 1.2.
2) A non-effervescent granulate according to claim 1 comprising Nacetylcysteine in an amount of about 30 - 45% by weight and maltodextrin in an amount of about 33-50% by weight.
3) A non-effervescent granulate according to claim 1 or 2 comprising
- 30-45% by weight of N-acetylcysteine,
- 33-50% by weight of maltodextrin,
- 0.1-0.5% by weight of a gliding agent,
- 2-6% by weight of a flavouring agent,
- 0.7-2% by weight of a sweetener.
4) A non-effervescent granulate according to claims from 1 to 3 wherein the gliding agent is fumed colloidal silicon dioxide or precipitated silica or talc, preferably the gliding agent is fumed colloidal silicon dioxide.
5) A non-effervescent granulate according to claims from 1 to 4 wherein the flavouring agent is orange flavour, lemon flavour, peppermint flavour, anise flavour, apricot flavour, strawberry flavour, preferably the flavouring agent is orange flavour.
6) A non-effervescent granulate according to claims from 1 to 5 wherein the sweetener is an artificial or natural sweetener selected from aspartame, saccharin, acesulfame potassium, sucralose, stevia, advantame, neotame, preferably the sweetener is sucralose.
7) A non-effervescent granulate according to claims from 1 to 6 further comprising a polyalcohol.
8) A non-effervescent granulate according to claim 7 wherein the polyalcohol is selected among sorbitol, xylitol, mannitol, maltitol, lactitol, preferably the polyalcohol is mannitol.
9) A non-effervescent granulate according to claim 1 having the following
quantitative composition:
N-acetylcysteine
600 mg
Maltodextrin
660 mg
Orange flavour
60 mg
Sucralose
18 mg
Colloidal silicon dioxide
2 mg
Total weight
1340 mg
10) A non-effervescent granulate according to claim 1 having the following
10
quantitative composition:
N-acetylcysteine
600 mg
Maltodextrin
660 mg
Mannitol
660 mg
Orange flavour
60 mg
15
Sucralose
18 mg
Colloidal silicon dioxide
2 mg
Total weight
2000 mg
Intellectual
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR1651458A FR3047898B1 (en) | 2016-02-23 | 2016-02-23 | NON-EFFERVESCENT GRANULES CONTAINING N-ACETYLCYSTEINE. |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| GB201701787D0 GB201701787D0 (en) | 2017-03-22 |
| GB2552728A GB2552728A (en) | 2018-02-07 |
| GB2552728A9 true GB2552728A9 (en) | 2019-07-17 |
| GB2552728B GB2552728B (en) | 2019-11-20 |
Family
ID=56117855
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB1701787.2A Active GB2552728B (en) | 2016-02-23 | 2017-02-03 | Non-effervescent granulates containing N-acetylcysteine |
Country Status (4)
| Country | Link |
|---|---|
| CH (1) | CH712181B1 (en) |
| DE (1) | DE102017103033A1 (en) |
| FR (1) | FR3047898B1 (en) |
| GB (1) | GB2552728B (en) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19931708A1 (en) * | 1999-07-08 | 2001-01-18 | Bayer Ag | Process for the preparation of rapidly disintegrating solid pharmaceutical preparations |
| EP1449525A1 (en) * | 2003-02-20 | 2004-08-25 | Cross Chem Llc | chewing gum in the form of multi-layer tablets |
| TR200900882A2 (en) * | 2009-02-05 | 2010-08-23 | Bi̇lgi̇ç Mahmut | Pharmaceutical compositions with high bioavailability, masked by taste and odor. |
| IT1399492B1 (en) | 2010-04-13 | 2013-04-19 | Alpex Pharma Sa | EFFERVESCENT PHARMACEUTICAL COMPOSITIONS CONTAINING N-ACETYLCISTEIN. |
| EP2571499A1 (en) * | 2010-05-18 | 2013-03-27 | Mahmut Bilgic | Pharmaceutical composition comprising n- acetylcysteine and a xanthine |
| US8747894B2 (en) * | 2012-05-08 | 2014-06-10 | Alpex Pharma S.A. | Effervescent compositions containing N-acetylcysteine |
-
2016
- 2016-02-23 FR FR1651458A patent/FR3047898B1/en not_active Expired - Fee Related
-
2017
- 2017-02-03 GB GB1701787.2A patent/GB2552728B/en active Active
- 2017-02-15 DE DE102017103033.6A patent/DE102017103033A1/en not_active Withdrawn
- 2017-02-20 CH CH00188/17A patent/CH712181B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FR3047898A1 (en) | 2017-08-25 |
| GB201701787D0 (en) | 2017-03-22 |
| GB2552728A (en) | 2018-02-07 |
| CH712181B1 (en) | 2020-09-30 |
| FR3047898B1 (en) | 2020-09-18 |
| DE102017103033A1 (en) | 2017-08-24 |
| CH712181A2 (en) | 2017-08-31 |
| GB2552728B (en) | 2019-11-20 |
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