WO2011158034A2 - Compositions et procédés - Google Patents

Compositions et procédés Download PDF

Info

Publication number
WO2011158034A2
WO2011158034A2 PCT/GB2011/051130 GB2011051130W WO2011158034A2 WO 2011158034 A2 WO2011158034 A2 WO 2011158034A2 GB 2011051130 W GB2011051130 W GB 2011051130W WO 2011158034 A2 WO2011158034 A2 WO 2011158034A2
Authority
WO
WIPO (PCT)
Prior art keywords
plasticiser
coating composition
glyceride
coating
polymer
Prior art date
Application number
PCT/GB2011/051130
Other languages
English (en)
Other versions
WO2011158034A3 (fr
Inventor
Robert Thomas Forbes
Tim Gough
Mohammad Isreb
Original Assignee
University Of Bradford
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
Application filed by University Of Bradford filed Critical University Of Bradford
Publication of WO2011158034A2 publication Critical patent/WO2011158034A2/fr
Publication of WO2011158034A3 publication Critical patent/WO2011158034A3/fr

Links

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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • Coatings typically polymer or polysaccharide based, are commonly used in the field of pharmaceuticals to protect the active ingredients in tablets or the like during transportation, storage and handling. Furthermore, a coating may also be used to inhibit release of the active ingredients until the tablet has reached the necessary body site and/or to control the rate of release in line with dosage requirements.
  • a coating composition is typically applied to a tablet in the final stage of manufacture.
  • the temperature at which film formation takes place from either the solvent-based solutions or aqueous-based suspensions is called the minimum film forming temperature, which is related to the glass transition temperature of the solution or suspension.
  • the minimum film forming temperature is related to the glass transition temperature of the solution or suspension.
  • Plasticisers are typically incorporated into polymer-based coating compositions to enhance the film forming properties of the coating composition and/or to impart plasticity, reducing the brittleness of the final coat. However, the presence of such plasticisers can also influence the temperature range at which the transition takes place.
  • Plasticisers used in the above process consist of triethyl citrate (TEC) in combination with acetylated monoglyceride (AMG).
  • TEC is commonly used in both solvent-based coating techniques and the solvent-free coating method to enhance film forming properties at coating conditions when combined with polymer-based coating compositions.
  • AMG is combined with TEC in the plasticising phase for solvent-free coating in order to enhance wetting of the surface of the substrate and the polymer powder, which is crucial to the success of the process.
  • plasticiser used in this method to have good wetting properties is crucial as plasticising time is relatively short compared to aqueous systems, in which the plasticiser has sufficient time to diffuse into the polymer while it is stored in the reservoir. Therefore, the plasticiser of the dry coating system has to diffuse into the coating polymer matrix more readily to form a film at the surface of the substrate, which has not been possible with known plasticisers. Accordingly, to compensate for the short plasticising time, conventional solvent-free coating methods include an additional curing step, which gives the polymer particles more opportunity to deform and so form a coherent film. However, such curing steps greatly increase the time for the coating process, therefore, increasing process costs. Accordingly, a plasticiser which exhibits enhanced wetting properties would reduce the time for curing and so reduce the overall costs of the coating process.
  • a coating composition based on HPMCAS is required which maintains sufficient rigidity of the polymer at the temperature and shear conditions near the nozzle tip, to prevent nozzle blocking, while possessing adequate viscoelastic flow behaviour at the temperature and shear conditions of the coating process, to ensure excellent coating of the substrate.
  • a polymer based on hydroxyl propyl methyl cellulose acetate succinate HPMCAS
  • HPMCAS hydroxyl propyl methyl cellulose acetate succinate
  • the polymer is HPMCAS.
  • the coating composition may further comprise a liquid carrier.
  • a liquid carrier is preferred so that the coating composition is suitable for use in spray coating techniques.
  • Spray coating techniques include aqueous coating in which the polymer and plasticiser are dispersed in an aqueous liquid carrier, wherein the dispersion is sprayed on to the substrate, and dry coating wherein the polymer, optionally pre- plasticised with part of the plasticiser, is sprayed through a powder feeder and a liquid carrier, predominantly comprising the plasticiser is sprayed onto the substrate.
  • the liquid carrier assists in driving particle
  • the liquid carrier may comprise the plasticiser, water, an aqueous polymeric solution of a water soluble polymer such as HPMC, HPC or any other water soluble polymer, or a mixture thereof.
  • the liquid carrier may further comprise a small proportion of water or aqueous polymeric solution.
  • Coating compositions of the type are extremely suitable for spray coating and do not include press coating compositions which coat using a very different process.
  • the plasticiser further comprises a glyceride or an acylated glyceride.
  • Glycerides are composed of a glycerol head group and one or more fatty acid chains.
  • the glyceride may be a monoglyceride (one fatty acid chain), a di-glyceride (two fatty acid chains) or a tri-glyceride (three fatty acid chains).
  • Preferably the glyceride is a monoglyceride.
  • the ester link between the fatty acid chain and the glycerol head group may be linked to the end carbon of the glycerol head group (1 -monoglycerine) or to the middle carbon of the glycerol head group (2-monoglycerine).
  • the number of carbon atoms present in the fatty acid chain is variable.
  • the fatty acid chain of the glyceride is from 12 to 22 carbons in length. More preferably the fatty acid is a polydisperse, predominantly comprising C16 and C18 chain mixture, e.g. monopalmatate and monostearate.
  • the glyceride may comprise a mixture of mono-, di and tri-glycerides.
  • acylated glycerides is understood to cover variations of mono- or di-carboxylic acid esters of 1 - or 2-monoglycerides or monocarboxylic acid esters of di-glycerides having a fatty acid chain with from 12 to 22 carbons in length, wherein the fatty acid chain may be saturated or unsaturated and mixtures thereof.
  • the plasticiser further comprises an acetylated monoglyceride.
  • acetylated monoglyceride covers multiple variations of mono- or di-acetic acid esters of monoglyceride in terms of fatty acid chain length and saturation, as discussed above.
  • the acetylated monoglyceride is an mono- or di-acetyl derivative of monoglycerides having fatty acid chains comprising predominantly 16 or 18 carbons or mixtures thereof.
  • a plasticiser comprising triethyl acetyl citrate (TEAC) alone or in combination with a glyceride or acylated glyceride in hydroxyl propyl methyl cellulose acetate succinate (HPMCAS)-based coating compositions overcomes the problems encountered in the prior art.
  • TEAC triethyl acetyl citrate
  • HPMCAS hydroxyl propyl methyl cellulose acetate succinate
  • glycerides comprise a hydrophilic glycerol head group and a hydrophobic esterified fatty acid chain
  • glycerides and acylated glycerides behave as surfactants and so are more favourably distributed towards the surface of HPMCAS particles.
  • the hydrophobic nature of the glycerides/acylated glycerides therefore reduces swelling of the HPMCAS particles and consequently the plasticising effect of any water present in the coating compositions is reduced. It has been surprisingly found that acetylated monoglycerides (AMGs) are particularly useful in this regard.
  • AMGs acetylated monoglycerides
  • a plasticiser comprising TEAC alone or in combination with a glyceride or an acylated glyceride in a HPMCAS-based coating composition provides an enhanced viscoelastic regime for each step of the coating process. Accordingly, such compositions overcome the nozzle- blocking problems frequently encountered during aqueous coating processes, while negating the need for pre-cooling of the coating compositions and providing good film formation properties once applied to the substrate. Moreover, in a solvent-free coating process, these compositions possess enhanced wettability, which is illustrated by lowering of the surface contact angle when it is dropped over the surface of the substrate/polymer powder, which improves the efficiency of the coating process as well as the final film qualities.
  • the plasticiser of the present invention is suitable for use with
  • the coating composition comprises a polymer coating based on HPMCAS comprising:
  • HPMCAS HPMCAS
  • plasticisers of the present invention being suitable for use with all commercially available particle sizes and grades of HPMCAS, it is expected that they will also be suitable for use with any additional grades, i.e. those with weight percentage of the functional groups outside the typical ranges. This is due to comparable backbone chemistry, which it is believed influences the positive interaction with the plasticiser, providing the enhanced film forming properties of the coating compositions of the present invention.
  • the weight to weight ratio of triethyl acetyl citrate to the glyceride or acylated glyceride is from 5:1 to 1 :1 , more preferably 4:1 to 2:1 and most preferably 3:2.
  • the plasticiser is present in the coating composition at an amount from about 10 to about 50 wt% of the dry polymer weight, more preferably from about 20 to about 40wt%. Most preferably the plasticiser is present at an amount of about 30 wt% of the dry polymer weight.
  • the coating composition is suitable for use in aqueous-based coating techniques
  • water is preferable present in the coating composition at an amount of from 50 to 99wt% of the composition, more preferably at from 85 to 95wt%, most preferably at from 90 to 93wt% of the composition.
  • the coating composition as set out above is preferably suitable for coating a variety of pharmaceutical oral dosage forms including capsulaes and tablets and also microparticles for encapsulation in a capsule or a tablet. This is because the coating composition is suitable for human or animal consumption and has the relevant enteric protection capabilities, ensuring the active ingredients of the microparticles or tablets are not released until it reaches the intestine.
  • the coating composition may further comprise other common additives such as surface active agents, antiadherents, opacifiers, antifoaming agents, glossants and/or colour agents.
  • a tablet coated with the coating composition as set out above there is provided a pharmaceutical tablet coated with the coating composition as set out above.
  • a pharmaceutical tablet coated with the coating composition as set out above there is provided an oral dosage form of a pharmaceutical composition coated with the coating composition as set out above.
  • a plasticiser for use in a polymer based coating composition the plasticiser comprising triethyl acetyl citrate.
  • the plasticiser further comprises a glyceride or an acylated glyceride.
  • the weight to weight ratio of triethyl acetyl citrate to the glyceride or acylated glyceride may be from 5:1 to 1 :1 , more preferably 4:1 to 2:1 and most preferably 3:2.
  • the plasticiser is suitable for use in a polymer coating composition based on hydroxyl propyl methyl cellulose acetate succinate.
  • kit of parts for a coating composition comprising:
  • plasticiser comprising triethyl acetyl citrate.
  • the plasticiser further comprises a glyceride or an acylated glyceride.
  • a seventh aspect of the present invention there is provided method of coating a substrate comprising the steps of:
  • the plasticiser further comprises a glyceride or an acylated glyceride.
  • the polymer and the plasticiser may be provided together in a suspension.
  • the suspension may then be applied to a substrate via spraying.
  • the coating composition is applied by spraying in the form of a suspension, the suspension comprises a dispersed phase and a dispersion medium.
  • the dispersed phase comprises the polymer and the plasticiser and the dispersion medium is aqueous.
  • a suspension may further comprise a surfactant, preferably an anionic surfactant, most preferably sodium lauryl sulphate.
  • surfactants would be apparent to the person skilled in the art.
  • the polymer may be in the form of a dry powder and the plasticiser may be in the form of a liquid phase.
  • the liquid phase comprises the plasticiser alone or in combination with water and/or an aqueous polymeric solution of a water soluble polymer such as HPMC, HPC or any other water soluble polymer.
  • the liquid phase may be applied to the substrate shortly before or simultaneous with application of the dry powder.
  • the dry powder may be pre-plasticised with at least a portion of the liquid phase comprising the plasticiser prior to application.
  • pre-plasticised it is meant that at least a portion of the plasticiser liquid can be added to the dry powder before application to impart an initial plasticity to the polymer or vice versa. This further speeds up the diffusion of the plasticiser into the polymer to form the film at the surface of the substrate after
  • pre-plasticising step enables the dry coating process of the present invention to be employed with a wider range of polymers, in particular those with high glass transition temperatures.
  • the dry powder further comprises one or more solid additives such as antiadherents, opacifiers, glossants and/or colouring agents.
  • solid additives such as antiadherents, opacifiers, glossants and/or colouring agents.
  • the liquid phase and the dry powder are applied to the substrate via spraying, either separately or simultaneously as discussed above.
  • the coating may be cured.
  • the coated substrate is subjected to an elevated temperature, with or without shearing, for an extended period of time to ensure coalescence of the plasticiser and polymer and so smooth coherent film formation.
  • Such a curing step preferably takes place at temperatures of around 40 to 100°C, more preferably at around 50 to 80°C.
  • HPMCAS-based polymer offers enhanced coating of the substrate and prevents nozzle-blocking, when compared with known plasticisers.
  • the coating compositions of the present invention are suitable for application to a substrate from a suspension. Furthermore, as such plasticisers have considerably lower contact angles, when compared to known systems, and have enhanced wetting
  • the coating compositions of the present invention are suitable for application to a substrate via "solvent-free" coating methods. It is believed that such methods lead to enhanced film formation at the surface of the substrate due to better and more rapid diffusion and interaction between the dry polymer powder and the plasticiser solution following application.
  • the enhanced film forming properties of the compositions of the present invention enable a relatively short curing time when compared to prior art compositions.
  • the films formed are typically more resilient at room temperature than those formed by conventional solvent- free methods, which is an advantageous property as it is desirable to have a strong, tough film to protect the tablet from everyday stresses such as handling and transportation.
  • conventional solvent-free methods require excess plasticiser (around 50wt%) to be used to aid particle coalescence, thereby achieving the same result. Excess plasticiser is required due to the lack of water (which acts as a temporary plasticiser in aqueous systems) and the shorter plasticising time compared to aqueous coatings.
  • a coating composition as set out above for spray coating a substrate there is provided use of a coating composition as set out above for spray coating a substrate.
  • coating composition as set out above which overcomes the problem of nozzle blocking when used in spray-coating techniques.
  • Figure 1 shows a graphical representation of the contact angle
  • Figure 2 shows a graphical representation of the complex viscosity data at a frequency range of 0.1 -100 Hz for plasticisers at a temperature range of 0-70°C;
  • Figure 3 shows a film deposit around a tip of a spray nozzle after 45 minutes of coating with a composition comprising a prior art plasticiser
  • Figure 4 shows the white light profilometer images displayed in 3D for each of the coated tablets of Example 3;
  • Figure 5 shows the scanning electron microscopy images of a cross- section of the coated tablets of Example 3.
  • Figure 6 shows a graphical representation of the results of a dissolution test for the coated tablets of Example 3.
  • the acetylated monoglyceride (AMG) used in following examples is Myvacet 9-45K (Kerry Bioscience). It is fully acetylated (greater than 96%), having the E-number E472a.
  • Myvacet 9-45K is derived from soyabean oil so it has a variety of fatty acid carbon chain lengths, the majority of which are palmitate (16 carbons atoms/saturated), stearate (18 carbon atoms/saturated), oleate (18 carbon atoms/monounsaturated), linoleate (18 carbon atoms/polyunsaturated) and linolenate (18 carbon atoms/polyunsaturated). However, as this is a natural oil, other longer and shorter chain fatty acids may be present in minor amounts.
  • HPMCAS used in the present invention is HPMCAS-MF, available from Shin-Etsu Chemical, Japan.
  • Tablets were kept in sealed plastic bag during the test to minimize moisture difference effect. All tablets were measured within 15 minutes of their removal from the desiccators. A drop of approximately 5-6 ⁇ of the liquid plasticiser (according to viscosity of liquid used) was dispensed using an automated micro-dispenser set, on the surface of a tablet and the contact angles were measured after five seconds.
  • TEAC has the lowest contact angle value between the three plasticisers (TEC, AMG and TEAC). Furthermore, mixture of TEAC with AMG (3:2) has the lowest contact angle of all the combinations. Solvent-free coating requires a plasticiser that can wet, spread and diffuse into the polymer in a relatively short time. These results therefore highlight the significance of TEAC, alone or in
  • HPMCAS-MG films containing various plasticisers were evaluated using standard dynamic mechanical analysis techniques. The films were studied in a dry state. Therefore, the "moisture plasticising effect", which is significant in the actual coating process, is eliminated here in order to make a direct comparison between the plasticisers.
  • the results, as shown in Figure 2, reveal that, at the lower temperature end (up to around 4Q°C), films containing TEAC alone or in combination with a glyceride or an acylated glyceride (3:2 ratio) exhibit higher complex modulus value, and so are more resistant to deformation (i.e. their elastic properties overcome their viscous ones) than the commonly used plasticisers (TEC alone or with AMG).
  • compositions used in aqueous coating techniques are provided.
  • HPMCAS suspensions were prepared using the following formula (w/w):
  • the placebo tablets were coated using a fluid bed coater, a Sterra 1
  • Example 3 The coated tablets produced in Example 3 were sliced using a sharp blade and then gold-sputtered before being scanned using a Scanning Electron Microscope (Oxford instruments; UK) to evaluate the degree of particle coalescence within the coat.
  • the enteric protection capabilities of each of the aqueous HPMCAS-MF formula mentioned in Example 3 was evaluated by studying drug release from theophylline pellets coated with each formula.
  • the theophylline pellets (1 -1 .2mm in length) were coated using a MP-micro (GEA-Aeromatic Fielder) fluid bed coater.
  • MP-micro GAA-Aeromatic Fielder
  • USP XXVII rotating paddle method This test is intended to mimic the release of theophylline in the gastrointestinal tract, whereby the coating protects the tablet as it passes through the acidic environment in the stomach and then releases the theophylline once the tablet reaches the intestine, where it is exposed to more basic conditions.
  • the dissolution test was carried out at 37°C ⁇ 0.5°C in 750 ml of 0.1 M hydrochloric acid for 120 min. After that 250ml of Na 3 PO 4 - 12H 2 O buffer solution (65 g/l) was added and the pH was adjusted to 6.8 using 2M NaOH. The test was continued for another 60 min.
  • TEAC/a glyceride or an acylated glyceride 3:2 is effective in protecting the active ingredients as it passes through the stomach and in fact achieves faster release of theophylline once the tablet reaches the intestines,
  • coating compositions comprising TEC or TEC/AMG 3:2.
  • TEAC/a glyceride or an acylated glyceride 3:2 has demonstrated great potential to solve the nozzle blocking problem frequently encountered
  • TEAC TEAC alone or in combination with a glyceride or an acylated glyceride has also demonstrated great potential for use in solvent-free, i.e. dry,
  • plasticisers offer superior wetting of the
  • the plasticisers of the present invention produce resilient, i.e. more elastic, films at room temperature compared with conventional plasticisers. This is especially important in dry coating techniques in which coatings usually have compromised mechanical strength as extra plasticiser is required to achieve the same level of resilience.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Paints Or Removers (AREA)

Abstract

Cette invention concerne une composition d'enrobage comprenant un polymère à base d'acétosuccinate d'hydroxylpropylméthylcellulose et un plastifiant, le plastifiant comprenant un citrate de triéthylacétyle. Des comprimés enrobés avec ladite composition d'enrobage, un plastifiant destiné à être utilisé dans ces compositions d'enrobage, un kit de constituants de cette composition d'enrobage, des procédés d'enrobage d'un substrat et l'utilisation de cette composition d'enrobage sont également décrits.
PCT/GB2011/051130 2010-06-16 2011-06-16 Compositions et procédés WO2011158034A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1010083.2 2010-06-16
GBGB1010083.2A GB201010083D0 (en) 2010-06-16 2010-06-16 Compositions and methods

Publications (2)

Publication Number Publication Date
WO2011158034A2 true WO2011158034A2 (fr) 2011-12-22
WO2011158034A3 WO2011158034A3 (fr) 2012-05-31

Family

ID=42471739

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2011/051130 WO2011158034A2 (fr) 2010-06-16 2011-06-16 Compositions et procédés

Country Status (2)

Country Link
GB (1) GB201010083D0 (fr)
WO (1) WO2011158034A2 (fr)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0689840A1 (fr) * 1994-06-28 1996-01-03 Spirig Ag Pharmazeutische Präparate Nouvelle composition pharmaceutique contenant de l'érythromycine base libre
US5733575A (en) * 1994-10-07 1998-03-31 Bpsi Holdings, Inc. Enteric film coating compositions, method of coating therewith, and coated forms
US5858411A (en) * 1994-12-19 1999-01-12 Daiichi Pharmaceutical Co., Ltd. Sustained-release granular preparations and production process thereof
JP2011503048A (ja) * 2007-11-08 2011-01-27 グラクソ グループ リミテッド 医薬製剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None

Also Published As

Publication number Publication date
WO2011158034A3 (fr) 2012-05-31
GB201010083D0 (en) 2010-07-21

Similar Documents

Publication Publication Date Title
Fulzele et al. Polymerized rosin: novel film forming polymer for drug delivery
TWI793141B (zh) 腸溶性硬質膠囊
US9789067B2 (en) Immediate release film coatings containing medium chain glycerides and substrates coated therewith
WO2011158034A2 (fr) Compositions et procédés
JP7489441B2 (ja) コーティング組成物並びに経口固形剤及びその製造方法
Reddy et al. Novel interpenetrating polymer matrix network microparticles for intestinal drug delivery
EP2776015A1 (fr) Enrobages lubrifiants
JP7174383B2 (ja) シームレスカプセル皮膜用組成物及びシームレスカプセル
JP5328768B2 (ja) 硬質カプセル剤
JP7192653B2 (ja) カプセル用組成物、カプセル、カプセル製剤及びカプセルの製造方法
TW201329171A (zh) 潤滑塗層
JP7194524B2 (ja) コーティング組成物並びに経口固形剤及びその製造方法
WO2019245031A1 (fr) Capsule dure gastrorésistante

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11729147

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11729147

Country of ref document: EP

Kind code of ref document: A2