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WO2012110971A2 - Procédé et composition pour retarder la sorption de conservateurs dans des matières plastiques - Google Patents

Procédé et composition pour retarder la sorption de conservateurs dans des matières plastiques Download PDF

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Publication number
WO2012110971A2
WO2012110971A2 PCT/IB2012/050703 IB2012050703W WO2012110971A2 WO 2012110971 A2 WO2012110971 A2 WO 2012110971A2 IB 2012050703 W IB2012050703 W IB 2012050703W WO 2012110971 A2 WO2012110971 A2 WO 2012110971A2
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
agents
caffeine
methylparaben
group
Prior art date
Application number
PCT/IB2012/050703
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English (en)
Other versions
WO2012110971A3 (fr
Inventor
Sateesh CHAUHAN
Manish DARE
Deepak Bahri
Arvind Kumar Bansal
Aeshna AMIN
Original Assignee
Promed Exports Pvt. Ltd.
National Institute Of Pharmaceutical Education And Research (Niper)
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.)
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Application filed by Promed Exports Pvt. Ltd., National Institute Of Pharmaceutical Education And Research (Niper) filed Critical Promed Exports Pvt. Ltd.
Priority to EA201391043A priority Critical patent/EA201391043A1/ru
Publication of WO2012110971A2 publication Critical patent/WO2012110971A2/fr
Publication of WO2012110971A3 publication Critical patent/WO2012110971A3/fr

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Classifications

    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches

Definitions

  • the present invention relates to the field of formulations, particularly solution preparations used for pharma, neutraceutical or cosmetic use.
  • the invention relates to liquid formulation comprising of one or more parabens as the preservatives and one or more additives to retard the sorption of paraben preservatives to the contacting plastic component of the product and method thereof.
  • the present invention also relates to use of one or more additives to retard the sorption of paraben preservatives to the contacting plastic or thermoplastic material.
  • Aqueous/non-aqueous solutions, emulsions and suspensions have to satisfy the primary objectives of safety and efficacy throughout their stated shelf-life. These liquids are susceptible to microbial contamination during manufacturing, shelf-life or product use. Such kind of contaminations can be detrimental to the product safety, efficacy and/or aesthetic appeal and most importantly can pose grave hazards to the health of the consumer. This is critical for sterile pharmaceutical preparations like injections, ophthalmic crops and other preparations. Rahman et al. in Br. J. Ophthalmol., vol 90. pages 139-141, year 2006, have shown that multiple-use, preservative-free, pharmaceutical solutions of anti-infectives got contaminated with pathogenic micro-organisms during use. Indeed, for multi-dose sterile parenteral products, incorporation of an effective preservative system has become a federal requirement.
  • the commonly used preservatives include quaternary ammonium compounds, mercury containing compounds, alcohols (aliphatic and aromatic) and p-hydroxybenzoates (also referred to as the parabens).
  • Parabens are one of the most commonly used antimicrobial preservatives in cosmetics and pharmaceuticals and are especially effective against yeasts and molds.
  • plastics Thermoplastic as the primary packaging material has emerged as a better alternative to the traditional glass packaging, for liquid solutions, including multi-dose sterile parenteral products.
  • Plastics are advantageous in terms of their cost, are light in weight, shatter-proof and can be molded in a variety of shapes and sizes and rigidity depending on the requirements. For these reasons, plastic is also the material of choice for specially inserted parts of a product container, including but not restricted to dropper, probe and stopper. Plastics are chemically varied, with polyolefms and polyvinylchloride being the most commonly used plastics. Plastics can be used in their virgin state (additive- free) or with additives.
  • plastics In spite of the extensive flexibility of options presented by plastics, they suffer from a major disadvantage of sorption. Sorption is a term that encompasses adsorption, absorption and permeation. Some plastics, including, but not restricted to, low-density polyethylene tend to sorb lipophilic compounds from their solutions. This may lead to a gradual loss of the lipophilic compounds if the solutions are kept in contact with the offending plastic for a substantially long time.
  • the main object of the present invention is to provide a composition and a method for retarding the sorption behavior exhibited by preservatives in liquids when they are in contact with plastics.
  • Another object of the invention is to provide a liquid formulation comprising of one or more parabens as the preservatives and one or more additives to retard the sorption of paraben preservatives to the plastic pack in which the formulation is stored.
  • Yet another object of the invention is to provide a liquid formulation comprising of one or more parabens as the preservatives and one or more additives to retard the sorption of paraben preservatives to the contacting plastic component of the product.
  • Yet another object of the invention is provide use of one or more additives to retard the sorption of paraben preservatives to the contacting plastics or thermoplastic material.
  • the present invention provides a method of retarding preservatives in liquid formulations from being sorbed to the contacting plastic material by incorporating into the liquid, one or more additives selected from the group consisting of caffeine, cyclodextrins, polyethylene glycols and propylene glycol.
  • the invention provides a pharmaceutical composition, comprising one or more parabens, and/or their salts, that retards the paraben sorption to the contacting plastic material which may be the primary pack.
  • the composition capable of achieving this object comprises of one or more additives selected from the group comprising of caffeine, cyclodextrins, polyethylene glycols and propylene glycol.
  • the present invention is related to a method and composition for retarding the sorption of a paraben preservative in liquid formulation to a thermoplastic solid in contact with the said liquid comprising providing in said solution one or more additives selected from the group consisting of caffeine, cyclodextrins, polyethylene glycols and propylene glycol, in an amount sufficient to retard the sorption of the paraben preservative to the contacting thermoplastic solid.
  • the said pharmaceutical compositions include aqueous or non-aqueous based liquids for pharmaceutical use. These compositions may include solutions, suspensions or emulsions.
  • the alkyl esters of p-hydroxybenzoic acid constitute one of the most important groups of chemical agents used as preservatives in pharmaceutical, cosmetic and other products.
  • Pharmaceutical salts of the various parabens are also sometimes used to enhance the dissolution rate.
  • Methylparaben, ethylparaben, propylparaben and butylparaben are the most commonly used parabens.
  • other parabens are also used, including but not limited to, benzylparaben, isopropylparaben and isobutylparaben. When two or more such parabens are used in combinations, they cause synergistic antimicrobial action, thus reducing the dose of total paraben content.
  • Parabens are effective over a wide range of pH (pH 4-7) and nonmutagenic, nonteratogenic, and noncarcinogenic. Sensitization to the parabens is rare. Given the wide range of application in both aqueous as well as non-aqueous media, parabens are very popular in cosmetics and pharmaceutical liquids. Methylparaben is used from about 0.015% w/v to about 0.25% w/v. Ethylparaben is effective from a range of about 0.0125% w/v to more than about 0.2%) w/v. Propylparaben is used from a range of about 0.005%) w/v to about 0.26%> w/v.
  • Butylparaben is effective from about 0.006%) w/v to about 0.4%> w/v. Although their activity increases with increasing alkyl ester chain length, in practice the usefulness of the higher homologues is limited by their decreasing water solubility which in turn limits their bioavailability within the system. However, studies (Darwish et al, Int. J. Pharm., vol 147, pages 51-60, year 1997) have shown that, use of co-solvents not only increases the solubility but also enhances their antimicrobial efficacy. Therefore, the conventional ranges of concentrations can be exceeded when co-solvents or non-aqueous systems are used.
  • the present invention employs an effective amount of one or more additives selected from the group consisting of caffeine, cyclodextrins, polyethylene glycols and propylene glycol, to retard the sorption of parabens from pharmaceutical liquids to plastics.
  • effective amount means an amount of additive(s) sufficient to retard the sorption of paraben(s) present in the pharmaceutical liquid, to the plastics.
  • precise amount of additive(s) required to retard sorption of paraben(s) to the plastics will depend on several factors including the type of additive, type/combination of parabens, the specific type of plastics, and the like.
  • plastics refer to thermoplastics. More preferably it includes polyolefms, polyvinylchloride and polyethylene terephthalate. More preferably it includes polyolefms. More preferably it includes polyethylene, polypropylene or a combination thereof. More preferably, it includes low density polyethylene (LDPE).
  • LDPE low density polyethylene
  • LDPE low density polyethylene
  • LDPE is a polymer made entirely or predominantly from ethylene. Its polymer structure is predominantly linear and often contains branches. While LDPE is considered to be semi-crystalline, LDPE can be used to fabricate a broad family of products by modifying its structural properties, and is commonly used for packaging pharmaceutical liquids. LDPE is typically characterized by density in the range of from about 0.910 to about 0.940 g/cc.
  • the LDPE is formed as a blow-fill-seal pack to contain multi-dose aqueous pharmaceutical liquids.
  • Caffeine shows complexing properties which enhances the solubility of lipophilic compounds in the liquid formulations.
  • Caffeine is a xanthine derivative known for its centrally acting stimulating properties.
  • Caffeine has been reported to increase the stability and solubility of arginine amide (US patent 5605892, Feb 25, 1997). It has been used to reduce incompatibility of benzalkonium chloride with acidic drug, thus enhancing the preservative action of benzalkonium chloride (US patent 5558876, Sept 24, 1996).
  • Xanthine derivatives have been found to be effective in reducing ocular discomfort and have been reported to reduce the stinging associated with the application of ophthalmic acidic anti-inflammatory agents (US patent 4559343, Dec 17, 1985 and US patent 5605892, Feb 25, 1997).
  • US patent 4988728, Jan 29, 1991 (Assignee Alcon Laboratories), which describes suprofen esters and amides as ophthalmic anti-inflammatory agents, has mentioned the concomitant use of xanthine derivatives preferably caffeine to reduce the stinging sensation.
  • Alcon's ophthalmic solution Profenal® 1% suprofen as the active ingredient
  • Caffeine is listed in the US FDA's Inactive Ingredient Guide (IIG) (UNII 3G6A5 W338E) for ophthalmic solutions with a maximum potency of 2%.
  • cyclodextrins useful in the present invention are cyclic oligosaccharides that may be produced by the enzymatic degradation of starch and have multiple glucose or glucopyranose units, usually 6 to 8 units. Depending on the particular preparation reaction conditions employed, cyclodextrins generally contain six, seven or eight of such units, connected by alpha-(l,4) bonds. The six, seven or eight unit cyclodextrins are commonly known as alpha-, beta-, and gamma-cyclodextrins, respectively. Cyclodextrins have the shape of truncated cones with primary and secondary hydroxyl groups located at opposite ends of the torus.
  • the glucosyl-o-bridges point into the center of the molecule and the primary hydrogel groups project from one outer edge while the secondary hydroxyl groups project from the other edge.
  • the result is a molecule with a relatively hydrophobic center and a hydrophilic outer surface. These shapes and hydrophilicl/hydrophobic domains provide for inclusion or incorporation of guest molecules into the center of the molecule. Due to this, it shows complexing properties which enhance the solubility of lipophilic compounds in the liquid formulations. This may reduce the plastic- formulation partition coefficient and can retard sorption of parabens.
  • cyclodextrins includes all cyclodextrin derivatives, such as cyclodextrin carbonates, ethers, esters, and polyethers; polymers or copolymers of polymerized cyclodextrins, such as polymerized beta-cyclodextrins; and substituted cyclodextrins such as those with functional groups bonded to one or more of the hydroxyl groups.
  • Suitable function groups include, but are not limited to, methyl, ethyl, hydroxyethyl, and hydroxypropyl and acetyl groups.
  • the cyclodextrin derivatives can also include cyclodextrins with functional groups replacing one or more of the hydroxyl groups such as amino-cyclodextrin, iodo-cyclodextrin and cyclodextrin sulfate. Some of these functional groups may also contribute preserving or disinfecting properties.
  • cyclodextrins are the gamma-cyclodextrin and derivatives thereof.
  • Propylene glycol or 1, 2-propanediol also acts by changing the polarity of the vehicle in which paraben is dissolved. This enhances the solubility of lipophilic compounds like parabens in the liquid formulations thus reducing the plastic- formulation partition coefficient and retarding sorption of parabens.
  • Concentrations of additive(s) useful herein may be adjusted by one reasonably skilled in the art depending on the amount and type of paraben(s) employed and the type of plastic contacting the pharmaceutical liquid.
  • caffeine is used in an amount from about 0.005% w/v to about 2.5% w/v.
  • Cyclodextrins, more preferably gamma cyclodextrins, are used in an amount from about 0.005% w/v to about 10% w/v.
  • PEGs are used in an amount from about 0.5%> w/v to about 30%> w/v.
  • Propylene glycol is used in an amount from about 5% w/v to about 30% w/v.
  • paraben(s) refers to one or more parabens preferably selected from the group methylparaben, ethylparaben, propylparaben, butylparaben and their inorganic or organic salts.
  • the pharmaceutical composition may contain a preserving or disinfecting amount of one or more antimicrobial agents in addition to the paraben(s) antimicrobial.
  • antimicrobial agents are defined as non-oxidative organic chemicals that derive their antimicrobial activity through a chemical or physicochemical interaction with the microbial organisms.
  • Preferred antimicrobials are alcohols and parabens.
  • alcohols are benzyl alcohol, phenoxyethanol, phenylethylalcohol, phenol.
  • parabens are methylparaben, ethylparaben, propylparaben, butylparaben, benzylparaben, isopropylparaben and isobutylparaben.
  • Methylparaben, ethylparaben, propylparaben, butylparaben and their inorganic or organic salts being most preferred.
  • the salts of the parabens used in the present composition may be derived from an inorganic or organic base. In most circumstances it is preferable that the salts be derived from a base which is readily water-soluble and which affords a cation which is suitable for human usage, for example a pharmaceutically acceptable cation.
  • Preferred cations are inorganic. Examples of such cations are sodium and potassium.
  • a preserving amount of antimicrobial agent is an amount that will substantially inhibit microorganism population from growing in the formulations employed. Most preferably, the amount should be sufficient to pass the preservative effectiveness test (Appendix, British Pharmacopoeia 2005). Typically, such agents are present in concentrations ranging from about 0.00001 to about 0.5%> w/v, and more preferably, from about 0.005 to about 0.5%> w/v.
  • a disinfecting amount of antimicrobial agent is an amount that will at least partially reduce the microorganism population in the formulations employed.
  • a disinfecting amount is that which will reduce the microbial burden by two log orders in four hours and more preferably by one log order in one hour.
  • a disinfecting amount is an amount which will eliminate the microbial burden on a contact lens when used in regimen for the recommended soaking time (FDA Chemical Disinfection Efficacy Test— July, 1985 Contact Lens Solution Draft Guidelines).
  • such agents are present in concentrations ranging from about 0.00001 to about 0.5% w/v, and more preferably, from about 0.00003 to about 0.5% w/v.
  • the said pharmaceutical compositions may also employ one or more, inactive components, including but not limiting to, buffers, pH modifying agents, tonicity adjusting agents, viscosity enhancing agents, lubricating agents, chelating and/or sequestering agents, antioxidants, suspending agents, emulsifying agents or dispersing agents depending on the type and use of liquid to be formulated, as known to one of ordinary skill in the art.
  • inactive components including but not limiting to, buffers, pH modifying agents, tonicity adjusting agents, viscosity enhancing agents, lubricating agents, chelating and/or sequestering agents, antioxidants, suspending agents, emulsifying agents or dispersing agents depending on the type and use of liquid to be formulated, as known to one of ordinary skill in the art.
  • a second disinfectant/preservative can be employed as a solution preservative, but it may also function to potentiate, compliment or broaden the spectrum of microbiocidal activity of another antimicrobial agent.
  • Suitable complementary germicidal agents include, but are not limited to propylene glycol, phenylethyl alcohol, imidurea, and mixtures thereof.
  • the amount of the germicide or other components in a solution according to the present invention refers to the amount formulated and introduced into the solution at the time the solution is made.
  • the pH of the present solutions should be maintained within the range of 4.0 to 7.0, more preferably about 5.0 to 7.0.
  • Suitable buffers may be added as known to a person reasonably skilled in the art, such as sodium acetate, acetic acid, boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS, and various mixed phosphate buffers (including combinations of Na 2 HP0 4 , NaH 2 P0 4 and KH 2 P0 4 ) and mixtures thereof.
  • Acetate and phosphate buffers are preferred.
  • buffers Generally, choice of buffers depends on the pH of the formulation and compatibility with other ingredients.
  • concentration of the buffer employed is typically between 5 to 100 rnMolar. Most preferably it is between 10-50 mMolar.
  • the aqueous solutions of the present invention are also adjusted with tonicity agents, depending on the route of administration. Typically it is equivalent to a 0.9% solution of sodium chloride or 2.5% of glycerol solution.
  • suitable tonicity adjusting agents include, but are not limited to: sodium and potassium chloride, dextrose, glycerin, calcium and magnesium chloride. These agents are typically used individually in amounts ranging from about 0.01 to about 2.5% w/v and preferably, from about 0.2 to about 1.5% w/v.
  • the tonicity agent will be employed in an amount to provide a final osmotic value of from about 200 to about 450 mOsm/kg and more preferably between about 250 to about 350 mOsm/kg, and most preferably between about 280 to about 320 mOsm/Kg.
  • the range of caffeine is selected in proportion to the specific paraben preservative.
  • the 1 : 1 to 1 : 103 molar proportions of methylparabenxaffeine were tried.
  • the molar proportions of methylparaben: caffeine in 1 : 1 did not showed any significant effect.
  • caffeine increased with respect to methylparaben such as l :4to 1 : 103, caffeine was able to retard the sorption. It is possible that methylparabenxaffeine proportion lower than 1 :4, may also retard its sorption.
  • the suitable range of caffeine that retards sorption is 1 :4 to 1 : 103 with respect to methylparabenxaffeine molar proportion.
  • the lower limit might be different for other parabens like propylparaben.
  • Both the upper and lower limit of caffeine proportion might vary for other preservatives like benzyl alcohol.
  • the pharmaceutical liquid composition may be selected from anti-infectives, steroidal and non-steroidal compositions, anti-inflammatory compositions, anti-pyretic compositions, antiemetics, sedatives, decongestants, antitussive agents, anti-glaucoma agents, irrigation compositions, contact lens solutions, diagnostic compositions and artificial tear compositions.
  • the present invention provides novel and inventive use of one or more additives selected from the group comprising of caffeine, polyethylene glycol (PEG), propylene glycol, cyclodextrin, to retard sorption of one or more paraben preservatives present in liquid formulation to the contacting plastic material or thermoplastic solid.
  • one or more additives selected from the group comprising of caffeine, polyethylene glycol (PEG), propylene glycol, cyclodextrin, to retard sorption of one or more paraben preservatives present in liquid formulation to the contacting plastic material or thermoplastic solid.
  • the liquid formulation is aqueous or non-aqueous based formulation such as solution, suspension or emulsion.
  • one or more parabens preservative is selected from group comprising of methylparaben, ethylparaben, propylparaben, butylparaben, benzylparaben, isopropylparaben, isobutylparaben or combination thereof.
  • one or more parabens preservative preferably selected from the group consisting of methylparaben, ethylparaben, propylparaben, butylparaben and inorganic or organic salts thereof.
  • the preservative methylparaben is present in liquid formulation from about 0.015% w/v to about 0.25% w/v, ethylparaben in a range of about 0.0125%) w/v to about 0.2%) w/v, propylparaben in a range of about 0.005%> w/v to about 0.26%> w/v, butylparaben from about 0.006%> w/v to about 0.4%> w/v.
  • the preferred cyclodextrins are the gamma-cyclodextrin or derivatives thereof.
  • the caffeine is present in an amount from about 0.005% w/v to about 2.5% w/v.
  • the cyclodextrins is present in an amount from about 0.005%) w/v to about 10%> w/v.
  • the polyethylene glycol (PEG) is present in an amount from about 0.5% w/v to about 30%) w/v.
  • the plastic material is low density polyethylene (LDPE), polypropylene, polyvinyl chloride, polyethylene terephthalate, thermoplastics such as polyolefms, polyvinylchloride, polyethylene terephthalate, or a combination thereof.
  • LDPE low density polyethylene
  • polypropylene polypropylene
  • polyvinyl chloride polyvinyl chloride
  • polyethylene terephthalate polyethylene terephthalate
  • thermoplastics such as polyolefms, polyvinylchloride, polyethylene terephthalate, or a combination thereof.
  • the low density polyethylene is formed as a blow-fill-seal (BFS) pack to contain single or multi-dose aqueous liquid formulation.
  • BFS blow-fill-seal
  • the said composition comprises a preserving or disinfecting amount of one or more antimicrobial agents in addition to the paraben(s) antimicrobial as explained in the specification.
  • the liquid formulation is selected from the group comprising anti- infectives, steroidal and non-steroidal compositions, anti-inflammatory compositions, antipyretic compositions, anti-emetics, sedatives, decongestants, antitussive agents, anti- glaucoma agents, irrigation compositions, contact lens solutions, diagnostic compositions, artificial tear compositions, cosmetics, oral syrups, food products which use the parabens like preservatives
  • the composition comprises methylparaben : caffeine in the range of 1 : 1 to 1 : 103 molar proportions.
  • the present invention provides method of retarding preservatives in liquid formulations from being sorbed to the contacting plastic material, said method comprising incorporating into the said liquid formulation, one or more additives selected from the group comprising of caffeine, cyclodextrins, polyethylene glycols and propylene glycol, in an amount sufficient to retard the sorption of pararben preservatives to the contacting plastic or thermoplastic material.
  • PTT Preservative Effectiveness Test
  • Example 6 Data of methylparaben and propylparaben sorption retarded by caffeine in pharmaceutical ophthalmic products.
  • DICLO and DICLO + CAFFEINE batches i. Take 90 ml SWFI (Sterile water for injection), previously boiled and cooled, in a beaker.
  • CIPRO and CIPRO + CAFFEINE batches i. Take 90 ml SWFI (Sterile water for injection), previously boiled and cooled, in a beaker.
  • Example 7 Data showing the HPLC analysis of diclofenac sodium and ciprofloxacin HC1 in their respective solutions at 0-day and 3-month time points revealed that the addition of caffeine was not causing any degradation of the APIs.
  • the present invention provides a pharmaceutical composition, comprising one or more parabens, and/or their salts, that retards the paraben sorption to the contacting plastic material which may be the primary pack.
  • the composition capable of achieving this object comprises of one or more additives selected from the group consisting of caffeine, cyclodextrins, polyethylene glycols and propylene glycol.
  • caffeine cyclodextrins
  • polyethylene glycols polyethylene glycols
  • propylene glycol propylene glycol

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Abstract

La présente invention porte sur un procédé et des compositions pour retarder la sorption de conservateurs présents dans des liquides pharmaceutiques vers une matière thermoplastique, comprenant un ou plusieurs additifs choisis dans le groupe constitué par la caféine, les cyclodextrines, les polyéthylèneglycols et le propylèneglycol, en une quantité suffisante pour retarder la sorption du conservateur dans la matière plastique ou le solide thermoplastique en contact avec celui-ci.
PCT/IB2012/050703 2011-02-17 2012-02-16 Procédé et composition pour retarder la sorption de conservateurs dans des matières plastiques WO2012110971A2 (fr)

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EA201391043A EA201391043A1 (ru) 2011-02-17 2012-02-16 Способ и композиция для замедления сорбции консервантов пластиками

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IN406/DEL/2011 2011-02-17
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017060329A1 (fr) * 2015-10-06 2017-04-13 Janssen Vaccines & Prevention B.V. Procédés pour la prévention de la dégradation induite par du plastique de produits biologiques
US9974737B2 (en) 2013-09-19 2018-05-22 Janssen Vaccines & Prevention B.V. Adenovirus formulations
CN109966502A (zh) * 2017-12-26 2019-07-05 财团法人工业技术研究院 用于改善难溶物的溶解度的组合物、其用途与含其的复合制剂
CN112316922A (zh) * 2020-10-19 2021-02-05 南通大学 一种防腐剂吸附微球及其制备方法与应用

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CN109966502B (zh) * 2017-12-26 2023-01-24 财团法人工业技术研究院 用于改善难溶物的溶解度的组合物、其用途与含其的复合制剂
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CN112316922B (zh) * 2020-10-19 2023-12-12 南通大学 一种防腐剂吸附微球及其制备方法与应用

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