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WO2010113176A2 - Nouveaux copolymères pour système d'administration à libération contrôlée - Google Patents

Nouveaux copolymères pour système d'administration à libération contrôlée Download PDF

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Publication number
WO2010113176A2
WO2010113176A2 PCT/IN2010/000204 IN2010000204W WO2010113176A2 WO 2010113176 A2 WO2010113176 A2 WO 2010113176A2 IN 2010000204 W IN2010000204 W IN 2010000204W WO 2010113176 A2 WO2010113176 A2 WO 2010113176A2
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Prior art keywords
insulin
particle
composition
copolymer
poly
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PCT/IN2010/000204
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English (en)
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WO2010113176A3 (fr
Inventor
Vidhya Rangaswamy
Tejraj Malleshappa Aminabhavi
Vadde Ramesh Babu
Raghavendra Chaluvayya Mundargi
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Reliance Life Sciences Pvt. Ltd.
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Publication of WO2010113176A2 publication Critical patent/WO2010113176A2/fr
Publication of WO2010113176A3 publication Critical patent/WO2010113176A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F226/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen
    • C08F226/06—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen by a heterocyclic ring containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/04—Acids; Metal salts or ammonium salts thereof
    • C08F220/06—Acrylic acid; Methacrylic acid; Metal salts or ammonium salts thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F222/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a carboxyl radical and containing at least one other carboxyl radical in the molecule; Salts, anhydrides, esters, amides, imides, or nitriles thereof
    • C08F222/02—Acids; Metal salts or ammonium salts thereof, e.g. maleic acid or itaconic acid

Definitions

  • the present invention relates to polymeric microparticles for drug delivery.
  • the invention relates to a pH-sensitive copolymer for oral delivery of active ingredients in the intestine.
  • the invention in particular relates to the synthesis of copolymer of poly(methacrylic acid-c ⁇ -JV-vinylcaprolactam), designated as P(MAA-co-VCL) for oral delivery of active ingredients.
  • Oral drug formulations or compositions require efficient delivery of the active ingredient to the site of absorption.
  • Controlled delivery formulations loaded with bioactive molecules have been widely developed and used for a variety of applications for delivering the active ingredient.
  • Such devices may include a simple capsule or microcapsules for oral administration, injections, microspheres, microparticles, nanospheres, nanoparticles, liposomes, implants, etc.
  • biopolymers available in developing these formulations are viz., biodegradable poly(glycolic acid), poly(lactic acid), poly(lactic acid-c ⁇ -glycolic acid), ⁇ oly(lactic acid-co- poly(ethylene glycol)), dextran ⁇ PEG, and pH-sensitive polymers like poly(acrylic acid) and poly(methacrylic acid) as well as complexing hydrogel graft polymers like poly methylmethacrylate with ethylene glycol, chitosan, cyclodextrin, etc.
  • the pH-sensitive hydrogels are made up of polymers, which can exhibit reversible formation of inter-polymer complexes, which are sensitive to pH. These complexes are usually developed to be insoluble at lower or gastric pH and as the polymer passes through the stomach into the intestine, the increase in pH causes swelling and dissociates these complexes thereby, leading to the release of the active ingredient in the intestine.
  • Wood et al. (AIChE Annual Meeting, Conference Proceedings, San Francisco, CA, United States, Nov. 12-17, 2006, American Institute of Chemical Engineers, New York) developed another method using stimuli-responsive complexation hydrogels of methacrylic acid grafted onto ethylene glycol chains functionalized with wheat germ agglutinin (WGA). In this study, insulin entrapment was unaffected by WGA functionalization .
  • Singh et al. (Indian Pat. Appl. 2008, 35 pp. IN 2006DE01437 A 20080104, Application: IN 2006-DE1437 20060616) invented ' hydrogel copolymeric microparticles of poly(methacrylic acid-c ⁇ -poly(ethylene glycol) dimethacrylate), poly(methacrylic acid-c ⁇ - poly(ethylene glycol) acrylate), poly(acrylic acid-co- poly(ethylene glycol) acrylate) and poly(acrylic acid-co-poly(ethylene glycol) dimethacrylate) by the copolymerization of poly(ethylene glycol) dimethacrylate (PEGDMA) and ⁇ oly(ethylene glycol) acrylate (PEGDA) of various molecular weights with methacrylic acid (MAA)/acrylic acid (AA), respectively.
  • PEGDMA poly(ethylene glycol) dimethacrylate
  • PEGDA ⁇ oly(ethylene glycol) acrylate
  • Hassan (Egypt. 2004, pp 19, EG 23187 A, 20040731, Application: EG 2002-827 20020720) developed the CR insulin oral capsule formulations containing chitosan, hydroxypropyl cellulose, methyl cellulose, and methacrylic acid copolymers providing optimum pH for insulin release.
  • Insulin-loaded polymer (ILP) microparticles composed of poly(methacrylic acid) and poly(ethylene glycol) having pH dependent complexation and mucoadhesive properties were suggested to be the potential carriers for insulin via oral route. (Morishita, et al., J. Control. ReL, 97, 2004, pp 115-124). Nevertheless, further optimization of the polymer delivery system is required to improve clinical application. Therefore, the effect of particle size of the ILP on insulin absorption was studied in the in situ loop system, hypothesizing that smaller particle sizes of ILP could induce bigger hypoglycemic effects due to increase in mucoadhesive capacity. To verify the hypothesis, the adhesive capacities of differently sized ILPs to the mucosal tissues were evaluated.
  • ILP insulin phosphatidylcholine
  • Intra- and inter-cellular integrity and/or damage were also examined by lactate dehydrogenase leakage and membrane electrical resistance change to ensure the safety of ILP as a carrier for oral route.
  • Other oral insulin delivery devices based on (i) biodegradable poly(glycolic acid), (PGA), polyOactic acid), (PLA), poly(lactic acid-co-glycolic acid), (PLGA), poly(lactic acid-co- poly(ethylene glycol), (PLA-PEG), dextran-PEG; (ii) pH-sensitive polymers like poly(acrylic acid) i.e., PAA and poly(methacrylic acid), PMAA; and (iii) complexing hydrogel graft polymers like P(MAA-g-EG) and P(PAA-g-EG) in addition to biopolymers like chitosan, cyclodextrin, etc., in various combinations with methacrylic or acrylic-polymers have been reported (Ramesh et al., Expert Opinion, Drug Delivery, 5, 2008, 403-415).
  • TCP tricalcium phosphate
  • Mahkam J. Biomed. Mater. Res. Part B Appl. Biomater. 75B, 2005, 108-112 developed the copolymeric hydrogels of 2-hydroxyethyl methacrylate (HEMA) and methacrylic acid (MAA) that contained 2, 4, and 6 % of cubane-l,4-dicarboxylic acid as the cross-linking agent by the free radical copolymerization at 70°C.
  • HEMA 2-hydroxyethyl methacrylate
  • MAA methacrylic acid
  • the pH-sensitive graft copolymers of poly(methacrylic acid) and poly(ethylene glycol) i.e., P(MAA-g-EG) were invented for insulin delivery (Lowman and Peppas Macromolecules 30, 1997, pp 4959-4965). In acidic environment of the stomach, these hydrogels stayed in a complexed state to protect the insulin, but at intestinal pH (alkaline condition), the complex was immediately dissociated releasing the insulin.
  • Hydrogels of PMMA-CS (Sajeesh and Sharma, J. Appl. Polym. Sci., 99, 2006, pp 506-512) prepared by free-radical polymerization using water-soluble initiator were also evaluated for oral insulin delivery.
  • the in vitro experiments of these systems exhibited pH-dependent insulin release in alkaline pH up to 3-4 h.
  • Foss et al. (Eur. J. Pharm. Biopharm,, 57, 2004, pp 163-169) reported the cross-linked networks of MAA grafted onto PEG (size, 200 run) by free-radical precipitation/dispersion methods.
  • the size of particles increased by increasing the pH of the medium i.e., the size ranged from 200 run at the pH of 2.0 to 2 mm at the pH of 6.0.
  • Insulin was encapsulated into these copolymers at 9.33 and 9.54 mg/140 mg of solid hydrogel matrix by partitioning from the concentrated insulin solution.
  • microencapsulation process of protein-based pharmaceutical products must be free from excessive heat and shear stress, sharp changes in pH, organic solvent, excessive freezing and drying. It is possible that the microencapsulated proteins may be hydrated even during storage and proteins are prone to denaturation and aggregation under these circumstances.
  • the polymer degrades after being administered, thereby creating highly concentrated acidic microenvironment inside and around the polymer due to the possible decomposed acidic monomer. Under these circumstances, proteins are prone to aggregation, hydrolysis and chemical change, thereby affecting the delivery rate, leading to denaturation, aggregation or inactivation of the proteins. '
  • the present invention relates to the development of microparticle-based encapsulation to attain the stability of insulin contained in the formulations.
  • the present invention has focused on the development of a copolymer of polyvinyl caprolactam) with methacrylic acid.
  • the invention in particular provides a copolymer of iV-vinylcaprolactam and methacrylic acid.
  • the most important application of these copolymers was studied in the formulation of insulin-loaded hydrogel microparticles.
  • the novel hydrogel prepared from N- vinylcaprolactam and methacrylic acid was sensitive to pH changes of the surrounding media in vitro.
  • the present invention provides the development of a novel copolymer of JV-vinyl caprolactam and methacrylic acid. This copolymer is sensitive to pH changes and thus, enables efficient formulations of pH-sensitive active ingredients.
  • the present invention also provides pH- sensitive hydrogel formulation of insulin.
  • the present invention provides a novel route of the synthesis of a pH-sensitive copolymer.
  • the present invention relates to a pH-sensitive copolymer of iV-vinylcaproIactam and methacrylic acid.
  • the present invention relates to hydrogel compositions of the insulin that allow negligible release of the insulin in certain pH ranges and is able to provide sufficient release of insulin in the intestine.
  • the present invention provides a method to prepare novel pH-sensitive copolymer.
  • the present invention provides a copolymer of iV-vinylcaprolactam and methacrylic acid.
  • the copolymer prepared can be used for oral delivery of pH-sensitive active ingredients.
  • the present invention provides copolymer of iV-vinylcaprolactam and methacrylic acid developed with two different proportions.
  • the copolymer has vinyl caprolactam (VCL) and methacrylic acid (MAA) components in proportions of 75:25 to 50:50.
  • the present invention provides methods of preparation of composition by using different methods such as emulsion polymerization, dispersion polymerization, solvent evaporation, in situ gel forming, and precipitation method.
  • the present invention provides a method of preparation of composition using free radical polymerization.
  • the present invention provides a copolymer of N- vinyl capro lactam and methacrylic acid, whose formulations are available in the size range of 50-100 microns.
  • the present invention provides methods for characterization of the copolymer.
  • the present invention provides FTIR, differential scanning calorimetry, thermogravimetry, size analyzer and scanning electron microscopy for establishing the chemical structure, thermal properties, size, shape and morphology of the copolymer.
  • the present invention provides compositions for the oral delivery of active ingredient using the pH-sensitive copolymeric formulations of the present invention.
  • the present invention provides compositions for oral delivery of insulin.
  • the present invention provides oral formulations of pH-sensitive active ingredient using copolymer of the present invention.
  • the oral formulation is a hydrogel.
  • the present invention provides hydrogel, which does not release the active ingredient in acidic pH, but swells in neutral pH to release the active ingredient.
  • the hydrogel of insulin shrinks at pH 1.2 and swells in pH 7.4 to release the insulin.
  • the present invention provides a novel copolymer composition, which does not alter the stability of the active ingredient.
  • FIG. 1 shows FTIR spectra of (IA) monomer vinyl caprolactum and (IB) copolymers of poly(VCL-co-MAA).
  • FIG. 2. shows DSC thermogram of poly(VCL-co-MAA).
  • FIG.3 shows particle size distribution curve of microparticles after 20 passes through a Microfluidizer
  • FIG. 4 shows a TGA thermogram of poly(VCL-co-MAA).
  • FIG. 5 shows photographs of scanning electron microscope, illustrating the group of microparticles of poly(VCL-co-MAA).
  • FIG. 6 shows HPLC chromatograms of standard human insulin released at pH 1.2 and at pH 7.4.
  • FIG. 7 shows in vitro release profile of insulin-loaded microparticles of poly(VCL-co-MAA) in simulated gastric medium (pH 1.2) and intestinal medium (pH 7.4). Results presented are the representative means of ⁇ SD of three experiments.
  • FIG. 8 (A) shows in vivo OGTT tests performed with ( ⁇ ) carboxymethyl cellulose in 0.1 N HCl, ( ⁇ ) standard human insulin and (A.) insulin-loaded poly(VCL-co-MAA) particles through oral route and % inhibition given in the bar diagrams.
  • FIG. 8 (B) shows the % reduction in glucose levels (bar diagram) in fasted rats fed with insulin-loaded poly(VCL-co- MAA) microparticles.
  • FIG. 9 (A) shows the in vivo efficacy of orally fed insulin-loaded microparticles on alloxan- induced diabetic rats using ( ⁇ ) carboxymethyl cellulose in 0.1 N HCl, ( ⁇ ) standard human insulin, and ( ⁇ ) insulin-loaded poly(VCL-co-MAA) microparticles through oral route.
  • FIG. 9 (B) shows the % reduction in glucose on alloxan-induced diabetic rats fed with insulin-loaded poly(VCL-co-MAA) microparticles.
  • copolymer refers to N-vinylcaprolactam and methacrylic acid abbreviated as "poly(VCL-co-MAA)”.
  • MAA methacrylic acid
  • pH-sensitive copolymer refers to poly(VCL-c ⁇ -MAA).
  • neutral pH refers to pH about 7.4.
  • insulin refers to human insulin, porcine insulin, bovine insulin as well as their analogues, such as recombinants!
  • the present invention provides a novel pH sensitive copolymers of poly(VCL-co-MAA) for the controlled delivery of insulin.
  • the copolymer of the present invention in particular is prepared from iV-vinylcaprolactam and methacrylic acid monomers.
  • the hydro gel was prepared by varying the proportions of monomer and % of the insulin loading.
  • the methacrylic acid moiety was varied from 10 % to 50 % in relation to vinyl caprolactam monomer in the total composition of the copolymer.
  • the particle size of hydrogel microparticles was measured by particle size analyzer (3000HS, Malvern, UK). The particles were produced by sieving the freeze-dried hydrogel through 200 micron size mesh. The particle size of the hydrogel microparticles are in the range of 50-100 ⁇ m. It was possible to further decrease the size of these hydrogels to 0.2 ⁇ m using a micro fluidizer. As the size of the particle increased, the agglomeration also increased, thereby leading to absorption of moisture and affecting the oral dosing of the formulation when administered to the animals. For this reason, the particle size was reduced by passing through 200 ⁇ m mesh, which resulted in a uniform distribution of particles that eased the oral administration of formulation in animal experiments.
  • the pH sensitivity of the copolymer alone was performed gravimetrically (i.e., measuring the weight uptake vs time) by swelling experiments in pH 1.2 and 7.4 at 37 0 C.
  • the copolymer was soaked in 1.2 pH and 7.4 pH media separately; at certain interval of time, the copolymer was removed from the swelling media, taken in test bottles and blotted carefully (without pressing hard) using soft tissue paper to remove the surface-adhered water droplets. The copolymer was then weighed on an electronic microbalance accurate to ⁇ 0.0001 g.
  • the weight gain of the copolymer as observed in pH 7.4 varied from 0.100 g to 0.160 g in 4 h, whereas no weight gain was observed in pH 1.2 during the entire process of swelling " , which confirms that the copolymer is sensitive to pH; this property is well correlated with insulin in vitro release experiments.
  • the insulin-loaded poly(VCL-co-MAA) hydrogel microparticles were stored at 4 0 C for 4 months. After 4 months, the formulated samples were evaluated for their in vitro release profile in acidic pH 1.2 for 2 h and later in 7.4 pH phosphate buffer. The in vitro release samples were analyzed by HPLC at 210 nm. In this study, the chromatogram shows the sharp peak of insulin without any deamidation peak confirming that insulin was stable and retained its activity even after 4 months.
  • the present invention describes the various compositions of monomer ratios, % insulin loading and its effects on in vitro release as well as encapsulation efficiency. Monomer ratio was varied from 10:90 to 50:50 of MAA: VCL and insulin loading was varied from 1-2 %.
  • the variation in monomer ratio has shown an effect on insulin encapsulation efficiency, but the release pattern remained the same for all the formulations. As the methacrylic acid content increased, the encapsulation efficiency decreased.
  • the in vitro release samples were also analyzed by the Western blot method using acrylamide gel. The blot showed the presence of a band in all the released samples, which confirmed the integrity of insulin.
  • the formulations are biocompatible, but not biodegradable. As regards the safety issues, the polymer does not cause harmful effects to the human body because it is being used in a commercial formulation for facial application.
  • nifedipine is a prototype 1,4- dihydropyridine calcium channel blocker and doxycycline (DXY), a member of the tetracycline antibiotics group.
  • NFD and DXY drugs were encapsulated into poly(MAA-c ⁇ - VCL) by in situ method using free radical polymerization technique.
  • the monomers viz., solid powder of JV-vinyl caprolactam (VCL) and liquid methacrylic acid (MAA) were mixed in appropriate weights to obtain a total solution of 1 g at the fixed ratio of 75:25 of VCL:MAA.
  • the mixture was dissolved in 5 mL MiIH Q water at room temperature. After complete dissolution of the monomers, nitrogen gas was bubbled through the well-mixed homogeneous solutions for 30 min to remove the dissolved oxygen, a free radical scavenger, which will otherwise act as an inhibitor. To this solution, 0.1 wt. % (with respect to the total solution of 1 g) of the catalyst viz., ammonium persulfate and 50 mg of NFD was added with stirring. The total solution was allowed to react to form the hydrogel for 4 h. After 4 h, the hydrogel was washed with water to remove excess of monomers and freeze-dried at - 47 0 C for overnight. In the same way, DXY was encapsulated into poly(MAA-c ⁇ -VCL) hydrogel.
  • Encapsulation efficiency of the formulation of the present invention fall in the range of 37- 52%.
  • Previously Choeng K and Lim L.Y., Drug Dev. Ind. Pharm. 2004, 30, 359-67
  • the desired formulation with pH ranging from 2.2 to 3.4, which gave the maximum EE was obtained by adding 0.25 M HCl (20 to 100 mL) or 0.25 M NaOH (50 mL) to the pectin solution (0.1% in water) prior to mixing with the insulin solution.
  • the concentration of the insulin solution was increased to 80 LVmL to enhance insulin EE to 92 %, while that of CaCl 2 solution was lowered to 0.1% to reduce the particle agglomeration; whereas in the present invention, the insulin was loaded by in situ method. Since N-vinylcaprolactam is slightly hydrophobic, it reduces the amount of insulin encapsulation into the matrix.
  • PVCL Poly(vinyl caprolactam), PVCL is a non-biodegradable polymer and is known to absorb numerous organic compounds from water.' The characteristics of PVCL have been studied and some of its applications in the area of biotechnology and biomedicine have been described in the prior art (Makhaeva et. al., Makromol. Chem. Phys. 197, 1996, 1973-1982). Enzyme immobilization has been achieved with the help of PVCL, wherein the stability of enzymes has been increased with PVCL-based hydrogel that protects the enzymes from denaturation by entrapment (Gao et. al.,. Macromolecules 32, 1999, 3674-3677).
  • PVCL has been utilized in multi-layered glass materials in the 1960's, as an ingredient in wound-healing film (Patent, 1998, RU2117492; wound-healing and osteoplastic agent).
  • PVCL is available as a hair-fixative excipient under the trade name, Luviskol® Plus by the BASF company.
  • Poly(methacrylic acid) is partially biodegradable and its biodegradability can be increased by copolymerizing with a biodegradable polymer, such as poly( ⁇ - caprolactone), poly(ethylene glycol), etc.
  • a rinse aid formulation containing a low foam non- ionic surfactant, a low molecular weight poly(methacrylic acid) and high molecular weight stabilizing polymer has been desrcibed before.
  • PVCL is a homologue of polyvinylpyrrolidone), (PVP), a biocompatible polymer, widely used in medicine and pharmaceutics. PVCL has been toxicologically assessed for its suitability in cosmetic preparations. On the basis of the information available at our disposal and provided that the recommended concentrations and fields of application are adhered to, there is no evidence of any toxicological risks associated with its use. PVCL is also known to be very stable against hydrolysis and owing to its stability, is expected to be a biocompatible polymer. The amide group in the ring is directly connected to the carbon-backbone chain. Hence, PVCL does not break easily hydrolytically, but if the PVCL is hydrolyzed, a polymeric carboxylic acid builds up and small toxic amide compounds will not form.
  • PVP polyvinylpyrrolidone
  • Poly(methacrylic acid) is a derivative of polycarbophil and carbomer.
  • Carboxylic acid groups in poly(methacrylic acid) binds divalent ions like calcium/zinc and this may lead to reduction in integrity of epithelial tight junctions.
  • divalent ions calcium and zinc
  • divalent ions are essential enzyme cofactors for serine proteases and binding of these ions may lead to a significant reduction in their activity.
  • excellent mucoadhesivity and pH- sensitivity make these systems promising for oral peptide delivery applications (Peppas N.A. Hydrogels. In: Ratner B.
  • Poly(methacrylic acid) was used in the manufacture of methacrylate resins and plastics in the form of pellets and granules, as absorbent for biological materials and as filters; also, as biological membranes and as hydrogels.
  • PBS phosphate buffer solution
  • Microparticles 50 mg were suspended in 1 mL of PBS and placed inside the dialysis bag.
  • the sample inside the dialysis bag was kept in a conical flask containing 50 mL PBS as the dissolution medium on a shaker at 100 rpm at 37 0 C (New Brunswick Scientific Innova 4230, MN, USA).
  • the amount of drug released was determined by withdrawing 2 mL aliquots at the selected time intervals. The volume withdrawn was replenished with an equal volume of fresh and prewarmed PBS at 37 0 C.
  • the copolymer of the present invention can also be used for targeted delivery to the colon not only for local colonic pathologies to avoid systemic effects of drugs or inconvenient and painful trans-colonic administration of drugs, but also for systemic delivery of drugs like proteins and peptides, which are otherwise degraded and/or poorly absorbed in the stomach and small intestine, but may be better absorbed from the more benign environment of the colon.
  • hydrogels have been generally used to deliver hydrophilic, small-molecular weight drugs, which have high solubilities in both hydrophilic hydrogel matrix and the surrounding aqueous media.
  • the matrices of the type invented herein it is possible to achieve good encapsulation efficiency into the swollen hydrogel matrix and subsequently release the hydrophilic drug payload into an aqueous environment.
  • the matrices of the present invention may be potential for the treatment of diseases sensitive to circadian rhythms such as asthma, angina and arthritis.
  • colon delivery of drugs that are absorbable in the colon, such as steroids which would increase the efficiency and enable reduction of the required effective dose, can be administered using these matrices.
  • the present invention relates to a system or systems for releasing a drug or drugs or any bioactive ingredient thereof, specifically in the colon of the gastrointestinal (GI) tract. More particularly, it relates to a colon-specific drug release system, which comprises a drug, encapsulated in an organic acid-soluble polymer material and/or polysaccharide (Mundargi et al., Drug Development and Industrial Pharmacy, 33, 2007, 1- 10).
  • the present invention and the matrices developed are not only useful for insulin delivery, but also can be effectively used in case of various polypeptides, proteins and derivatives thereof that are easily degraded in the upper part of the GI tract and are absorbed in the lower part of the GI tract to exhibit their pharmacological activities.
  • drugs may include insulin, calcitonin, angiotensin, vasopressin, desmopressin, luteinizing hormone-releasing hormone (LH-RH); somatostatin, glucagon, oxytocin, gastrin, cyclosporin, somatomedin, secretin, human artial natriuretic peptide (h-ANP), melanocyte- stimulating hormone, (MSH), adrenocorticotropic hormone (ACTH), ⁇ -endorphin, muramyl dipeptide, enkephalin, neurotensin, bombesin, vasoacive intestinal polypeptide (VIP), parathyroid hormone (PTH), calcitonin gene-related peptide (CGRP), cholecystokinin-8 (CK-8), thyrotropin-releasing hormone (TRH), endocerine, human growth hormone (hGH), cytokines (e.g., interleukin, interferon, colon-stimuls,
  • peptides and proteins include not only the naturally occurring substances, but pharmacologically active drug derivatives thereof and the analogues thereof (Mundargi et al., J Control Release, 125, 2008, 193-209).
  • insulin used in the present art includes human insulin, porcine insulin, bovine insulin as well as their analogues, such as recombinants.
  • Drugs effective on diseases of lower part of GI tract are also useful in the present invention.
  • examples of such drugs include: salazosulfapyridine, 5-aminosalicylic acid, cortisone acetate, triamcinolone, dexamethasone, budesonide, tegafur, budesonide, metronidazole, mesalazine, sulfasalazine, fiuorouracil (Rokhade et al, J Microencapsulation, 24, 2007, 274- 288) and derivatives thereof.
  • physiologically active substances that can be used as the main active ingredient that is absorbed efficiently from the lower part of the GI tract.
  • physiologically active substances include for instance, antitussive expectorants, such as theophylline (Rokhade et al, Carbohydrate Polymers, 69, 2007, 678-687), vasodilators, such as nicardipine hydrochloride (Soppimath et al, Drug Dev Ind Pharm, 27, 2001, 507-515) and nifedipine " (Ramesh et.al., Carbohydrate Polymers, 69, 2007, 241-250), atenolol and carvedilol (Mundargi et al., Carbohydrate Polymers, 69, 2007, 130- 141), diltiazem hydrochloride (Aminabhavi et al., Designed Monomers and Polymers, 1, 1998, 347-372), coronary
  • the developed oral controlld-release (CR) formulations of insulin in which insulin was microencapsulated can reduce the denaturation of insulin that may possibly occur during microencapsulation step as well as reduce the initial burst of insulin in a living body and thereby, preventing the risk of hypoglycemia.
  • the insulin-loaded micron or submicron level formulations are suitably prepared for the successful oral delivery of insulin. Further, increased encapsulation efficiency and % inhibition of insulin on fasted as well as diabetic- induced rat experiments suggest the success of this approach in developing the devices for oral insulin delivery in a living body.
  • the CR formulation according to the present invention exhibits stable pharmaceutical efficacy in a living body continuously for a long period of time; it is thus possible to adjust the serum glucose concentration of a diabetic patient in a more stable and controllable manner, while reducing the number of administrations and avoiding the subcutaneous route injections. Further, the method developed is so simple that it can easily be scaled-up for large-scale applications.
  • the copolymers of this invention were prepared by free radical polymerization, whose general protocols are known in the prior art.
  • the monomers viz., solid powder of N- vinylcaprolactam (VCL) and liquid methacrylic acid (MAA) were mixed in appropriate weights to obtain the total solution of 1 g to maintain the ratios of 50:50 and 75:25 compositions of VCL.MAA.
  • This mixture was dissolved in 5 mL of Milli Q water taken in 50 mL beaker at room temperature.
  • nitrogen gas was bubbled through the well-mixed homogeneous solutions for 30 min to remove any dissolved oxygen, a free radical scavenger, which will otherwise act as an inhibitor.
  • 0.1 wt. % (with respect to the total solution of 1 g) of ammonium persulfate (APS) catalyst was added with stirring.
  • APS ammonium persulfate
  • the copolymeric hydrogel microparticles thus formed were designated as: P(VCL-Co-MAA) (50:50) and P(VCL-CO-MAA) (75:25).
  • the above compositions were fixed based on several trial experiments. However, of these two compositions, the one that gave the optimum results viz., the formulation containing 75:25 matrix was selected for the detailed final study.
  • the effect of insulin loading on encapsulation efficiency in this hydrogel preparation was studied by varying insulin from 1 to 2 %. Insulin-loaded P(VCL-c ⁇ -MAA) hydrogel microparticles were prepared at room temperature (22 0 C) because of the thermal instability of insulin at higher temperatures.
  • thermo-stable drug molecules such as NFD and DXY
  • the copolymeric hydrogel microparticles were prepared both at room temperature (i.e., 22 0 C) and at 5O 0 C.
  • the encapsulation efficiency and in vitro release of thermo-stable drug formulations prepared at room temperature and at 5O 0 C are the same, indicating that the property of the copolymer remains unchanged at these two temperatures investigated.
  • VCL MAA Poly(VCL-co-MAA)
  • Carbonyl (C-O) stretching vibrations are seen at 1665 cm “1 , but the bands at 1390 cm *1 and 1347 cm “1 are due to C-H stretching and C-H bending vibrations, respectively.
  • the bands at 1259 cm “1 and 1185 cm “1 belong to C-N stretching vibrations.
  • the region 1500 - 1700 cm * corresponds to absorption bands of VCL and the copolymer.
  • the amide band splits into a doublet at 1621 cm “ ' and 1615 cm “1 .
  • the formation of carbonyl-stretching band in the copolymer indicates hydrogen- bonding interactions between VCL and MAA in the copolymer.
  • the OH band appearing at 3398 cm “1 is shifted to lower frequencies, implying change in the nature of H-bonding, which further confirms the formation of H-bonds between amide and carboxyl groups.
  • Thermal stability of the copolymer was studied by TGA in the temperature range from O 0 C to 800 0 C under inert nitrogen atmosphere.! Thermal degradation patterns of copolymer (Fig. 3) has three weight loss stages occurring in the regions 60-140 0 C, 190-310 0 C and 350- 460 0 C. The first stage of weight loss between 60-140 0 C corresponds to a loss of water molecules/moisture present in the polymer. The maximum weight of 54 % has been occurred between 350-460 0 C.
  • the drug-loaded sample was successfully processed using a Microfluidizer processor.
  • the mean particle size for the insulin-loaded sample after twenty passes was reduced from its original size of 50 microns to about ⁇ 10 microns.
  • the instrument used was an M-110S microfluidizer processor, using the GlOZ interaction chamber at 23,000 psi at various numbers of passes. Prior to exit, the sample passed through a cooling coil. Graphic results are shown in Figure 4. Size distribution analysis was done by laser diffraction spectroscopy using Malvern zeta sizer (3000HS Malvern Instruments, UK). Mean diameters of the aqueous suspensions were determined in triplicate and the size distribution was estimated based on the number.
  • SEM scanning electron microscopy
  • JSM-840 Joel Instruments, Tokyo, Japan
  • Insulin was encapsulated into the hydrogel during the preparation of hydrogel by free radical polymerization technique. Its encapsulation was found to be around 52 %
  • Microparticles of this study loaded with insulin were evaluated for encapsulation efficiency (EE).
  • the EE was estimated by sonicating a known amount of insulin- loaded microparticles and extracting the insulin from the particles.
  • the amount of insulin released from the hydrogels was collected by taking 100 ⁇ L samples at predetermined time intervals of 1 h up to 8 h and analyzed using HPLC. Insulin was separated on a Cl 8 Vydac 218MS54 column (4.6 x 250 mm) having a pore size of 300 A 0 and a particle size of 5 microns.
  • the buffer for mobile phase was prepared by dissolving 28.4 g of anhydrous sodium sulfate in 1000 mL of double distilled water and adjusting the pH of the buffer to 2.3 with 2.7 mL of orthophosphoric acid.
  • the mobile phase consisted of (A) 82:18 of acetonitrile:buffer and
  • EE of the formulations developed varied from 37 to 56 %. Table 1 depicts the mean values of EE. Of the many trial experiments using both bovine insulin and human insulin taken in polymer systems, human insulin was used in the final studies that gave 52 %.
  • the in vitro release experiments were done by taking 100 mg of insulin-loaded P(VCL-CO- MAA), particles in a flask containing 50 mL of buffer solution. Particles were placed in buffer solution to allow insulin release. The dissolution was carried out in an incubator maintained at 37 0 C under constant stirring at 200 rpm. At regular intervals of time, aliquot samples (2 mL each time) were withdrawn and analyzed for insulin using the HPLC at the ⁇ max value of 210 nm employing the gradient method. In order to simulate the stomach and intestinal environments, all release experiments were performed in solutions of pH of 1.2 and 7.4, respectively. The formulations were kept in 1.2 pH media for the first 2 h and later, in pH of 7.4 media to simulate the intestinal environment. The in vitro data of formulation prepared are graphically displayed in Figure 7.
  • P(VCL-co-MAA) exhibit pH-dependent swelling due to reversible formation of inter- polymer complexes stabilized by the hydrogen-bonding between ethereal groups of the grafted VCL, and carboxylic acidic protons of PMAA network.
  • This type of complex formation is very sensitive to the pH of media as well as copolymer composition and graft chain length.
  • hydrogels are in a complexed state such that insulin cannot readily diffuse through the membrane barrier.
  • the pH increases above the transition pH of the hydrogel and the complex immediately dissociates; the network pore size will then rapidly increase, leading to the release of insulin.
  • the in vitro release of insulin hydrogel particles displayed in Figure 7 represent unique pH- responsive property of P(VCL-co-MAAc) hydrogels in which inter-polymer complexes are formed in acidic media and dissociated in neutral environment.
  • the insulin release can be significantly retarded in acidic media, while rapidly releasing it in neutral/basic conditions
  • the EE of insulin within the hydrogel would greatly reduce.
  • the content of methacrylic acid in the copolymer was varied from 25 to 50 % with respect to the total weight of the monomer content.
  • the P(VCL-Co-MAAc) copolymeric hydrogel was prepared by employing lower quantity of MAA., because of the possible toxicity of byproducts generated during degradation.
  • the MAA proportion has a profound effect on the encapsulation of insulin into the copolymeric hydrogel and it was found that lower content of MAA favors higher encapsulation into the hydrogel.
  • EXAMPLE 5 Oral efficacy of insulin formulations for oral glucose tolerance test (OGTT) and antidiabetic activity in rats
  • Group 1 For insulin preclinical studies, the fasted rats were divided into three groups of six rats each Group 1 is the control group, which received saline.
  • Group 2 rats received the formulation equivalent to 20 IU of insulin-loaded poly(methacrylic acid-co-JV- vinyl caprolactam) particles dispersed in a mixture of 9 mL of 5 % carboxy methyl cellulose (CMC) and 1 mL of cone. HCl solution through the oral route using the oral feeding needle.
  • Group 3 received 400 ⁇ L of 5 IU of pure insulin solution through the IP route.
  • rats of all groups were orally treated with 2 g/kg of glucose.
  • Blood samples were collected from the rat tail vein/retro orbital just prior to glucose administration i.e., 0 min and at 30, 60 and 90 min after glucose loading. Blood glucose levels were measured immediately using a glucometer.
  • the pulsatom gluco-strips (stored in refrigerator) were used for estimation.
  • the glucometer was calibrated to 660 units or as according to the specifications mentioned in the strips.
  • the blood removed from the rat is immediately spread on the marked end of the strip.
  • the strip was then inserted in the glucometer where, two electrodes are situated. After few seconds the glucometer displayed the blood glucose level.
  • Figure 8A represents the in vivo efficacy (oral glucose tolerance test; OGTT) of insulin- loaded poly(iV-vinylacaprolactam-co-methacrylic acid).
  • OGTT oral glucose tolerance test
  • the standard insulin gave glucose drop from 21 1 to 137 with 64 % inhibition
  • the insulin-loaded particles administered by the oral route gave glucose drop from 170 to 80 with 53 % inhibition as shown in Figure 8B.
  • the inhibition rate was 53 % owing to the mucoadhesive property of iV-vinylcaprolactam and other enzymes in the stomach.
  • mice Male Wistar rats (250 g) were housed in a 12-12 h light-dark cycle, constant temperature environment of 22 0 C, relative humidity of 55 % and allowed free access to water and food during acclimatization. To minimize the diurnal variance of blood glucose, all the experiments were performed in the morning. Diabetes was induced with intravenous injection of 150 mg/kg alloxan in saline (0.9% NaCl). Ten days after the treatment, rats with frequent urination, loss of weight and blood glucose levels higher than 300 mg/dL were included in the experiments. Blood glucose levels were determined by glucose oxidase/peroxidase method using a glucometer. The 5 % dextrose solution was given in feeding bottle for a day to overcome the early hypoglycemic phase. After 72 hours blood glucose was measured by glucometer. The diabetic rats (glucose level > 300 mg/dl) were separated.
  • the Figure 9A represents the in vivo efficacy of orally fed insulin-loaded (VCL-co-MAA) on alloxan-induced diabetic rats.
  • the standard insulin gave glucose drop from 217 to 44 with 80 % inhibition
  • the insulin-loaded particles (VCL-co-MAA) by the oral route gave glucose drop from 219 to 86 with 60 % inhibition as shown in Figure 9B.
  • the release profile of hydrogel changes with time and pH.
  • the in vitro release was carried out at both pH 1.2 and 7.4.
  • pH 1.2 From 1 to 2 hrs, there is a suppression of swelling of the hydrogel and there is no release.
  • compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in the light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents that are chemically or physiologically related may be substituted- for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

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Abstract

La présente invention concerne des copolymères de poly(acide méthacrylique-co-N-vinylcaprolactame) sensibles au pH, nommés P(MAA-co-VCL). L'invention concerne en particulier la synthèse d'un copolymère de poly(acide méthacrylique-co-N-vinylcaprolactame) et son application pour l'administration orale, sensible au pH, de principes actifs in vitro et in vivo. L'invention décrit en particulier des microparticules contenant les copolymères pour la libération contrôlée d'un médicament administré. L'invention décrit également des méthodes d'administration de médicament au tractus gastro-intestinal inférieur, permettant d'éviter ce faisant une exposition aux acides de l'estomac, ainsi que des méthodes de traitement du diabète à l'aide de particules prévues pour l'administration d'insuline à libération contrôlée.
PCT/IN2010/000204 2009-03-31 2010-03-30 Nouveaux copolymères pour système d'administration à libération contrôlée WO2010113176A2 (fr)

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CN114431339A (zh) * 2022-02-14 2022-05-06 浙江汇能生物股份有限公司 一种低添加增稳微囊化二甲酸钾饲料添加剂及其制备方法

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108066313A (zh) * 2017-12-29 2018-05-25 成都恒瑞制药有限公司 一种盐酸二甲双胍包合物的制备方法及制备设备
CN114431339A (zh) * 2022-02-14 2022-05-06 浙江汇能生物股份有限公司 一种低添加增稳微囊化二甲酸钾饲料添加剂及其制备方法
CN114431339B (zh) * 2022-02-14 2023-06-27 浙江汇能生物股份有限公司 一种低添加增稳微囊化二甲酸钾饲料添加剂及其制备方法

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