WO2008064338A2 - Valsartan formulation for pulsatile delivery - Google Patents
Valsartan formulation for pulsatile delivery Download PDFInfo
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- WO2008064338A2 WO2008064338A2 PCT/US2007/085434 US2007085434W WO2008064338A2 WO 2008064338 A2 WO2008064338 A2 WO 2008064338A2 US 2007085434 W US2007085434 W US 2007085434W WO 2008064338 A2 WO2008064338 A2 WO 2008064338A2
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- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
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- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
Definitions
- the present invention relates to the method of increasing the bioavailability of Angiotensin Il Receptor Blockers (ARBs) by preparing a composition of an ARB that is capable of releasing the medicament intermittently in the Gl tract in pulses at predetermined time intervals.
- ARBs Angiotensin Il Receptor Blockers
- the present invention relates to orally deliverable compositions designed to release solubilized ARB, in particular valsartan in the upper gastrointestinal tract.
- Angiotensin Il is a very potent end product chemical that causes the muscles surrounding the blood vessels to contract, which thereby significantly narrowing the blood vessels. This narrowing increases the pressure within arterial vessels, causing high blood pressure (hypertension).
- Angiotensin receptor blockers are drugs that block the action of angiotensin II. As a result, arterial vessels dilate and blood pressure is reduced, thereby making it easier for the heart to pump blood. ARBs can therefore also be used to improve heart failure as well as hypertension. In addition, they slow the progression of kidney disease due to high blood pressure or diabetes.
- Drugs in this class include candesartan (Atacand, Astra-Zeneca), eprosartan (Teveten, Solvay and Biovail), irbesartan (Avapro, BMS), losartan (Cozaar, Merck), olmesartan ⁇ Benicar, Medoxomil; Sankyo and Forest), telmisartan (Micardis, Boehringer Ingelheim), valsartan (Diovan, Novartis) and pratosartan (Kotobuki).
- ARBs are used alone or in combination with other classes of antihypertensive agents that include thiazide diuretics, ⁇ -blockers, calcium channel blockers, rennin inhibitor, and ACE inhibitors, both for the treatment of hypertension and congestive heart failure.
- Valsartan a selective ARB, is a well-known antihypertensive agent. Valsartan is rapidly absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of valsartan is about 25% (10-35%). This relatively low bioavailability of valsartan is primarily due to its poor solubility in the acid milieu of the gastrointestinal tract. Valsartan is an acid, and therefore, has good solubility at pH>5 and low solubility in acidic conditions of the gastrointestinal (Gl) milieu. Valsartan is absorbed from the upper gastrointestinal tract where its solubility is low.
- valsartan The synthesis and use of valsartan are described in US Patent No. 5399578 ('578 patent). Various polymorphs and salt forms of valsartan are described by WO 04083192, WO04087681 , and WO03066606.
- WO 04101535 relates to pharmaceutical compositions and a method of reducing the risk of morbidity and mortality in patients having symptomatic heart failure comprising administering to such patient an effective amount of valsartan, or pharmaceutically acceptable salts thereof, alone or in combination with another therapeutic agent, optionally in the presence of a pharmaceutically acceptable carrier.
- This patent describes the novel use or novel crystalline forms of valsartan, but does not tackle the problem associated with the poor bioavailability of valsartan.
- US Patent No. 6,294,197 ('197 patent) and US Patent Application Publication No. 2003/0035832 describe the solid oral dosage forms of valsartan alone or in combination with hydrochlorothiazide (HCTZ) along with a pharmaceutical additive for the preparation of solid dosage forms by a compression method.
- the solid dosage form according to this invention contains more than 35% by weight of the active agent in the formulation.
- a process of making such dosage form employing roll compaction is also disclosed.
- US Patent No. 6,485,745 (745) solid dosage forms of valsartan are described which exhibit accelerated release of the active agent in pH 6.8 phosphate buffer. However release in 0.1 N HCI is not addressed where the solubility of valsartan is minimal.
- US Patent Application Publication No. 2002/0132839 and US Patent Application Publication No. 2003/0152620 discuss pharmaceutical compositions of valsartan tablet dosage form are at least 1.2 times more bioavailable than the conventional valsartan capsule.
- the tablet formulation according to the invention contains a disintegrant at concentration level of 10-80% based on total weight of the composition. The higher amount of disintegrant ensures that the hydrophobic valsartan is wetted well during the granulation stage.
- the tablet is readily dispersed as granules in the dissolution medium resulting in a better dissolution and improved bioavailability over the normal formulation.
- the invention does not, however, describe methods to increase solubility of the valsartan itself in the gastric milieu; and therefore, the dissolution of valsartan in 0.1 N HCI still remains low which results in low bioavailability.
- Candesartan cilexitil like valsartan, is a hydrophobic molecule with poor aqueous solubility resulting in poor oral availability (about 14%).
- WO 2005/070398 A2 claims pharmaceutical compositions in the form of tablets that include candesartan cilexitil, fatty acid glycerides, a surfactant, a co-solvent and pharmaceutically acceptable additives.
- the formulation is further coated with a film forming polymer and polyethylene glycol.
- the co- solvent employed only improves the stability of candesartan and does not alter its solubility or dissolution rate in acidic medium.
- United States Patent Application Publication No. US 2005/0220881 provide methods of improving dissolution of Eprosartan by preparing its association complex with one or more solid poloxamers.
- a large amount of poloxamers is required to achieve significant dissolution enhancement.
- the dosage form development of such a complex that would achieve a higher oral bioavailability becomes very difficult due to weight limitations.
- large amount of poloxamers for chronic use may not be allowed.
- the low bioavailability associated with poor aqueous solubility warrants administration of larger doses of the ARBs to maintain desired therapeutic activity. None of the patents described above details methods of achieving an improved ARB composition.
- solubilized pulsatile systems can be employed for increasing bioavailability of the ARB by releasing drug in pulses at predetermined sites in gastrointestinal tract and thus maximizing its absorption. It was surprisingly found that the use of solubilized valsartan in different pulses not only achieves the desired in-vitro dissolution rate but is also predictably able to release drug at predetermined time intervals.
- An object of the present invention is to increase the therapeutic effectiveness of an ARB over a 24-hour period.
- Another object of the present invention is to provide a dosage form to effectively control the hypertension, for the treatment of myocardial infarction and other heart diseases and for the end organ protection in the patient population.
- the present invention provides a method of increasing the bioavailability of an ARB by administering solubilized ARB in pulses.
- An object of the present invention relates to delivery systems and methods of predictably increasing the bioavailability of ARBs, especially valsartan, and insuring consistent absorption over a wide pH range of the gastrointestinal (Gl) tract by releasing the drug at different sites of Gl tract in pulses at different absorption site such as stomach, duodenum, jejunum and ileum.
- Gl gastrointestinal
- this novel composition of valsartan provides at least 40% dissolution in acidic and weakly acidic dissolution medium.
- acidic refers to pH less than about 3.
- Weakly acidic refers to pH of about 3 to 5.
- Another object of the present invention also relates to a physically and chemically stable formulation of ARBs, in particular valsartan, utilizing generally recognized as safe (GRAS) excipients.
- GRAS generally recognized as safe
- This invention also relates to an oral dosage formulation of valsartan having reduced intra- and inter-patient variability in absorption, particularly at low Gl pH.
- a formulation containing an ARB is designed to release the active pharmaceutical ingredients in pulses or over a longer period of time.
- the term "pulse” as used herein refers to the release of the ARB in the Gl tract in intermittent dosages. The release, for example, will be in different parts of the Gl tract depending on the pH of intestinal milieu as the solid dosage form makes its way through the Gl tract exposing to different pH environment.
- the pulsed release of the active ingredient is preferably accomplished by coating the drug granules with pH sensitive polymers which dissolves only in specific pH environment.
- a desired agent for example, a drug
- a delivery method that provides a brief, sudden increase in an otherwise constant amount of the agent to a patient in need of the same.
- These short bursts are characterized by separate peaks in the release profile of a dosage form as it travels through the gastrointestinal tract after ingestion.
- a "pulse" of a desired agent results in a brief, sudden release of a desired amount of an agent from a delivery system such that as a result of this release, there is a rapid increase in the concentration of the agent at the desired site in the patient.
- Such increase is over and above whatever level of the agent had been previously present, if any, prior to the "pulse.”
- the increase is not sustained in a prolonged fashion unless repeated pulses are provided.
- the pulse is the result of an immediate release or a short sustained release of the drug.
- the dosage form contains multiple parts, each of which is designed to releases at a particular site of the digestive system.
- the dosage form may contain a firs part that is immediate release, a second part that is coated for release at 6-8 hours; and a third part that is coated for release at 10-12 hours.
- pulses occur at 0 hr, 5-7 hours, and 10-12 hours after ingestion.
- Coatings can be designed to release the active ingredient at pre-selected time intervals as discussed below.
- the different parts of a dosage form for releasing at different time intervals may be nested together.
- the dosage form may contain an outer layer of immediate release part and inner cores of delayed release parts.
- the dosage form may also contain different layers pressed together with each layer releasing at a different time interval.
- the innermost layer would be the last to be released, while the outermost layer would be the first to be released.
- the different parts of the dosage form may be a plurality of mini-tablets enclosed in a capsule.
- the mini-tablets are designed to be released at different time intervals to effect pulsed release. For example, there may be three groups of mini-tablets, each group releasing the active ingredient at a different time interval (e.g. immediate, 5-7 hours, and 10-12 hours). Upon ingestion of the capsule, the mini-tablets are released in the stomach to effect pulsed release of the active ingredient.
- the first pulse occurs 0-1 hour after ingestion and the second pulse occurs 2-3 hours after ingestion;
- the first pulse occurs 0-1 hour after ingestion, the second pulse occurs 3-4 hours after ingestion;
- the first pulse occurs 1-2 hours after ingestion and the second pulse occurs 3-6 hours after ingestion;
- the first pulse occurs 1-2 hours after ingestion and the second pulse occurs 3-6 hours after ingestion and third pulse occurs 7-10 hours after ingestion;
- the pharmaceutical composition of claim 12 wherein the first pulse occurs 2-5 hours after ingestion and the second pulse occurs 6-9 hours after ingestion;
- the second pulse occurs 5-7 hours after ingestion and the third pulse occurs 10-12 hours after ingestion;
- the first pulse occurs 0-1 hour after ingestion
- the second pulse occurs 4-8 hours after ingestion
- the third pulse occurs 10-14 hours after ingestion.
- an ARB particularly valsartan
- a solubility enhancing agent significantly increases its solubility in acidic environment (pH ⁇ 3) as well as an improved dissolution rate which is in sharp contrast to the currently marketed ARB formulations.
- the bioavailability will also increase as more absorbable form of the drug (free acid form of valsartan) is present in the solubilized form at the absorption site.
- the increase in bioavailability reduces the dose of the ARB required to achieve the desired effect as well as patient to patient variability, and thus, enhances the therapeutic utility of the ARB.
- the solid dosage form can be manufactured using conventional manufacturing processes and standard processing equipments that are generally used to manufacture the solid dosage form.
- the active ingredient for the purpose of this invention is an ARB, which may be, but not limited to, candesartan, eprosartan, irbesartan, losartan, olmesartan, teimisartan, valsartan, or eprosartan.
- the active ingredient of the invention may be present in crystalline or amorphous form.
- the crystalline form may have different polymorphs. All different polymorphs, solvates, hydrates, salts are within the purview of this invention.
- the preferred active ingredient is valsartan.
- the dosage form of the present invention in addition to an ARB, one or more, for example two or three, active ingredients may be combined.
- the therapeutic agents which may be combined with an ARB include, but are not limited to, anti-hypertensive agents, such as hydrochlorothiazide (HCTZ), calcium blockers, beta-blockers, ACE inhibitors, inotropic agents, hypolipidemic agents, anti-obesity agents, rennin inhibitors, and/or anti- diabetic agents.
- anti-hypertensive agents such as hydrochlorothiazide (HCTZ), calcium blockers, beta-blockers, ACE inhibitors, inotropic agents, hypolipidemic agents, anti-obesity agents, rennin inhibitors, and/or anti- diabetic agents.
- the present invention is also applicable to other active pharmaceutical ingredients having similar low solubility related bioavailability issues.
- the active ingredient may be present in an amount of about 1-80%, preferably 5- 50%, and more preferably 10-30% by weight of the composition.
- composition of the present invention of valsartan may be used to treat the diseases described below and to deliver the solubilized form of the drug over the wide pH range of the Gl tract to increase bioavailability. Therefore, the dose and frequency of administration can be reduced, compared with administration of conventional valsartan. Moreover, the inter- and tntra-patient variability associated with the current formulation of valsartan can also be reduced. Therefore, it is expected that there will be an increased therapeutic effect from this composition of the present invention of valsartan.
- diseases to be treated by this agent include 1. circulatory disease, such as hypertension, cardiac disease (heart failure, myocardial infarction, valvular disease), peripheral circulatory insufficiency; 2.
- kidney disease e.g., glomerulonephritis, renal insufficiency
- cerebral dysfunction e.g., stroke, Alzheimer's disease, depression, amnesia, dementia
- diabetic complications e.g., retinopathy, nephropathy
- arteriosclerosis manifested by hypertension, stroke, heart attack, angina, or ischemia of gastrointestinal (Gl) tract or extremities
- unique conditions e.g.; hyperaldosteronism, multiple system organ failure, scleroderma
- anxiety neurosis catatonia, and dyspepsia. Many of these conditions are caused or exacerbated by vasoconstriction expressed secondary to angiotensin II.
- Solubilization of an ARB is achieved by using one or more suitable solubility enhancing agent.
- the solubility enhancing agent may include one or more surfactant, solubilizer, complexing agent, hydrotropic agent, and the like.
- the solubility enhancing agent could be the same or different for different ARB's.
- the solubility enhancing agent may be, but not limited to, hydrophilic surfactants, lipophilic surfactants, mixtures there of.
- the surfactants may be anionic, nonionic, cationic, zwitterionic or amphophilic.
- the relative hydrophilicity and hydrophobicity of surfactants is described by HLB (hydrophilic-lipophilic balance) value.
- Hydrophilic surfactants include surfactants with HLB greater than 10 as well as anionic, cationic, amphiphilic or zwitterionic surfactants for which the HLB scale is not generally applicable.
- lipophilic surfactants are surfactants having an HLB value less than 10.
- the solubility enhancing agent may be PEG-20-glyceryl stearate ⁇ Capmul® by Abitec), PEG-40 hydrogenated castor oil (Cremophor RH 40® by BASF), PEG 6 corn oil (Labrafil® by Gattefosse), lauryl macrogol - 32 glyceride ⁇ Gelucire 44/U® by Gattefosse), stearoyl macrogol glyceride (Gelucire 50/13® by Gattefosse), polyglyceryl - 10 mono dioleate (Caprol ® PEG 860 by Abitec), propylene glycol oleate (Lutrol OP® by BASF), propylene glycol dioctanoate (Captex® by Abitec), propylene glycol caprylate/caprate (Labrafac® by Gattefosse), glyceryl monooleate (Peceol® by Gattefosse), glycerol monolinoleate (
- the solubilizers may also include pH modifiers such as buffers, amino acids and amino acid sugars and complexing agent such as cyclodextrin class of molecules, such as alpha- cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, or their derivatives, such as hydroxypropyl beta cyclodextrins, or mixtures thereof.
- the complexing agents may also include cyclic amides, hydroxyl benzoic acid derivatives as well as gentistic acid. In this complexation process, a hydrophilic polymer may be additionally added to further enhance the solubility along with the complexing agent.
- the ARB and one or more solubility enhancing agents may be employed in different ratios.
- the selected ratio depends upon the desired improvement in solubility and the type of solubility enhancing agents employed. It is contemplated within the scope of the invention that the ratio of ARB to solubility enhancing agents may range from about 20:1 to about 1 :20, preferably from about 10:1 to about 1 :10, and most preferably about 5:1 to about 1 :5.
- a combination of solubility enhancing agents may also be included where the total amount of solubility enhancing agent employed is maintained in the above-mentioned ratios.
- the solubilized ARB is converted into a powder, granule or tablet formulation.
- ARB and the solubilizers are dissolved in a common solvent and sprayed onto beads made up of sugar or cellulose.
- These dosage forms such as powder, beads, granules, tablets, capsules containing solubilized ARBs are coated with release retardants which releases drug under predetermined conditions, of pH or alternatively after a fixed time intervals.
- test product was more bioavailable than the marketed product (Diovan®).
- the test product provided faster onset of action.
- the test product achieved more uniform plasma levels with reduced the variability.
- a better formulation is thus obtained which reduces variability, possibly allows reduction in dose, and also, gives rapid onset of action, which may lead to increased patient compliance.
- the increase in bioavailability is only 1.6 fold which means about 40% and thus there is a scope for further improvement in the bioavailability of valsartan.
- WO 2006/113631 showed much higher plasma concentration (Cmax), rapid onset (T max ) and higher AUC (extent of absorption).
- Cmax plasma concentration
- T max rapid onset
- AUC extent of absorption
- the elimination of drug from plasma is similar for the both formulations (Diovan and WO 2006/113631 ).
- the plasma concentrations of valsartan for the both formulations are similar after 10 hours. This is realiy not offering a true once a day formulation. Even though the tested formulation has much higher bioavailability and high plasma concentration in the first 4 to 6 hours, it eliminates from the central compartment rapidly. What we need is a formulation that will have somewhat higher plasma concentrations than Diovan for at least 18 hours.
- the C ma ⁇ of Diovan is 4405.7 ng/ml.
- the 50 mg of our bioenhanced formulation gives a C max of 4510 ng/ml.
- the concentration of valsartan in plasma is 2255 ng/mi.
- the new calculated C max is 2255 plus 15X90.2 ng/ml/mg valsartan which is 3608 ng/ml.
- the concentration of valsartan at the end of 12 hours is 1804 ng/ml.
- the new burst releases additional 15 mg of valsartan and the new C max is 3157 ng/ml.
- the plasma concentration of valsartan is1578 ng/ml and at the end of 24 hours 789 ng/ml. If the higher drug amount is needed we can increase the initial burst concentration.
- This type of release can be accomplished with the use of pH sensitive polymers.
- the pH of Gl tract varies from 1 to 7.2. As the drug formulation moves through the Gl tract, it exposes to the Gl fluid of increasing pH. If the drug is formulated with pH sensitive polymers, it will release the drug depending on the pH. Thus taking advantage of Gl pH conditions, one can achieve drug release in pulses at different pH conditions.
- the pH 5 polymer coated beads will dissolve when exposed to pH 5 environment and thus releasing the first pulse of the drug and the second pulse will be release when the granules exposed to pH 6.8 of Gl milieu.
- the aforementioned pulsatile release profile is achieved with dosage forms that are closed and preferably sealed capsules housing at least two drug- containing "dosage units" wherein each dosage unit within the capsule provides a different drug release profile.
- Control of the delayed release dosage unit ⁇ s is accomplished by a controlled release polymer coating on the dosage unit, or by incorporation of the active agent in a controlled release polymer matrix.
- Each dosage unit may comprise a compressed or molded tablet, wherein each tablet within the capsule provides a different drug release profile. For dosage forms mimicking a twice a day dosing profile, a first tablet releases drug substantially immediately following ingestion of the dosage form, while a second tablet releases drug as per predetermined time interval. A third tablet extending the duration of drug release may also be added.
- each dosage unit in the capsule may comprise a plurality of drug- containing beads, granules or particles.
- drug-containing beads refer to beads made with drug and one or more excipients or polymers.
- Drug-containing beads can be produced by applying drug to an inert support, e.g., inert sugar beads coated with drug or by creating a "core” comprising both drug and one or more excipients.
- drug-containing "granules" and “particles” comprise drug particles that may or may not include one or more additional excipients or polymers. In contrast to drug-containing beads, granules and particles do not contain an inert support.
- Granules generally comprise drug particles and require further processing. Generally, particles are smaller than granules, and are not further processed. Although beads, granules and particles may be formulated to provide immediate release, beads and granules are generally coated to provide delayed release. The capsule may contain different groups of beads which release drug at different yet predetermined time intervals.
- the individual dosage units are compacted in a single tablet, and may represent integral but discrete segments thereof (e.g., layers), or may be present as a simple admixture.
- drug-containing beads, granules or particles with different drug release profiles e.g., immediate and delayed release profiles
- a dosage form in a further alternative embodiment, comprises an inner drug-containing core and at least one drug-containing layer surrounding the inner core.
- An outer layer of this dosage form contains an initial, immediate release dose of the drug whereas the inner layers contain a coating that delays the release of the drug.
- a dosage form of the invention comprises a coated core- type delivery system wherein the outer layer is comprised of an immediate release dosage unit, such that active agent therein is immediately release following oral administration, an intermediate layer thereunder surrounds a core, and the core is comprised of immediate release beads or granules and delayed release beads or granules, such that the second dose is provided by the immediate release beads or granules and the third dose is provided by the delayed release beads or granules.
- Such methods include, but are not limited to, the following: coating a drug or drug-containing composition with an appropriate coating material, typically although not necessarily a incorporating a polymeric material; increasing drug particle size; placing the drug within a matrix; and forming complexes of the drug with a suitable complexing agent.
- the delayed release dosage units in any of the above embodiments can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material.
- the drug-containing composition may be, e.g., a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core” dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule.
- the dissolution time of the individual subunits can be controlled by several methods to be discussed herein below.
- Two illustrative means of controlling dissolution are (1 ) pH- sensitive enteric coatings which are eroded in response to the pH of the aqueous environment in the gastrointestinal tract and (2) permeability-controlled systems which are subject to disruption in response to absorption of water from the environment which creates a pressure as the core contents expand.
- Variation of process variables and coating and core compositions, in manners to be discussed hereinbelow, enables precise tailoring of the dissolution, or pulse, time of the individual unit cores.
- the individual units are combined into a unitary depot which may be single tablet or a gelatin capsule or any other form known in the art.
- Enteric coatings of pH-sensitive polymers are employed to control the time of delivery of a drug-containing core composition to the small intestine of a living mammal.
- enteric coatings include: insolubility in the stomach, solubility in the intestines, no toxicity, moisture permeability resistance, stability, and good coating capability.
- enteric coating give list-
- Permeability-controlled systems are generally based on polymeric coatings which are water-permeable to permit water from the aqueous environment in the gastrointestinal tract of a living being to enter into a coated drug-containing core at a controllable rate and to displace air from the core followed by a build-up of pressure as the core contents expand until the coating is ruptured at the appropriate time.
- the polymeric coating for the permeability-controlled system must be impermeable to the drug and permeable to the intake of water and the expulsion of air.
- the core composition for permeability-controlled systems may advantageously contain osmotic agents, such as salt, to facilitate water transport to the core.
- Preferred coating materials are comprised of bioerodible, gradually hydrolyzable, gradually water-soluble, and/or
- the coating composition may include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc.
- excipients whose performance is dependent on the pH of the medium.
- excipients known in the art include poly methacrylic acid derivatives, cellulose derivatives, acrylic acid derivatives, maleic acid copolymers, polyvinyl derivatives etc.
- Cellulose based pH dependent release retardant include hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethylethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, carboxymethylethylcellulose, ethylhydroxyethylcellulose phthalate and the like.
- Acrylic copolymer based pH dependent release retardant include styrene • acrylic acid copolymer, methyl acrylate ⁇ acrylic acid copolymer, methyl acrylate ⁇ methacrylic acid copolymer, butyl acrylate ⁇ styrene ⁇ acrylic acid copolymer, methacrylic acid • methyl methacrylate copolymer (e.g. Trade-names: Eudragit L 100 and Eudragit S, available from Rohm Pharma), methacrylic acid ⁇ ethyl acrylate copolymer (e.g. Trade-name: Eudragit L 100-55, available from Rohm Pharma), methyl acrylate ⁇ methacrylic acid ⁇ octyl acrylate copolymer
- Maleic copolymer based pH dependent release retardant include vinylacetate • maleic acid anhydride copolymer, styrene • maleic acid anhydride copolymer, styrene ⁇ maleic acid monoester copolymer, vinylmethylether • maleic acid anhydride copolymer, ethylene ⁇ maleic acid anhydride copolymer, vinylbutylether • maleic acid anhydride copolymer, acrylonitrile ⁇ methyl acrylate • maleic acid anhydride copolymer, butyl acrylate ⁇ styrene ⁇ maleic acid anhydride copolymer and the like.
- Polyvinyl derivative based pH dependent release retardant includes polyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinyl butylate phthalate, polyvinylacetoacetal phthalate and the like.
- methacrylic acid • methylmethacrylate copolymer and methacrylic acid • ethylacrylate copolymer are preferable which are available under the brand name Eudragit®.
- Eudragit is the trade name for a number of film coating substances on an acrylic resin basis produced by Rohm Pharma.
- Eudragit L100® is used in matrix sustained release formulations especially for reducing burst release (excessive drug release in initial hours) by reducing the extent of water penetration in the initial hours as eudragit L100® is hydrophobic in nature and it causes poor wettability of the tablet surface.
- Eudragit L100® shows pH dependent solubility in aqueous media; insoluble in acidic media but soluble from pH 6.0, which results in a pH dependent drug release profile (which means slower release in acidic media and faster release in alkaline media). This pH dependent behavior poses major limitation on the use of Eudragit L100® as sustained release matrix forming agent especially when pH independent drug release is desired. Examples of other pH dependent polymers belonging to class of polymethacrylates that can be used in the present invention are provided in Table 1.
- pH insensitive release retardants may be selected from excipients that include polyvinyl alcohol, polyvinyl acetate; Kollicoat Protect; Kollicoat SR 3OD; Polymethacrylic acid derivatives such as Eudragit RL, Eudragit RS, Eudragit NE30D; cellulose derivatives such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyi methylcellulose; triglycerides, waxes such as compritol, lubritab, peceol, gelucires, lipids, fatty acids or their salts or derivatives such as stearic acid, etc
- Prefered pH dependent polymers include Eudragit L and hydroxypropylmethylcellulose phthalate where as preferred pH independent polymers include ethyl cellulose, hydroxypropylmethylcellulose, Kollicoat protect and Kollicoat SR30D. These are employed alone or in combination with each other.
- excipients such as plasticizers like triethyl citrate, triacetin, castor oil, polyethylene glycol, pore forming agents such as lactose, sodium chloride, HPMC, opacifiers such as titanium dioxide and anti-tackifying agent such as Talc may also be included in coating composition anti tacking agent such as.
- the coating level is dependent on the type of dosage form and the dependent on the type of dosage form and the desired release rate.
- coating range includes 2-20% in case of tablets and capsules and 5-30% in case of powder, beads or granules. Desired release rate could also be obtained using compression coated systems wherein tablet core containing solubilized ARB is coated with polymeric release retardant as mentioned above using a non solvent methodology such as compression coating.
- the formulation releases 0-20% of ARB in 0.1 N HCI up to 1 Hr. and NLT 75% release in pH 4.5 buffer.
- formulation releases 0-20% of ARB in 0.1 N HCI up to 2 hrs. and NLT 75% in 4.5 buffer up to 2 Hrs.
- formulation releases 0-50% of ARB in 0.1 N up to 1 Hr and NLT 80% in 4.5 buffer up to 2 Hrs.
- formulation releases 0-50% of ARB in 0.1 N HCI up to 2 Hrs. and NLT 80% in 4-5 in 1 Hr.
- formulation releases 0-70% of ARB in 0.1 N HCI up to 2 Hrs. and NLT 80% in 4-5 in 1 Hr.
- formulation releases 0-20% of ARB in 1Hr. in 0.1 N HCI, 0-50% in 4.5 buffer in 1 hour and NLT 80% released in 1 Hr in 5.5 buffer
- formulation releases 0-20% of ARB in 1 Hr in 0.1 N HCl, 0- 50% released in 4.5 buffer, and NLT 75% in 6.8 buffer over 10-12 Hrs.
- formulation releases 0-75% of ARB in 2 Hrs. in 0.1 N HCI and NLT 85% release in 2 Hrs. in 6.8 buffer
- Example I Coated spheres in capsules for pulsatile release (three pulses) A) Preparation of immediate release spheres (Pulse I)
- Valsartan is added to molten Lutrol F127 & Vitamin E TPGS in a low shear mixer and mixed well. 2. Zeopharm, microcrystalline cellulose, fumaric acid and Kollidon CL are added to above mass and mixed further to get a homogeneous blend.
- This blend is then granulated using a solution of polyvinylpyrrolidone in water.
- Valsartan spheres are initially coated with a combination of hypromellose and ethylcellulose (20:80 ratio) in a fluidized bed processor to a weight gain of 20%.
- the hypromellose and ethylcellulose coated beads were further coated with Eudragit L ⁇ in the form of aqueous dispersion 30 %) which provides enteric properties to the spheres.
- a combination of enteric polymer and release retarding polymer determines the lag-time of 5-7 hrs.
- the Eudragit L polymer dissolves when exposed to pH 5 and above of intestinal milieu exposing the spheres coated with the retarding polymer which in turn release the drug slowly about 1 to 2 hours time.
- the second pulse of the drug is released when the drug exposed to a pH environment of 5 and above.
- the hypromellose and ethylcellulose coated beads were further coated with Eudragit S (in the form of aqueous dispersion) which provides enteric properties to the spheres.
- Eudragit S in the form of aqueous dispersion
- a combination of enteric polymer and release retarding polymer determines the lag-time of 10-12 hours.
- the Eudragit S polymer dissolves when exposed to pH 6.8 and above of intestinal milieu exposing the spheres coated with the retarding polymer which in turn release the drug slowly about 1 to 2 hours time.
- the second pulse of the drug is released when the drug exposed to a pH environment of 5 and above.
- the immediate release beads, beads coated to achieve 5-7 hours lag time and beads coated to achieve 10-12 hours lag time are blended in the ratio of (2:1 :1 ).
- the blended beads are filled in size "0 e ⁇ " "OO" or "000" capsules'.
- the above example illustrate about developing a capsule dosage form that releases the drug in three pulses (pulse 1 releases immediately , pulse 2 release between 5 to 7 hours and pulse 3 release 10 — 12 hours.
- the following example illustrates the mini-tablets approach to deliver the pulsatile dosage form.
- Example II Coated mini-tablets in capsules A) Immediate release mini-tablets
- Valsartan is added to molten Lutrol F127 & Vitamin E TPGS in a low shear mixer and mixed well.
- Neusillin is added to above mass and mixed further.
- Valsartan is added to molten Lutrol F127 & Vitamin E TPGS in a low shear mixer and mixed well.
- Neucilin is added to above mass and mixed further.
- a part of the above mini-tablets are coated with Eudragit RS 30D at 20% weight gain to get the retardation of drug for 6-8 hrs.
- Remaining mini-tablets are coated with Eudragit RS 3OD at 30% weight gain to get the retardation of drug for 10-12 hrs.
- Two immediate release tablets of 60 mg each and 1 each of the delayed release coated tablet weighting 53 and 61 mg respectively are filled in capsule of size '0 e ⁇ ' to make a total drug dose of 40 mg per capsule. More mini tablets can be incorporated in we use size "00" or "000" capsules.
- Dissolution Medium pH change media i.e. 0.1 N HCI (700ml) for 2 hr followed by pH 6.8 buffer for further 12 hrs. (pH changed to 6.8 with addition of 200 ml of salt solution)
- Drug release was found satisfactory as desire pulsed release was achieved : about 60% in first two hours, about 20 % each in 6-8 hours and 10-14 hours.
- pulse I was release at 1 hr; pulse Il starts at 4 hr; and pulse III starts at 10 hr.
- Example 111 Tablets with pulsatile release components (outer immediate release and inner core for delayed release)
- Valsartan is added to molten Lutrol F127 & Vitamin E TPGS in low shear mixer and mixed well. 2. Mixture of zeopharm, microcrystalline cellulose and Kollidon CL is added to above mass and mixed further.
- Table 15 composition of delayed release Coating for retardation up to 10-14 hours
- coated tablets are then compression coated with lubricated blend of immediate release layer using 21 x 9 mm punches such that one coated tablet at each of the coating level i.e. Eudragit L & S at (70:30 & 10:90) are put into immediate release layer blend and compressed to achieve the final tablet weight of around 968 mg i.e. the final dosage strength of 160 mg.
- the coating level i.e. Eudragit L & S at (70:30 & 10:90
- Example IV Compression coated tablets with pulsatile controlled release Composition of outer immediate release layer
- Valsartan is added to molten Lutrol F127 & Vitamin E TPGS in low shear mixer and mixed well.
- Valsartan is added to molten Lutrol F127 & Vitamin E TPGS in tow shear mixer and mixed well.
- Microcrystalline cellulose and zeopharm are added to above mass and mixed further.
- the delayed release core tablets are coated with a combination of Methocel E5LV and Ethyt cellulose (50:50) at 20% weight gain.
- Dissolution Medium pH change media i.e. 0.1 N HCI (700m!) for 2 hr followed by pH 6.8 buffer for remaining 10 hrs. (pH changed to 6.8 with addition of 200 ml of salt solution)
- Example V Valsartan Pulsatile formulation using pH sensitive polymer coating
- the formulation efforts were aimed at releasing the drug in pulses in the proximal intestine region covering the pH range of 4 to 5.
- the combination of release in 0.1 N HCI and a pulse at pH about 4,5 might ensure sustained blood levels.
- the approach involved seal coating of the core tablets followed by functional coating with various pH sensitive polymers like PVAP, HPMCP, Eudragit L 100-55 and Eudragtt L 30-D55.
- Example V- A Composition of core tablets: Table 20
- Valsartan was added to molten Lutrol F127 & Vitamin E TPGS in low shear mixer and mixed well. Mixture of zeopharm, microcrystalline cellulose and Kollidon CL was added to above mass and mixed further. All other ingredients were added to above mass and mixed well to achieve uniform blend.
- the core tablets prepared as per table 20 were first seal coated to avoid moisture ingress followed by coat of pH sensitive PVAP based polymer at predetermined weight gain levels.
- Coating was done to achieve different weight gain levels like 2,4, 6 and 8.
- the tablets were cured for definite time period in tray dryer after which disintegration of the tablets was studied.
- Pulsatile formulation using HPMCP The same core tablets as shown in example 20 were prepared and seal coated using Kollidon VA 64 followed by coat of pH sensitive hydroxy! propyl methyl cellulose phthalate based polymer for different weight gain levels.
- Talc was dispersed well in a mixture of absolute alcohol and DM water with the help of homogenizer to which triethy! citrate was added. HPMCP HP 50 was added to this mixture and dissolved to get the coating solution. Coating was done to achieve different weight gain levels like 2,4, 6 and 8.
- the tablets were cured for definite time period in tray dryer after which disintegration of the tablets was studied.
- the core tablets as shown in example 20 were prepared and seal coated using Kollidon VA 64 followed by coat of Eudragit L30- D55 with pore forming agents for different weight gain levels.
- PVP K 30 was used as a pore forming agent in this coating solution to enhance drug release.
- Talc was dispersed well in water with the help of homogenizer and triethyl citrate was added to this system along with PVP K 30.
- This suspension was added with slow speed to Eudragit L30 D 55 suspension and kept stirring throughout coating operation.
- This coating solution was used to coat valsartan core tablets to achieve different weight gain levels like 2,4, 6 and 8. The tablets were cured for definite time period in tray dryer after which disintegration of the tablets was studied.
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Abstract
The present invention relates to the method of increasing the bioavailability of Angiotensin II Receptor Blockers (ARBs) by preparing a composition of an ARB that is capable of releasing the medicament intermittently in the GI tract in pulses at predetermined time intervals. In one aspect, the present invention relates to orally deliverable compositions designed to release solubilized ARB, in particular valsartan in the upper gastrointestinal tract.
Description
VALSARTAN FORMULATION FOR PULSATILE DELIVERY
This invention claims the priority of U.S. Provisional Patent Application Serial No. 60/860,484, filed November 22, 2006, which is incorporated herein by reference. FIELD OF THE INVENTION
The present invention relates to the method of increasing the bioavailability of Angiotensin Il Receptor Blockers (ARBs) by preparing a composition of an ARB that is capable of releasing the medicament intermittently in the Gl tract in pulses at predetermined time intervals. In one aspect, the present invention relates to orally deliverable compositions designed to release solubilized ARB, in particular valsartan in the upper gastrointestinal tract.
BACKGROUND OF THE INVENTION
Angiotensin Il is a very potent end product chemical that causes the muscles surrounding the blood vessels to contract, which thereby significantly narrowing the blood vessels. This narrowing increases the pressure within arterial vessels, causing high blood pressure (hypertension). Angiotensin receptor blockers (ARBs) are drugs that block the action of angiotensin II. As a result, arterial vessels dilate and blood pressure is reduced, thereby making it easier for the heart to pump blood. ARBs can therefore also be used to improve heart failure as well as hypertension. In addition, they slow the progression of kidney disease due to high blood pressure or diabetes.
The importance of aggressive blood pressure control is undisputed, but the therapeutic focus is now extending to end-organ protection as a treatment goal of equal importance to BP reduction. Thus, the value of ARBs in slowing the progression of kidney disease due to high blood pressure or diabetes has very positive medical as well as commercial implications.
Drugs in this class include candesartan (Atacand, Astra-Zeneca), eprosartan (Teveten, Solvay and Biovail), irbesartan (Avapro, BMS), losartan (Cozaar,
Merck), olmesartan {Benicar, Medoxomil; Sankyo and Forest), telmisartan (Micardis, Boehringer Ingelheim), valsartan (Diovan, Novartis) and pratosartan (Kotobuki). ARBs are used alone or in combination with other classes of antihypertensive agents that include thiazide diuretics, β-blockers, calcium channel blockers, rennin inhibitor, and ACE inhibitors, both for the treatment of hypertension and congestive heart failure.
Valsartan, a selective ARB, is a well-known antihypertensive agent. Valsartan is rapidly absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of valsartan is about 25% (10-35%). This relatively low bioavailability of valsartan is primarily due to its poor solubility in the acid milieu of the gastrointestinal tract. Valsartan is an acid, and therefore, has good solubility at pH>5 and low solubility in acidic conditions of the gastrointestinal (Gl) milieu. Valsartan is absorbed from the upper gastrointestinal tract where its solubility is low.
The synthesis and use of valsartan are described in US Patent No. 5399578 ('578 patent). Various polymorphs and salt forms of valsartan are described by WO 04083192, WO04087681 , and WO03066606.
WO 04101535 relates to pharmaceutical compositions and a method of reducing the risk of morbidity and mortality in patients having symptomatic heart failure comprising administering to such patient an effective amount of valsartan, or pharmaceutically acceptable salts thereof, alone or in combination with another therapeutic agent, optionally in the presence of a pharmaceutically acceptable carrier. This patent describes the novel use or novel crystalline forms of valsartan, but does not tackle the problem associated with the poor bioavailability of valsartan.
US Patent No. 6,294,197 ('197 patent) and US Patent Application Publication No. 2003/0035832 describe the solid oral dosage forms of valsartan alone or in combination with hydrochlorothiazide (HCTZ) along with a pharmaceutical additive for the preparation of solid dosage forms by a compression method. The solid dosage form according to this invention contains more than 35% by weight of the active agent in the formulation. A process of making such dosage form employing roll compaction is also disclosed.
In US Patent No. 6,485,745 (745), solid dosage forms of valsartan are described which exhibit accelerated release of the active agent in pH 6.8 phosphate buffer. However release in 0.1 N HCI is not addressed where the solubility of valsartan is minimal.
US Patent Application Publication No. 2002/0132839 and US Patent Application Publication No. 2003/0152620 discuss pharmaceutical compositions of valsartan tablet dosage form are at least 1.2 times more bioavailable than the conventional valsartan capsule. The tablet formulation according to the invention contains a disintegrant at concentration level of 10-80% based on total weight of the composition. The higher amount of disintegrant ensures that the hydrophobic valsartan is wetted well during the granulation stage. The tablet is readily dispersed as granules in the dissolution medium resulting in a better dissolution and improved bioavailability over the normal formulation. The invention does not, however, describe methods to increase solubility of the valsartan itself in the gastric milieu; and therefore, the dissolution of valsartan in 0.1 N HCI still remains low which results in low bioavailability.
Candesartan cilexitil, like valsartan, is a hydrophobic molecule with poor aqueous solubility resulting in poor oral availability (about 14%). WO 2005/070398 A2 claims pharmaceutical compositions in the form of tablets that include candesartan cilexitil, fatty acid glycerides, a surfactant, a co-solvent and pharmaceutically acceptable additives. The formulation is further coated with a film forming polymer and polyethylene glycol. The co- solvent employed only improves the stability of candesartan and does not alter its solubility or dissolution rate in acidic medium.
United States Patent Application Publication No. US 2005/0220881 provide methods of improving dissolution of Eprosartan by preparing its association complex with one or more solid poloxamers. However, a large amount of poloxamers is required to achieve significant dissolution enhancement. The dosage form development of such a complex that would achieve a higher oral bioavailability becomes very difficult due to weight limitations. Moreover, large amount of poloxamers for chronic use may not be allowed.
The low bioavailability associated with poor aqueous solubility warrants administration of larger doses of the ARBs to maintain desired therapeutic activity. None of the patents described above details methods of achieving an improved ARB composition. Thus there remains a need and opportunity for an improved ARB formulation that delivers the active form of medicament both in the solubilized form and in a predictable manner. This can be accomplished by first increasing the solubility of the ARB in gastric milieu and releasing it using different delivery systems. For example, an immediate release of valsartan in the solubilized form will result in dose dumping and may saturate the transport carriers thereby compromising the overall bioavailability of the medicament. Thus, the saturation of the transport carriers which are involved in the permeation of drug through the gastric membrane limits the extent of absorption. There is therefore a need of a delivery system which prevents saturation of the transporters and increases the bioavailability of ARBs.
Since ARBs are known to have window of absorption, a formulation which releases drug at the site of absorption would maximize absorption leading to improved bioavailability. The saturation effect can also be reduced by releasing drug in multiple pulses. A number of pulsatile delivery systems are reported in the prior art. lshino et al. disclose a dry-coated tablet form in Chemical Pharm. Bull. Vol. 40 (11), 3036-041 (1992). U.S. Pat. No. 4,851 ,229 to Magruder et al., U.S. Pat. No. 5,011 ,692 to Fujioka et al., U.S. Pat. No. 5,017,381 to Maruyama et al., U.S. Pat. No. 5,229,135 to Philippon et al., and U.S. Pat. No. 5,840,329 to Bai disclose preparation of pulsatile release systems. Some other devices are disclosed in U.S. Pat. No. 4,871 ,549 to Ueda et al. and U.S. Pat. Nos. 5,260,068; 5,260,069; and 5,508,040 to Chen. U.S. Pat. Nos. 5,229,135 and 5,567,441 both to Chen disclose a pulsatile release system consisting of pellets coated with delayed release or water insoluble polymeric membranes incorporating hydrophobic water insoluble agents or enteric polymers to alter membrane permeability. U.S. Pat. No. 5,837,284 to Mehta et al. discloses a dosage form which provides an immediate release dose of methyl p hen id ate upon oral administration, followed by one or more additional doses spread over several hours. All these pulsatile delivery systems essentially employ drugs having good water solubility. ARBs
however have very poor solubility and therefore there is a need to deliver the medicament in the solubilized form in multiple pulses at different segments of Gl tract such as stomach, duodenum, jejunum and ileum at predetermined time intervals, thereby increasing its therapeutic effectiveness over a 24-hour period to effectively control the hypertension, for the treatment of myocardial infarction and other heart diseases and for the end organ protection in the patient population. Alternatively these solubilized pulsatile systems can be employed for increasing bioavailability of the ARB by releasing drug in pulses at predetermined sites in gastrointestinal tract and thus maximizing its absorption. It was surprisingly found that the use of solubilized valsartan in different pulses not only achieves the desired in-vitro dissolution rate but is also predictably able to release drug at predetermined time intervals.
SUMMARY OF THE INVENTION
An object of the present invention is to increase the therapeutic effectiveness of an ARB over a 24-hour period.
Another object of the present invention is to provide a dosage form to effectively control the hypertension, for the treatment of myocardial infarction and other heart diseases and for the end organ protection in the patient population.
In one aspect, the present invention provides a method of increasing the bioavailability of an ARB by administering solubilized ARB in pulses.
An object of the present invention relates to delivery systems and methods of predictably increasing the bioavailability of ARBs, especially valsartan, and insuring consistent absorption over a wide pH range of the gastrointestinal (Gl) tract by releasing the drug at different sites of Gl tract in pulses at different absorption site such as stomach, duodenum, jejunum and ileum.
In yet another aspect, this novel composition of valsartan provides at least 40% dissolution in acidic and weakly acidic dissolution medium. "Acidic" as used herein refers to pH less than about 3. "Weakly acidic" as used herein refers to pH of about 3 to 5.
Another object of the present invention also relates to a physically and chemically stable formulation of ARBs, in particular valsartan, utilizing generally recognized as safe (GRAS) excipients. This invention also relates to an oral dosage formulation of valsartan having reduced intra- and inter-patient variability in absorption, particularly at low Gl pH.
To accomplish the objects of the present invention, a formulation containing an ARB, especially valsartan, is designed to release the active pharmaceutical ingredients in pulses or over a longer period of time. The term "pulse" as used herein refers to the release of the ARB in the Gl tract in intermittent dosages. The release, for example, will be in different parts of the Gl tract depending on the pH of intestinal milieu as the solid dosage form makes its way through the Gl tract exposing to different pH environment. The pulsed release of the active ingredient is preferably accomplished by coating the drug granules with pH sensitive polymers which dissolves only in specific pH environment.
By delivering a desired agent, for example, a drug, as a "pulse" is intended a delivery method that provides a brief, sudden increase in an otherwise constant amount of the agent to a patient in need of the same. These short bursts are characterized by separate peaks in the release profile of a dosage form as it travels through the gastrointestinal tract after ingestion. Thus, a "pulse" of a desired agent results in a brief, sudden release of a desired amount of an agent from a delivery system such that as a result of this release, there is a rapid increase in the concentration of the agent at the desired site in the patient. Such increase is over and above whatever level of the agent had been previously present, if any, prior to the "pulse." The increase is not sustained in a prolonged fashion unless repeated pulses are provided. Preferably, the pulse is the result of an immediate release or a short sustained release of the drug.
By delivering a desired agent such as a drug in a "pulsating" manner is intended the delivery of a drug in a manner that provides more than one, that is, repeated sudden releases of desired concentrations of the drug, so that repeated rapid increases in drug concentrations can be detected that are over and above whatever level of the drug had been present, if any, immediately prior to each release.
In an embodiment the dosage form contains multiple parts, each of which is designed to releases at a particular site of the digestive system. For example, the dosage form may contain a firs part that is immediate release, a second part that is coated for release at 6-8 hours; and a third part that is coated for release at 10-12 hours. As such, with the three part dosage form, pulses occur at 0 hr, 5-7 hours, and 10-12 hours after ingestion. Coatings can be designed to release the active ingredient at pre-selected time intervals as discussed below.
The different parts of a dosage form for releasing at different time intervals may be nested together. The dosage form may contain an outer layer of immediate release part and inner cores of delayed release parts. The dosage form may also contain different layers pressed together with each layer releasing at a different time interval. Here, it is preferable that the outer layer releases before the inner layers. Thus, the innermost layer would be the last to be released, while the outermost layer would be the first to be released.
Alternatively, the different parts of the dosage form may be a plurality of mini-tablets enclosed in a capsule. The mini-tablets are designed to be released at different time intervals to effect pulsed release. For example, there may be three groups of mini-tablets, each group releasing the active ingredient at a different time interval (e.g. immediate, 5-7 hours, and 10-12 hours). Upon ingestion of the capsule, the mini-tablets are released in the stomach to effect pulsed release of the active ingredient.
The following release profiles are preferred:
1 ) the first pulse occurs 0-1 hour after ingestion and the second pulse occurs 2-3 hours after ingestion;
2) the first pulse occurs 0-1 hour after ingestion, the second pulse occurs 3-4 hours after ingestion;
3) the first pulse occurs 1-2 hours after ingestion and the second pulse occurs 3-6 hours after ingestion;
4) the first pulse occurs 1-2 hours after ingestion and the second pulse occurs 3-6 hours after ingestion and third pulse occurs 7-10 hours after ingestion;
5) the pharmaceutical composition of claim 12, wherein the first pulse occurs 2-5 hours after ingestion and the second pulse occurs 6-9 hours after ingestion;
6) the second pulse occurs 5-7 hours after ingestion and the third pulse occurs 10-12 hours after ingestion; and
7) the first pulse occurs 0-1 hour after ingestion, the second pulse occurs 4-8 hours after ingestion and the third pulse occurs 10-14 hours after ingestion.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
It has been discovered that an ARB, particularly valsartan, when combined with a solubility enhancing agent significantly increases its solubility in acidic environment (pH < 3) as well as an improved dissolution rate which is in sharp contrast to the currently marketed ARB formulations. The bioavailability will also increase as more absorbable form of the drug (free acid form of valsartan) is present in the solubilized form at the absorption site. The increase in bioavailability reduces the dose of the ARB required to achieve the desired effect as well as patient to patient variability, and thus, enhances the therapeutic utility of the ARB. The solid dosage form can be manufactured using conventional manufacturing processes and standard processing equipments that are generally used to manufacture the solid dosage form.
Active Ingredient
The active ingredient for the purpose of this invention is an ARB, which may be, but not limited to, candesartan, eprosartan, irbesartan, losartan, olmesartan, teimisartan, valsartan, or eprosartan. The active ingredient of the invention may be present in crystalline or amorphous form. The crystalline form may have different polymorphs. All different polymorphs, solvates, hydrates, salts are within the purview of this invention. The preferred active ingredient is valsartan.
In the dosage form of the present invention, in addition to an ARB, one or more, for example two or three, active ingredients may be combined. The therapeutic agents, which
may be combined with an ARB include, but are not limited to, anti-hypertensive agents, such as hydrochlorothiazide (HCTZ), calcium blockers, beta-blockers, ACE inhibitors, inotropic agents, hypolipidemic agents, anti-obesity agents, rennin inhibitors, and/or anti- diabetic agents.
The present invention is also applicable to other active pharmaceutical ingredients having similar low solubility related bioavailability issues.
The active ingredient may be present in an amount of about 1-80%, preferably 5- 50%, and more preferably 10-30% by weight of the composition.
The composition of the present invention of valsartan may be used to treat the diseases described below and to deliver the solubilized form of the drug over the wide pH range of the Gl tract to increase bioavailability. Therefore, the dose and frequency of administration can be reduced, compared with administration of conventional valsartan. Moreover, the inter- and tntra-patient variability associated with the current formulation of valsartan can also be reduced. Therefore, it is expected that there will be an increased therapeutic effect from this composition of the present invention of valsartan. Examples of the diseases to be treated by this agent include 1. circulatory disease, such as hypertension, cardiac disease (heart failure, myocardial infarction, valvular disease), peripheral circulatory insufficiency; 2. kidney disease, e.g., glomerulonephritis, renal insufficiency; 3. cerebral dysfunction, e.g., stroke, Alzheimer's disease, depression, amnesia, dementia; 4. diabetic complications, e.g., retinopathy, nephropathy; 5. arteriosclerosis manifested by hypertension, stroke, heart attack, angina, or ischemia of gastrointestinal (Gl) tract or extremities; 6. unique conditions, e.g.; hyperaldosteronism, multiple system organ failure, scleroderma; and 7. anxiety neurosis, catatonia, and dyspepsia. Many of these conditions are caused or exacerbated by vasoconstriction expressed secondary to angiotensin II.
Solubilization of an ARB
According to this invention, the increase in instantaneous solubility of an ARB in a composition is achieved by using one or more suitable solubility enhancing agent. The solubility enhancing agent may include one or more surfactant, solubilizer, complexing agent, hydrotropic agent, and the like. The solubility enhancing agent could be the same or different for different ARB's.
The solubility enhancing agent may be, but not limited to, hydrophilic surfactants, lipophilic surfactants, mixtures there of. The surfactants may be anionic, nonionic, cationic, zwitterionic or amphophilic. The relative hydrophilicity and hydrophobicity of surfactants is described by HLB (hydrophilic-lipophilic balance) value. Hydrophilic surfactants include surfactants with HLB greater than 10 as well as anionic, cationic, amphiphilic or zwitterionic surfactants for which the HLB scale is not generally applicable. Similarly, lipophilic surfactants are surfactants having an HLB value less than 10.
Preferably, the solubility enhancing agent may be PEG-20-glyceryl stearate {Capmul® by Abitec), PEG-40 hydrogenated castor oil (Cremophor RH 40® by BASF), PEG 6 corn oil (Labrafil® by Gattefosse), lauryl macrogol - 32 glyceride {Gelucire 44/U® by Gattefosse), stearoyl macrogol glyceride (Gelucire 50/13® by Gattefosse), polyglyceryl - 10 mono dioleate (Caprol ® PEG 860 by Abitec), propylene glycol oleate (Lutrol OP® by BASF), propylene glycol dioctanoate (Captex® by Abitec), propylene glycol caprylate/caprate (Labrafac® by Gattefosse), glyceryl monooleate (Peceol® by Gattefosse), glycerol monolinoleate (Maisine ® by Gattefosse), glycerol monostearate (Capmul® by Abitec}, PEG- 20 sorbitan monolaurate {Tween 20® by Id), PEG - 4 lauryl ether (Brij 30® by Id), sucrose distearate (Sucroester 7® by Gattefosse), sucrose monopalmitate (Sucroester 15® by Gattefosse), polyoxyethylene-polyoxypropylene block copolymer (Lutrol® series BASF), polyethylene glycol 660 hydroxystearate, (Solutol® by BASF), sodium lauryl sulphate, sodium dodecyl sulphate, dioctyl suphosuccinate, L- hydroxypropyl cellulose, hydroxylethylcellulose, hydroxy propylcellulose, propylene glycol alginate, sodium taurocholate, sodium glycocholate, sodium deoxycholate, betains, polyethylene glycol
(Carbowax® by DOW), d-a- tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS® by Eastman), or mixtures thereof.
The solubilizers may also include pH modifiers such as buffers, amino acids and amino acid sugars and complexing agent such as cyclodextrin class of molecules, such as alpha- cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, or their derivatives, such as hydroxypropyl beta cyclodextrins, or mixtures thereof. The complexing agents may also include cyclic amides, hydroxyl benzoic acid derivatives as well as gentistic acid. In this complexation process, a hydrophilic polymer may be additionally added to further enhance the solubility along with the complexing agent.
In the composition of the present invention, the ARB and one or more solubility enhancing agents may be employed in different ratios. The selected ratio depends upon the desired improvement in solubility and the type of solubility enhancing agents employed. It is contemplated within the scope of the invention that the ratio of ARB to solubility enhancing agents may range from about 20:1 to about 1 :20, preferably from about 10:1 to about 1 :10, and most preferably about 5:1 to about 1 :5. A combination of solubility enhancing agents may also be included where the total amount of solubility enhancing agent employed is maintained in the above-mentioned ratios.
The solubilized ARB is converted into a powder, granule or tablet formulation. Alternatively ARB and the solubilizers are dissolved in a common solvent and sprayed onto beads made up of sugar or cellulose. These dosage forms such as powder, beads, granules, tablets, capsules containing solubilized ARBs are coated with release retardants which releases drug under predetermined conditions, of pH or alternatively after a fixed time intervals.
The bioenchanced formulation previously developed and published as WO 2006/113631 showed the following pharmacokinetic parameters
Table 1: Summary statistics of pharmacokinetic parameters
The invention exhibited a higher Cmax, AUC0.t and, AUCO-X compared to the marketed product (Figure 1). Thus test product was more bioavailable than the marketed product (Diovan®). The test product provided faster onset of action. Also the test product achieved more uniform plasma levels with reduced the variability. A better formulation is thus obtained which reduces variability, possibly allows reduction in dose, and also, gives rapid onset of action, which may lead to increased patient compliance. However the increase in bioavailability is only 1.6 fold which means about 40% and thus there is a scope for further improvement in the bioavailability of valsartan.
The formulation of WO 2006/113631 showed much higher plasma concentration (Cmax), rapid onset (Tmax) and higher AUC (extent of absorption). However, the elimination of drug from plasma is similar for the both formulations (Diovan and WO 2006/113631 ). As shown in figure 1 , the plasma concentrations of valsartan for the both formulations are similar after 10 hours. This is realiy not offering a true once a day formulation. Even though the tested formulation has much higher bioavailability and high plasma concentration in the first 4 to 6 hours, it eliminates from the central compartment rapidly. What we need is a formulation that will have somewhat higher plasma concentrations than Diovan for at least 18 hours.
Both above problems of increasing bioavailability and developing a true once a day formulation can be achieved by releasing the drug in pulses at different time intervals. For example the window of absorption for valsartan is in the upper gastrointestinal tract and
therefore delivering solubilized valsartan intermittently in pulses near absorption site would possibly increase the bioavailability or maintain higher level of valsartan in the body over a long period. The following calculations describe the dose calculations for pulsatile once a day formulations. The Cmax for 80mg of test tablet is 7215.2 ng/ml, which amounts to 90.2 ng/ml per one mg of drug. In order to reach the same Cmax as Diovan formulation, we need only 50 mg of valsartan with the test formulation. If we release the drug in our proposed novel formulation as 50 mg initial burst from stomach, and 15 mg each as second and third burst for every six hours, we can achieve plasma concentration higher than at least 2000 ng/ml at the end of 12 hours. We have chosen to release drug every six hour as the half life of valsartan is six hours.
For example, the Cmaχ of Diovan is 4405.7 ng/ml. The 50 mg of our bioenhanced formulation gives a Cmax of 4510 ng/ml. At the end of 6 hours the concentration of valsartan in plasma is 2255 ng/mi. If 30 mg pulse released at this time, the new calculated Cmax is 2255 plus 15X90.2 ng/ml/mg valsartan which is 3608 ng/ml. The concentration of valsartan at the end of 12 hours is 1804 ng/ml. When the new burst releases additional 15 mg of valsartan and the new Cmax is 3157 ng/ml. At the end of 18 hours of post ingestion of the drug, the plasma concentration of valsartan is1578 ng/ml and at the end of 24 hours 789 ng/ml. If the higher drug amount is needed we can increase the initial burst concentration. This type of release can be accomplished with the use of pH sensitive polymers. The pH of Gl tract varies from 1 to 7.2. As the drug formulation moves through the Gl tract, it exposes to the Gl fluid of increasing pH. If the drug is formulated with pH sensitive polymers, it will release the drug depending on the pH. Thus taking advantage of Gl pH conditions, one can achieve drug release in pulses at different pH conditions. For examples, if we coat a portion of the drug granules with a polymer that dissolves in pH 5 gastric milieu and the other portion of the granules with a polymer that dissolves in pH 6.8 intestinal milieu, the pH 5 polymer coated beads will dissolve when exposed to pH 5 environment and thus releasing the first pulse of the drug and the second pulse will be release when the granules exposed to pH 6.8 of Gl milieu.
In one embodiment, the aforementioned pulsatile release profile is achieved with dosage forms that are closed and preferably sealed capsules housing at least two drug- containing "dosage units" wherein each dosage unit within the capsule provides a different drug release profile. Control of the delayed release dosage unit{s) is accomplished by a controlled release polymer coating on the dosage unit, or by incorporation of the active agent in a controlled release polymer matrix. Each dosage unit may comprise a compressed or molded tablet, wherein each tablet within the capsule provides a different drug release profile. For dosage forms mimicking a twice a day dosing profile, a first tablet releases drug substantially immediately following ingestion of the dosage form, while a second tablet releases drug as per predetermined time interval. A third tablet extending the duration of drug release may also be added.
Alternatively, each dosage unit in the capsule may comprise a plurality of drug- containing beads, granules or particles. As is known in the art, drug-containing "beads" refer to beads made with drug and one or more excipients or polymers. Drug-containing beads can be produced by applying drug to an inert support, e.g., inert sugar beads coated with drug or by creating a "core" comprising both drug and one or more excipients. As is also known, drug-containing "granules" and "particles" comprise drug particles that may or may not include one or more additional excipients or polymers. In contrast to drug-containing beads, granules and particles do not contain an inert support. Granules generally comprise drug particles and require further processing. Generally, particles are smaller than granules, and are not further processed. Although beads, granules and particles may be formulated to provide immediate release, beads and granules are generally coated to provide delayed release. The capsule may contain different groups of beads which release drug at different yet predetermined time intervals.
In another embodiment, the individual dosage units are compacted in a single tablet, and may represent integral but discrete segments thereof (e.g., layers), or may be present as a simple admixture. For example, drug-containing beads, granules or particles with
different drug release profiles (e.g., immediate and delayed release profiles) can be compressed together into a single tablet using conventional tableting means.
In a further alternative embodiment, a dosage form is provided that comprises an inner drug-containing core and at least one drug-containing layer surrounding the inner core. An outer layer of this dosage form contains an initial, immediate release dose of the drug whereas the inner layers contain a coating that delays the release of the drug.
In still another embodiment, a dosage form of the invention comprises a coated core- type delivery system wherein the outer layer is comprised of an immediate release dosage unit, such that active agent therein is immediately release following oral administration, an intermediate layer thereunder surrounds a core, and the core is comprised of immediate release beads or granules and delayed release beads or granules, such that the second dose is provided by the immediate release beads or granules and the third dose is provided by the delayed release beads or granules.
As will be appreciated by those skilled in the art and as described in the pertinent texts and literature, a number of methods are available for preparing drug-containing tablets, beads, granules or particles that provide a variety of drug release profiles. Such methods include, but are not limited to, the following: coating a drug or drug-containing composition with an appropriate coating material, typically although not necessarily a incorporating a polymeric material; increasing drug particle size; placing the drug within a matrix; and forming complexes of the drug with a suitable complexing agent.
The delayed release dosage units in any of the above embodiments can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material. The drug-containing composition may be, e.g., a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule.
The dissolution time of the individual subunits can be controlled by several methods to be discussed herein below. Two illustrative means of controlling dissolution are (1 ) pH-
sensitive enteric coatings which are eroded in response to the pH of the aqueous environment in the gastrointestinal tract and (2) permeability-controlled systems which are subject to disruption in response to absorption of water from the environment which creates a pressure as the core contents expand. Variation of process variables and coating and core compositions, in manners to be discussed hereinbelow, enables precise tailoring of the dissolution, or pulse, time of the individual unit cores. The individual units are combined into a unitary depot which may be single tablet or a gelatin capsule or any other form known in the art.
Erosion-Dependent Systems
Enteric coatings of pH-sensitive polymers are employed to control the time of delivery of a drug-containing core composition to the small intestine of a living mammal.
Characteristics of suitable enteric coatings include: insolubility in the stomach, solubility in the intestines, no toxicity, moisture permeability resistance, stability, and good coating capability. A widely used enteric coating, give list-
Permeability-Controlled Systems
Permeability-controlled systems are generally based on polymeric coatings which are water-permeable to permit water from the aqueous environment in the gastrointestinal tract of a living being to enter into a coated drug-containing core at a controllable rate and to displace air from the core followed by a build-up of pressure as the core contents expand until the coating is ruptured at the appropriate time. The polymeric coating for the permeability-controlled system must be impermeable to the drug and permeable to the intake of water and the expulsion of air. The core composition for permeability-controlled systems may advantageously contain osmotic agents, such as salt, to facilitate water transport to the core.
Preferred coating materials are comprised of bioerodible, gradually hydrolyzable, gradually water-soluble, and/or The coating composition may include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc.
pH Dependent Release Retardants
These are the excipients whose performance is dependent on the pH of the medium. A number of such excipients known in the art include poly methacrylic acid derivatives, cellulose derivatives, acrylic acid derivatives, maleic acid copolymers, polyvinyl derivatives etc.
Cellulose based pH dependent release retardant include hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethylethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, carboxymethylethylcellulose, ethylhydroxyethylcellulose phthalate and the like.
Acrylic copolymer based pH dependent release retardant include styrene • acrylic acid copolymer, methyl acrylate ■ acrylic acid copolymer, methyl acrylate ■ methacrylic acid copolymer, butyl acrylate ■ styrene ■ acrylic acid copolymer, methacrylic acid • methyl methacrylate copolymer (e.g. Trade-names: Eudragit L 100 and Eudragit S, available from Rohm Pharma), methacrylic acid ■ ethyl acrylate copolymer (e.g. Trade-name: Eudragit L 100-55, available from Rohm Pharma), methyl acrylate ■ methacrylic acid ■ octyl acrylate copolymer
Maleic copolymer based pH dependent release retardant include vinylacetate • maleic acid anhydride copolymer, styrene • maleic acid anhydride copolymer, styrene ■ maleic acid monoester copolymer, vinylmethylether • maleic acid anhydride copolymer, ethylene ■ maleic acid anhydride copolymer, vinylbutylether • maleic acid anhydride copolymer, acrylonitrile ■ methyl acrylate • maleic acid anhydride copolymer, butyl acrylate ■ styrene ■ maleic acid anhydride copolymer and the like.
Polyvinyl derivative based pH dependent release retardant includes polyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinyl butylate phthalate, polyvinylacetoacetal phthalate and the like.
Among these examples, methacrylic acid • methylmethacrylate copolymer and methacrylic acid • ethylacrylate copolymer are preferable which are available under the brand name Eudragit®.
Eudragit is the trade name for a number of film coating substances on an acrylic resin basis produced by Rohm Pharma. Eudragit L100® is used in matrix sustained release formulations especially for reducing burst release (excessive drug release in initial hours) by reducing the extent of water penetration in the initial hours as eudragit L100® is hydrophobic in nature and it causes poor wettability of the tablet surface. However, Eudragit L100® shows pH dependent solubility in aqueous media; insoluble in acidic media but soluble from pH 6.0, which results in a pH dependent drug release profile (which means slower release in acidic media and faster release in alkaline media). This pH dependent behavior poses major limitation on the use of Eudragit L100® as sustained release matrix forming agent especially when pH independent drug release is desired. Examples of other pH dependent polymers belonging to class of polymethacrylates that can be used in the present invention are provided in Table 1.
Table 1. pH dependent polymers of polymethacrylates class
Generic name Brand names Marketed by
Poly (methacrylic acid, methyl Eudragit L 100 Rohm GmbH methacrylate) 1 : 1
Eudragit L J 2.5 Rohm GmbH
Eudragit L 12.5 P Rohm GmbH
Eudragit L 30 D-55 Rohm GmbH
Poly(methacrylic acid, ethyl
Eudragit L 100-55 Rohm GmbH acrylate) 1 : 1
Eastacryi 3OD Eastman Chemical
Kollicoat MAE 30 D BASF Fine Chemicals
Kollicoat MAE 30 DP BASF Fine Chemicals
Poly(methacrylic acid, methyl Eudragit S 100 Rohm GmbH methacrylate) 1 : 2
Eudragit S 12.5 Rohm GmbH
Eudragit S 12.5 P Rohm GmbH
pH Independent Release Retardants
Alternatively pH insensitive release retardants may be selected from excipients that include polyvinyl alcohol, polyvinyl acetate; Kollicoat Protect; Kollicoat SR 3OD; Polymethacrylic acid derivatives such as Eudragit RL, Eudragit RS, Eudragit NE30D; cellulose derivatives such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyi methylcellulose; triglycerides, waxes such as compritol, lubritab, peceol, gelucires, lipids, fatty acids or their salts or derivatives such as stearic acid, etc
Prefered pH dependent polymers include Eudragit L and hydroxypropylmethylcellulose phthalate where as preferred pH independent polymers include ethyl cellulose, hydroxypropylmethylcellulose, Kollicoat protect and Kollicoat SR30D. These are employed alone or in combination with each other.
Other excipients such as plasticizers like triethyl citrate, triacetin, castor oil, polyethylene glycol, pore forming agents such as lactose, sodium chloride, HPMC, opacifiers
such as titanium dioxide and anti-tackifying agent such as Talc may also be included in coating composition anti tacking agent such as.
The coating level is dependent on the type of dosage form and the dependent on the type of dosage form and the desired release rate. Typically coating range includes 2-20% in case of tablets and capsules and 5-30% in case of powder, beads or granules. Desired release rate could also be obtained using compression coated systems wherein tablet core containing solubilized ARB is coated with polymeric release retardant as mentioned above using a non solvent methodology such as compression coating.
In-vitro disintegration apparatus followed by pH change dissolution are employed as testing methodologies.
In-vitro disintegration apparatus followed by pH change dissolution are employed as testing methodologies.
In one of the embodiment the formulation releases 0-20% of ARB in 0.1 N HCI up to 1 Hr. and NLT 75% release in pH 4.5 buffer.
In another embodiment formulation releases 0-20% of ARB in 0.1 N HCI up to 2 hrs. and NLT 75% in 4.5 buffer up to 2 Hrs.
In yet another embodiment formulation releases 0-50% of ARB in 0.1 N up to 1 Hr and NLT 80% in 4.5 buffer up to 2 Hrs.
In another embodiment formulation releases 0-50% of ARB in 0.1 N HCI up to 2 Hrs. and NLT 80% in 4-5 in 1 Hr.
In another embodiment formulation releases 0-70% of ARB in 0.1 N HCI up to 2 Hrs. and NLT 80% in 4-5 in 1 Hr.
In yet another embodiment formulation releases 0-20% of ARB in 1Hr. in 0.1 N HCI, 0-50% in 4.5 buffer in 1 hour and NLT 80% released in 1 Hr in 5.5 buffer
In yet another embodiment formulation releases 0-20% of ARB in 1 Hr in 0.1 N HCl, 0- 50% released in 4.5 buffer, and NLT 75% in 6.8 buffer over 10-12 Hrs.
In yet another embodiment formulation releases 0-75% of ARB in 2 Hrs. in 0.1 N HCI and NLT 85% release in 2 Hrs. in 6.8 buffer
Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. The following examples are given to illustrate the present invention. It should be understood that the invention is not to be limited to the specific conditions or details described in these examples.
Example I: Coated spheres in capsules for pulsatile release (three pulses) A) Preparation of immediate release spheres (Pulse I)
Table 2
Process:
1. Valsartan is added to molten Lutrol F127 & Vitamin E TPGS in a low shear mixer and mixed well.
2. Zeopharm, microcrystalline cellulose, fumaric acid and Kollidon CL are added to above mass and mixed further to get a homogeneous blend.
3. This blend is then granulated using a solution of polyvinylpyrrolidone in water.
4. Above mass is extruded and spheronized to get around 1 mm spheres.
B) Preparation of spheres for delayed release coating (Pulse Il & III)
Table 3
Same process as mentioned above was employed for preparation of spheres for delayed release coating.
C) Coating for retardation of release up to 5-7 hours for the second pulse release Table 4
Valsartan spheres are initially coated with a combination of hypromellose and ethylcellulose (20:80 ratio) in a fluidized bed processor to a weight gain of 20%.
Table 5. Coating with pH sensitive polymer:
The hypromellose and ethylcellulose coated beads were further coated with Eudragit L {in the form of aqueous dispersion 30 %) which provides enteric properties to the spheres. A combination of enteric polymer and release retarding polymer determines the lag-time of 5-7 hrs. The Eudragit L polymer dissolves when exposed to pH 5 and above of intestinal milieu exposing the spheres coated with the retarding polymer which in turn release the drug slowly about 1 to 2 hours time. Thus the second pulse of the drug is released when the drug exposed to a pH environment of 5 and above.
D) Coating for retardation of release up to 10-12 Hours
Table 6
The hypromellose and ethylcellulose coated beads were further coated with Eudragit S (in the form of aqueous dispersion) which provides enteric properties to the spheres. A combination of enteric polymer and release retarding polymer determines the lag-time of 10-12 hours. The Eudragit S polymer dissolves when exposed to pH 6.8 and above of intestinal milieu exposing the spheres coated with the retarding polymer which in turn release the drug slowly about 1 to 2 hours time. Thus the second pulse of the drug is released when the drug exposed to a pH environment of 5 and above.
The immediate release beads, beads coated to achieve 5-7 hours lag time and beads coated to achieve 10-12 hours lag time are blended in the ratio of (2:1 :1 ). The blended beads are filled in size "0eι" "OO" or "000" capsules'. The above example illustrate about developing a capsule dosage form that releases the drug in three pulses (pulse 1 releases immediately , pulse 2 release between 5 to 7 hours and pulse 3 release 10 — 12 hours. The following example illustrates the mini-tablets approach to deliver the pulsatile dosage form.
Example II: Coated mini-tablets in capsules A) Immediate release mini-tablets
Table 7
Process
1. Valsartan is added to molten Lutrol F127 & Vitamin E TPGS in a low shear mixer and mixed well.
2. Neusillin is added to above mass and mixed further.
3. All other ingredients are added to above mass and the same is compressed into tablets at a tablet weight of 60 mg using 5 mm circular punches.
B) Delayed release tablets (Pulse Il & III)
Table 8
1. Valsartan is added to molten Lutrol F127 & Vitamin E TPGS in a low shear mixer and mixed well.
2. Neucilin is added to above mass and mixed further.
3. All other ingredients are added to above mass and the same is compressed into tablets at a tablet weight of 45 mg using 5 mm circular punches.
C) Coating composition
Table 9: Coating composition for 6-8 hours retardation
A part of the above mini-tablets are coated with Eudragit RS 30D at 20% weight gain to get the retardation of drug for 6-8 hrs.
Table 10: coating composition for 10-12 hours retardation
Remaining mini-tablets are coated with Eudragit RS 3OD at 30% weight gain to get the retardation of drug for 10-12 hrs.
Two immediate release tablets of 60 mg each and 1 each of the delayed release coated tablet weighting 53 and 61 mg respectively are filled in capsule of size '0eι' to make a total drug dose of 40 mg per capsule. More mini tablets can be incorporated in we use size "00" or "000" capsules.
In-vitro dissolution rate studies
In-vitro dissolution rate studies are carried out with following specifications
Dissolution Test Apparatus: USP Type Il
Temperature: 37.5 ± 0.50C
Dissolution Medium: pH change media i.e. 0.1 N HCI (700ml) for 2 hr followed by pH 6.8 buffer for further 12 hrs. (pH changed to 6.8 with addition of 200 ml of salt solution)
Basket Speed: 50 rpm
Sampling intervals: 1 , 2, 4, 6, 8, 10,12 and 14 hours.
Sampling volume: 10ml
Table 11 : Dissolution of valsartan pulsatile dosage from capsule
Drug release was found satisfactory as desire pulsed release was achieved : about 60% in first two hours, about 20 % each in 6-8 hours and 10-14 hours. Here pulse I was release at 1 hr; pulse Il starts at 4 hr; and pulse III starts at 10 hr.
Example 111: Tablets with pulsatile release components (outer immediate release and inner core for delayed release)
A) Compression blend for outer (immediate release) layer
Table 12
Process
1. Valsartan is added to molten Lutrol F127 & Vitamin E TPGS in low shear mixer and mixed well.
2. Mixture of zeopharm, microcrystalline cellulose and Kollidon CL is added to above mass and mixed further.
3. All other ingredients are added to above mass and mixed well to achieve uniform blend.
B) Composition of Inner delayed release core tablets for coating with different delayed release polymers
Table 13
C) Composition of delayed release Coating for retardation up to 6-8 hours:
Table 14
Process:
50% of the above tablets are coated with a combination of Eudragit L and Eudragit S (70:30) at a weight gain of 20% w/w.
Table 15: composition of delayed release Coating for retardation up to 10-14 hours
Remaining 50% of the above tablets are coated with a combination of Eudragit L and Eudragit S (10:90) at a weight gain of 20% w/w.
Compression of pulsatile components with immediate release granules :
Above coated tablets are then compression coated with lubricated blend of immediate release layer using 21 x 9 mm punches such that one coated tablet at each of the coating level i.e. Eudragit L & S at (70:30 & 10:90) are put into immediate release layer
blend and compressed to achieve the final tablet weight of around 968 mg i.e. the final dosage strength of 160 mg.
Example IV: Compression coated tablets with pulsatile controlled release Composition of outer immediate release layer
Table 16
Process:
1. Valsartan is added to molten Lutrol F127 & Vitamin E TPGS in low shear mixer and mixed well.
2. Mixture of zeopharm, microcrystalline cellulose and Kollidon CL is added to above mass and mixed further.
3. All other ingredients are added to above mass and mixed well to achieve uniform blend. Composition of inner delayed release core
Table 17
Process
1. Valsartan is added to molten Lutrol F127 & Vitamin E TPGS in tow shear mixer and mixed well.
2. Microcrystalline cellulose and zeopharm are added to above mass and mixed further.
3. External phase ingredients are added to above mass and mixed well to achieve uniform blend.
4. Above blend is then compressed into tablets using 8.5 mm circular punches
The delayed release core tablets are coated with a combination of Methocel E5LV and Ethyt cellulose (50:50) at 20% weight gain.
Compression coating:
Above coated tablets are then compression coated with lubricated blend of immediate release layer using 13 mm circular punches to achieve the final tablet weight of around 504 mg with the final dosage strength of 80 mg.
In-vitro dissolution rate studies
In-vitro dissolution rate studies are carried out with following specifications
Dissolution Test Apparatus: USP Type Il
Temperature: 37.5 ± 0.50C
Dissolution Medium: pH change media i.e. 0.1 N HCI (700m!) for 2 hr followed by pH 6.8 buffer for remaining 10 hrs. (pH changed to 6.8 with addition of 200 ml of salt solution)
Basket speed: 50 rpm
Sampling intervals: 1 , 2, 4, 6, 8,10 and12 hours.
Sampling volume: 10ml
Example V: Valsartan Pulsatile formulation using pH sensitive polymer coating
The formulation efforts were aimed at releasing the drug in pulses in the proximal intestine region covering the pH range of 4 to 5. The combination of release in 0.1 N HCI and a pulse at pH about 4,5 might ensure sustained blood levels. The approach involved seal coating of the core tablets followed by functional coating with various pH sensitive polymers like PVAP, HPMCP, Eudragit L 100-55 and Eudragtt L 30-D55.
Example V- A a) Composition of core tablets:
Table 20
Valsartan was added to molten Lutrol F127 & Vitamin E TPGS in low shear mixer and mixed well. Mixture of zeopharm, microcrystalline cellulose and Kollidon CL was added to above mass and mixed further. All other ingredients were added to above mass and mixed well to achieve uniform blend.
b) PVAP based Polymer coating
The core tablets prepared as per table 20 were first seal coated to avoid moisture ingress followed by coat of pH sensitive PVAP based polymer at predetermined weight gain levels.
Table 21 Coating composition using PVAP based opadry white enteric polymer
Sr. No. Ingredients % w/w
1 Opadry white enteric 15
2 lsopropyl alcohol 68
3 DM Water 17
lsopropyl alcohol and DM water were mixed well in which Opadry white enteric was dispersed well and kept on stirring while coating the core tablets.
Coating was done to achieve different weight gain levels like 2,4, 6 and 8. The tablets were cured for definite time period in tray dryer after which disintegration of the tablets was studied.
Table 22: Disintegration test of PVAP coated valsartan core tablets
Table 23: dissolution conditions for the selected tablets of example 21
Table 24 Dissolution profile of PVAP coated valsartan tablets
Dissolution Time (min) 4 % coated 6 % coated medium
0.1 N HCI 15 0.7 0.2
30 0.4 0.1
60 0.3 0.6
PH 4.5 75 1.4 1.0
120 3.7 1.3
DH 5.5 150 108.4 85.3
Example V-B
Pulsatile formulation using HPMCP
The same core tablets as shown in example 20 were prepared and seal coated using Kollidon VA 64 followed by coat of pH sensitive hydroxy! propyl methyl cellulose phthalate based polymer for different weight gain levels.
Table 25 : Coating solution composition
Sr. No. Ingredients % w/w
1 HPMCP- HP 50 18.39
2 Triethyl citrate 1.84
3 Talc 10.42
4 Ethanol 80
5 DM water 20
Talc was dispersed well in a mixture of absolute alcohol and DM water with the help of homogenizer to which triethy! citrate was added. HPMCP HP 50 was added to this mixture and dissolved to get the coating solution. Coating was done to achieve different weight gain levels like 2,4, 6 and 8.
The tablets were cured for definite time period in tray dryer after which disintegration of the tablets was studied.
Table 26: Disintegration test of HPMCP HP-50 coated valsartan core tablets
8% 0.1 N HCI Did not disintegrate for 60 min
4.5 acetate buffer Disintegrated in 25 minutes
The dissolution behavior of these tablets was studied in 0.1 N HCI for 1 hour followed by pH 4.5 buffer for 1 hour and pH 5.5 buffer using USP Il dissolution apparatus.
Table 27 Dissolution profile of HPMCP coated valsartan tablets
Dissolution Time (min) 4 % coated 6 % coated medium
0.1 N HCI 15 0.5 0.4
30 0.3 03
60 05 02
DH 4.5 75 77.8 5J2
120 94.7 92.2
Example V- C
Pulsatile formulation using Acryl-eze
The same core tablets as shown in example 20 were prepared and seal coated using Kollidon VA 64 followed by coat of Acryl- eze (Eudragit L100-55) for different weight gain levels. Table 28 : Coating solution composition
Sr. No. Ingredients % w/w
1 Eudragit L 100-55 20
2 DM water 80
Eudragit L 100-55 was dispersed well in demineralized water with the help of homogenizer. This coating solution was used to coat valsartan core tablets to achieve different weight gain levels like 2,4, 6 and δ.The tablets were cured for definite time period in tray dryer after which disintegration of the tablets was studied.
Table 29: Disintegration test of acyl-eze coated valsartan core tablets
The dissolution behavior of these tablets was studiedand the results are summarized in Table 30.
Table 30 Dissolution profile of Eudragit L 100-55 coated valsartan tablets Dissolution Time (min) 4 % coated 6 % coated medium
0.1 N HCI 15 3.0 0.3
30 4.5 0.4
60 15.6 3.6
PH 4.5 75 44.9 19.8
120 54.3 26.6
JH 5.5 150 78.5 30.6
Example V- D
Pulsatile formulation using Eudragit L30 D 55 with pore forming agents
The core tablets as shown in example 20 were prepared and seal coated using Kollidon VA 64 followed by coat of Eudragit L30- D55 with pore forming agents for different weight gain levels.
Table 31 : Coating solution composition
Sr. No. Ingredients % w/w
1 Eudragit L 30 D 55 15.33
2 Triethyl citrate 3.83
3 PVP K 30 5.11
4 Talc 12.77
2 DM water 62.96
PVP K 30 was used as a pore forming agent in this coating solution to enhance drug release. Talc was dispersed well in water with the help of homogenizer and triethyl citrate was added to this system along with PVP K 30. This suspension was added with slow speed to Eudragit L30 D 55 suspension and kept stirring throughout coating operation. This coating solution was used to coat valsartan core tablets to achieve different weight gain levels like 2,4, 6 and 8.The tablets were cured for definite time period in tray dryer after which disintegration of the tablets was studied.
The dissolution behavior of these tablets was studied and the results are summarized in Table 33.
Table 33 Dissolution profile of Eudragit L 30 D 55 coated valsartan tablets Dissolution Time (min) 6 % coated 8 % coated medium
0.1 N HCI 15 16.5 0.4
30 44.4 1.3
60 55.4 3.1
PH 4.5 75 79.2 9.3
120 84.8 13.7
DH 5.5 150 91.0 16.0
Although certain presently preferred embodiments of the invention have been specifically described herein, it will be apparent to those skilled in the art to which the
invention pertains that variations and modifications of the various embodiments shown and described herein may be made without departing from the spirit and scope of the invention. Accordingly, it is intended that the invention be limited only to the extent required by the appended claims and the applicable rules of law.
Claims
1. A pharmaceutical composition comprising angiotensin Il receptor blockers (ARB), wherein the ARB is released from the composition in pulses at predetermined time intervals.
2. The pharmaceutical composition of claim 1 , wherein 0-70% of the total ARB is released in 0.1 N HCI up to 2 hours and no less than 85% of the total ARB is released in at pH 4.5 for up to 2-4 hours.
3. The pharmaceutical composition of claim 1 , wherein 0-50% of the total ARB is released in 0.1 N HCI up to 2 hours and no less than 80% of the total ARB is released in at pH 4.5 for up to 1 hours.
4. The pharmaceutical composition of claim 1 , wherein 0-20% of the total ARB is released in 0.1 N HCI up to 2 hours and no less than 0-50% of the total ARB is released at pH 4.5 in 1 hour, and no less than 80% of the total ARB is released at pH 5.5 in 1 hour.
5. The pharmaceutical composition of claim 1 , wherein 0-20% of the total ARB is released in 0.1 N HCI in 1 hour and no less than 0-50% of the total ARB is released at pH 4.5 in 1 hour, and no less than 80% of the total ARB is released at pH 5.5 over 10-12 hours.
6. The pharmaceutical composition of claim 1 , wherein 0-50% of the total ARB is released in 0.1 N HCI in 1 hour and no less than 75% of the total ARB is released at pH 4.5 in 1-3 hour, and no less than 85% of the total ARB is released at pH 6.8 over 10-12 hours.
7. The pharmaceutical composition of claim 1 , wherein 0-75% of the total ARB is released in 0.1 N HCI in 2 hours and no less than 80% of the total ARB is released at pH 6.8 in 2 hours.
8. The pharmaceutical composition of claim 1 , having a dosage strength of about 150 to 320 mg.
9. The pharmaceutical composition of claim 1 , wherein 0-50% of the total ARB is released in the first pulse, and remainder 50% releases in 2 or 3 pulses.
10. The pharmaceutical composition of claim 12, wherein the first pulse occurs 0-1 hour after ingestion and the second pulse occurs 2-3 hours after ingestion.
11. The pharmaceutical composition of claim 12, wherein the first pulse occurs 0-1 hour after ingestion, the second pulse occurs 3-4 hours after ingestion.
12. The pharmaceutical composition of claim 12, wherein the first pulse occurs 1 -2 hours after ingestion and the second pulse occurs 3-6 hours after ingestion.
13. The pharmaceutical composition of claim 12, wherein the first pulse occurs 1-2 hours after ingestion and the second pulse occurs 3-6 hours after ingestion and third pulse occurs 7-10 hours after ingestion.
14. The pharmaceutical composition of claim 12, wherein the first pulse occurs 2-5 hours after ingestion and the second pulse occurs 6-9 hours after ingestion.
15. The pharmaceutical composition of claim 1 , wherein the ARB released from the first burst ranges from about 0-50% of the total ARB.
16. The pharmaceutical composition of claim 1 , wherein the ARB is contained in several parts, each part designed to be released at a different pulse.
17. The pharmaceutical composition of claim 16, wherein the several parts are nested in layers.
18. The pharmaceutical composition of claim 17, wherein the outermost layer releases in the first pulse, and the innermost layer releases in the last pulse.
19. The pharmaceutical composition of claim 16, wherein the several parts are mini- tablets contained in a capsule.
20. The pharmaceutical composition of claim 1 , wherein the ARB is valsartan.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US86048406P | 2006-11-22 | 2006-11-22 | |
US60/860,484 | 2006-11-22 |
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WO2008064338A2 true WO2008064338A2 (en) | 2008-05-29 |
WO2008064338A3 WO2008064338A3 (en) | 2008-11-20 |
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PCT/US2007/085434 WO2008064338A2 (en) | 2006-11-22 | 2007-11-21 | Valsartan formulation for pulsatile delivery |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009148990A1 (en) * | 2008-06-03 | 2009-12-10 | Novartis Ag | Pulsatile release of valsartan |
DE102008051783A1 (en) * | 2008-10-17 | 2010-04-22 | Tiefenbacher Pharmachemikalien Alfred E. Tiefenbacher Gmbh & Co. Kg | Valsartan-containing tablet |
US9675585B1 (en) | 2016-03-24 | 2017-06-13 | Ezra Pharma | Extended release pharmaceutical formulations |
US9687475B1 (en) | 2016-03-24 | 2017-06-27 | Ezra Pharma Llc | Extended release pharmaceutical formulations with controlled impurity levels |
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US6485745B1 (en) * | 1996-06-27 | 2002-11-26 | Novartis Ag | Solid oral dosage forms of valsartan |
US20060210633A1 (en) * | 2003-04-03 | 2006-09-21 | Sun Pharmaceutical Industries Limited | Programmed drug delivery system |
WO2006113631A2 (en) * | 2005-04-18 | 2006-10-26 | Rubicon Research Pvt. Ltd. | Bioenhanced compositions |
US20060240105A1 (en) * | 1998-11-02 | 2006-10-26 | Elan Corporation, Plc | Multiparticulate modified release composition |
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Patent Citations (4)
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US6485745B1 (en) * | 1996-06-27 | 2002-11-26 | Novartis Ag | Solid oral dosage forms of valsartan |
US20060240105A1 (en) * | 1998-11-02 | 2006-10-26 | Elan Corporation, Plc | Multiparticulate modified release composition |
US20060210633A1 (en) * | 2003-04-03 | 2006-09-21 | Sun Pharmaceutical Industries Limited | Programmed drug delivery system |
WO2006113631A2 (en) * | 2005-04-18 | 2006-10-26 | Rubicon Research Pvt. Ltd. | Bioenhanced compositions |
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Publication number | Priority date | Publication date | Assignee | Title |
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WO2009148990A1 (en) * | 2008-06-03 | 2009-12-10 | Novartis Ag | Pulsatile release of valsartan |
DE102008051783A1 (en) * | 2008-10-17 | 2010-04-22 | Tiefenbacher Pharmachemikalien Alfred E. Tiefenbacher Gmbh & Co. Kg | Valsartan-containing tablet |
US9675585B1 (en) | 2016-03-24 | 2017-06-13 | Ezra Pharma | Extended release pharmaceutical formulations |
US9687475B1 (en) | 2016-03-24 | 2017-06-27 | Ezra Pharma Llc | Extended release pharmaceutical formulations with controlled impurity levels |
US10010529B2 (en) | 2016-03-24 | 2018-07-03 | Ezra Pharma Llc | Extended release pharmaceutical formulations with controlled impurity levels |
Also Published As
Publication number | Publication date |
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WO2008064338A3 (en) | 2008-11-20 |
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