CA2380333A1 - Pharmaceutical formulations - Google Patents
Pharmaceutical formulations Download PDFInfo
- Publication number
- CA2380333A1 CA2380333A1 CA002380333A CA2380333A CA2380333A1 CA 2380333 A1 CA2380333 A1 CA 2380333A1 CA 002380333 A CA002380333 A CA 002380333A CA 2380333 A CA2380333 A CA 2380333A CA 2380333 A1 CA2380333 A1 CA 2380333A1
- Authority
- CA
- Canada
- Prior art keywords
- dosage form
- release
- active agent
- form according
- formulation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7125—Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—Poly(meth)acrylates
-
- 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
-
- 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
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
Abstract
The application discloses novel pharmaceutical formulations adapted for delaying the release of a pharmaceutically active agent. A delayed-release drug formulation encapsulates the active ingredient, which may be applied to microparticles or in tableted form, in a release-delaying coat comprising polymeric materials of predetermined swelling/permeability characteristics. In particular, acrylate and/or acrylic acid polymer blends modified with ionic groups may be used. One preferred embodiment uses a polymer of pH dependent permeability as a more permeable element of the coat. The delayed-release formulations are deployed in a single dosage form together with instant release or sustained release formulations, so that a unit dosage form, preferably an oral dosage form, can effectively administer two doses to a patient at different times.
Description
Pharmaceutical Formulations Field of the Invention The present invention relates to methods of .
pharmaceutical formulation and administrate~n', and in particular, orally administrable formulations capable of providing a desired pharmacokinetic profile for an active agent.
Background to the Invention Many pharmaceutically active agents are metabolised by mammalian systems. Any dosing regime must take into account the pharmacokinetic properties of the active ingredient and its interaction with the metabolic system of the subject in order to obtain the required pharmacokinetic profile and bioavailability of the drug.
It may be desirable to achieve a slow sustained release rate of a pharmaceutically active agent. This is ideal where a single administration or dose of an active agent is required to act over a long time period, especially where metabolism or degradation of the drug will not significantly reduce its bioavailability.
However, metabolism or degradation can seriously impair bioavailability of many drugs. In such cases, the method of administration must be tailored in order to overcome the problems associated with drug metabolism. The metabolism of some active agents may be saturable. Where this is the case, a pulse of active ingredient sufficient to saturate the relevant metabolic or degradative pathway can enable a therapeutically acceptable quantity of active agent to be delivered to the target tissue or organ.
pharmaceutical formulation and administrate~n', and in particular, orally administrable formulations capable of providing a desired pharmacokinetic profile for an active agent.
Background to the Invention Many pharmaceutically active agents are metabolised by mammalian systems. Any dosing regime must take into account the pharmacokinetic properties of the active ingredient and its interaction with the metabolic system of the subject in order to obtain the required pharmacokinetic profile and bioavailability of the drug.
It may be desirable to achieve a slow sustained release rate of a pharmaceutically active agent. This is ideal where a single administration or dose of an active agent is required to act over a long time period, especially where metabolism or degradation of the drug will not significantly reduce its bioavailability.
However, metabolism or degradation can seriously impair bioavailability of many drugs. In such cases, the method of administration must be tailored in order to overcome the problems associated with drug metabolism. The metabolism of some active agents may be saturable. Where this is the case, a pulse of active ingredient sufficient to saturate the relevant metabolic or degradative pathway can enable a therapeutically acceptable quantity of active agent to be delivered to the target tissue or organ.
It is desirable to produce a single dose form of administration capable of releasing a pulse of active agent, as provided by an immediate release formulation, after a specified lag period. Combination of one or more such dosage forms with immediate release anc~jor sustained release formulations may enable a single dose formulation to provide multiple, temporally distinct pulses of active agent to a patient. Such a combination would reduce the need for multiple dose administration regimes, and could therefore have significant benefits, for example, in improving patient compliance.
Thus there is a need for novel modes of administration of pharmaceutically active agents capable of delivering tailored release of active agents.
Summary of the Invention We have developed a method of formulating active ingredients to provide novel orally administrable pharmaceutical formulations or dosage forms giving delayed or sustained release of the active agent.
One object of the present invention is to provide sustained release formulations, capable of releasing active ingredient over a required time period. A further object of the present invention is to provide delayed release formulations capable of delivering a pulse of active agent, similar to that obtained with an immediate release formulation, after a suitable delay period.
A further object of the invention is to provide a dosage form capable of releasing active agent at two different release rates. In a preferred embodiment the dosage form is capable of releasing active agent in two distinct peaks, separated by an appropriate time period.
Typically the peaks will be separated by at least two hours, possibly at least five hours, possibly at least 8 hours.
Accordingly, the present invention provides a particulate oral dosage form comprising a pharmaceutically active agent, the dosage form also comprising a release modifying layer, the release modifying layer comprising a polymer having solubility properties predetermined to affect the rate of release of the active agent under enteric physiological conditions.
The particulate dosage form may be manufactured as a multiparticulate formulation. This may be a granulate, or alternatively a pellet or "non-pareil" type formulation, in which the active agent is applied to an inert support. The particulate dosage form may also be manufactured in a "minitablet" type formulation, in which the active agent is compressed into a minitablet with appropriate excipients.
Thus, in one embodiment, the pharmaceutically active agent is applied to an inert, particulate, pharmaceutically acceptable support. In a preferred embodiment the inert, particulate, pharmaceutically acceptable support comprises carbohydrate beads, such as non-pareil seeds (often referred to as neutral pellets, or sugar spheres).
The active ingredient may be sprayed onto the inert, particulate, pharmaceutically acceptable support from solution, preferably an aqueous solution. Alternatively, the active ingredient may be coated onto the inert, particulate, pharmaceutically acceptable support from suspension, for example, by means of a fluidised bed coating system such as a Wurster system. Tne active agent may be applied to the inert, particulate, pharmaceutically acceptable support alone or in combination with further pharmaceutically acceptable exc.i-pients .
In a further embodiment, the particulate dosage form may be manufactured as a "minitablet" formulation of the pharmaceutically active agent. Minitablets may be formed by the direct compression of active agent with fillers such as microcrystalline cellulose, lactose, dicalcium phosphate, lubricants such as magnesium stearate or stearic acid, disintegrants such as sodium starch glycolate and glidants such as colloidal silicon dioxide.
Minitablets may also be formed by wet granulation of the drug with suitable excipients in a fluidised bed.
These particulate dosage forms will typically initially constitute "immediate release" type formulations, whose release properties may be altered by application of suitable coatings, as will be described below. Typically the active agent will constitute 1 to 20%, preferably 3 to 100, of the total weight of the immediate release particulate dosage form prior to the application of any coating.
The particulate dosage form may also comprise a protective sealant.or barrier coat, applied to the particulate dosage form. Preferably, this protective sealant or barrier layer is soluble and does not substantially modify the release of the active drug under physiological conditions, but protects it during processing. In one embodiment, the protective coat is composed mainly of hydroxypropyl methylcellu'Tose. Other agents can be added to improve the processability of the sealant layer. The protective coat can be applied from solution, such as an aqueous solution, or suspension using a fluidised bed coater (for example, a Wurster system), or in a pan coating system.
Minitablet formulations may include excipients which affect the rate of dissolution of the minitablet, and thus the rate of release of the active agent. Such minitablet formulations may be regarded as "sustained release" type minitablets before any modifying coatings are applied. Their release properties may be further modified by application of release modifying coatings.
Thus, minitablets providing sustained release of the active agent may be formed by the direct compression or wet granulation of the drug with excipients, as described above, plus the inclusion of rate controlling excipients such as hydroxypropylcellulose, polyethylene glycolate and ethylcellulose, typically in a concentration of 20-80%.
The release profile of the active agent can be modified according to the present invention~by applying a modifying coating of material having predetermined dissolution properties to the particulate dosage form.
Such a modifying coating may be used to provide a sustained release profile or a delayed release profile for the active agent, and typically comprise soluble polymers (with solubility being pH independent or pH
dependent) that can modify the release of the drug.
For example, a "sustained release" type formulation may release between 2.5% and 25% of the active agent in 0.5 hours, between 25% and 70% of the active agent in 1 hour, between 65o and 95% of the active agent in 2 hours, and at least 90% of the active agent in 4 hours, as determined in standard USP method II dissolution assay, in phosphate buffer at pH 6.8 (as described later). Thus a typical sustained release formulation may provide approximately loo release of the active agent in 0.5 hours, approximately 50% release of the active agent in 1 hour, approximately 75% release of the active agent in 2 hours, and approximately 95% release of the active agent in 4 hours. The release profile required will vary depending on the active agent employed and the pharmacokinetic profile desired.
In preferred embodiments the modifying coating may comprise soluble or permeable acrylate polymers, e.g.
ammonio methacrylate polymers or co-polymers, or methacrylic acid polymers or co-polymers. The polymers can be used alone or in combination with each other.
Additionally or alternatively such modifying materials may be blended with active agent as a matrix ingredient.
The coatings can also include other agents to improve the processability of the coating. Examples of such agents include talc, silicon dioxide and glyceryl monostearate.
The quantity of such anti-caking agents used for preparing coatings for the dosage form is e.g. from about 2% to about 100% by weight, preferably 30 to 600, based on the total dry weight of the polymer.
The coatings can also include a material that improves the characteristics of the polymer material. Such materials are generally referred to as "plas~icisers" and include, for example, dibutyl sebacate (DBS), diethyl phthalate, citric acid esters, or triethyl citrate (TEC), stearates, polyethylene glycols and ethylene glycol.
Dibu-tyl sebacate or triethyl citrate are the preferred plasticisers. The amount of plasticiser to be used in the coating is preferably from about 10% to 50%, most preferably about 20%, based on the weight of the dry polymer.
The coating solutions can also include an anti-foaming agent. An example of such an agent is simethicone emulsion. The amount of anti-foaming agent to be used in the coating is preferably from less than 0.5% of the final coating solution.
The amount of coating to be used in preparing the dosage form will be determined by the desired delivery properties, including the amount of drug to be delivered, the time delay desired, and the size of the particles.
The coating polymers will typically be coated from 5 to 20% weight gain on the instant release particles, preferably 6-10% polymer weight gain. The polymer layer can be coated by any known method, including spray application. Spraying can be carried out using a fluidised bed coater (preferably using a Wurster system), or in a pan coating system.
The coated particles can be dried and/or cured after _g_ application of the polymer layers. "Curing" means that the particles are held at a controlled temperature for a time sufficient to provide stable release rates. Curing can be performed for example in an oven or in a fluid bed drier. Curing can be carried out at temperature within 25° and 50°C, preferably 35° to 45°C.
The particulate dosage form may, alternatively or adds-tionally, be coated with a modifying layer able to modify the release of the active agent, to form delayed release particles.
The process and the materials used to prepare a delayed release coating can be similar to those used to provide sustained release coatings, as described above. More particularly, however, we envisage a delayed release or sustained release coating comprising a blend of a relatively insoluble or impermeable polymeric material with a more soluble or permeable material, the choice of polymers and the proportions in the blend controlling the release rate. A particularly preferred embodiment. uses for the relatively permeable polymer a polymer whose permeability or solubility is pH dependent; in particular being more soluble or permeable in alkaline conditions than in acidic conditions. This enables passage of the coating through the stomach relatively undisrupted, for release of the active agent further along the gut. For sustained release the pH dependence of polymer solubility or permeability may not be needed. A pH dependent system may be used to provide a delay in initial drug release.
It may also be used to provide protection against acid degradation of acid labile drugs in the gut and/or maximise the concentration of drug available to _g-absorption sites in the intestine.
Film forming polymers which are swellable or soluble under appropriate conditions and suitable for oral formulation, are available commercially and=7cnown to the skilled person, e.g. Eudragit polymethacrylate coating systems from Rohm. Poly(meth)acrylates with varying proportions of ionic groups in the acrylate-forming moi~-ty, e.g. quaternary ammonium salt groups, can be used to provide correspondingly varying film permeabilities.
Eudragit L may be used to provide drug release in the duodenum/jejunum, and Eudragit S for release in the ileum.
One particular novel procedure proposed herein is to form a release-delaying coating from a blend of film-forming, swellable acrylate polymers of any suitable kinds as described herein, one of which is in aqueous dispersion (latex) and the other of which is in non-aqueous dispersion (latex), creating a characteristic and useful difference in film permeability behaviours of the two polymers in the layer.
The amount of coating to be used may be determined by the desired delivery properties, including the amount of drug to be delivered, the time delay desired, and the size of the particles. The modifying layer will typically provide 15 to 80% weight gain on the uncoated or sustained release particles, preferably 15 to 40% polymer weight gain on a first layer and possibly 5 to 30%
polymer weight gain on a subsequent layer. The first and subsequent layers may have identical or different compositions.
Increasing the amount of coating increases the distance the drug has to travel by diffusion through the swelled or permeabilised polymer film to be released into the surrounding medium, and therefore reduces the rate of drug release by diffusion. Decreasing the proportion of permeable component will give less opportunity for the drug to be directly solubilised by the dissolution medium and therefore may provide a longer lag time before drug release begins.
Typically, the particulate dosage forms will be encapsulated into individual doses. Administration is preferably in a "prophylactically effective amount" or a "therapeutically effective amount", as the case may be (although prophylaxis may be considered therapy), this being sufficient to show benefit to the individual. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of the condition to be treated. Prescription of treatment, e.g. decisions on dosage etc, is within the responsibility of general practitioners and other medical doctors, and typically takes accour~t of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed), 1980.
It is envisaged that one or more varieties of the particulate dosage forms may be encapsulated together.
The quantity of particles filled into any individual capsule will vary depending on the active agent to be administered, the specific activity of the active agent in the particular particulate dosage form, and the pharmacokinetic profile required. Any combination of the above described components may be encapsulated to obtain a desired release profile, and they may be Combined in various ratios or strengths. For example, uncoated neutral pellet ("non-pareil") type multiparticulates providing an initial release, and coated neutral pellet ("nan-pareil") type multiparticulates providing a delayed release, may be encapsulated together e.g. in a hard gelatine capsule, preferably using standard dual filling encapsulation equipment. Alternatively sustained or delayed release minitablets could be encapsulated with instant release non-pareil seeds. Depending on the formulations, any one of the possible component types may contribute to initial, sustained or delayed release elements of the overall pharmacokinetic profile provided.
Specific embodiments of the present invention will now be described in more detail by way of example, with reference to the accompanying Figures, in which:
Figure 1 shows dissolution profiles for sustained release multiparticulate formulations.
Figure 2 shows dissolution profiles for delayed release multiparticulate formulations.
Figure 3 shows dissolution profiles for sustained release minitablet formulations without a modifying coat.
Figure 4 shows dissolution profiles for sustained release minitablet formulations coated with Eudragit RS/RL
Figure 5 shows dissolution profiles for delayed release minitablet formulations.
Figure 6 shows dissolution profiles for co-encapsulated sustained release minitablets and delayed release multiparticulate formulations.
Experimental For formulations comprising pH dependent polymer, dissolution profiles were established by immersion of test formulation for two hours in O.O1M HC1, followed by immersion in pH 6.8 phosphate buffer. For formulations comprising only pH independent polymer, the immersion in acid was omitted, and test formulations were immersed in pH 6.8 phosphate buffer for the duration of the assay.
Aliquots of the dissolution buffers were removed at intervals and analysed for released rivastigmine by HPLC.
Buffers O.O1M HC1 was prepared by diluting 8.5m1 of concentrated HCl 1 litre with de-ionised water to give a solution of O.1M HCl. This was then diluted to O.O1M HCl with deionised water, and then degassed by sparging with helium at 1.2 litres/min for 20 minutes.
1 litre of phosphate buffer (pH6.8 ~ 0.05) was prepared by adding 250m1 of 0.2M potassium phosphate solution (27.228 of monobasic potassium phosphate(KH2P04).per litre distilled water) to 112m1 of 0.2M sodium hydroxide solution and diluting to 1000m1 with distilled water.
Phosphate buffer was degassed as above.
Dissolution Test formulation corresponding to 12.5m8 of rivastigmine base was placed into a clean dry dissolution basket assembly (USP Apparatus I, with 40 mesh baskets). The _13_ basket was attached to the apparatus shaft, lowered into a dissolution vessel containing 500m1 O.O1M HCl or phosphate buffer at 37.0 ~ 0.5°C, and rotated at 100rpm.
For pH dependent formulations, after two hours dissolution time, the O.O1M HCl was neutralised by addition of approximately 50m1 O.1N NaOH to the vessel, with mixing. The basket was then transferred to a second dissolution apparatus containing 500m1 phosphate buffer (pH 6.8).
At each time point, a 4m1 aliquot of dissolution buffer was removed and filtered through a Millipore Millex-HV
Hydrophilic PVDF 0.45mm filter into a suitable vial for analysis by HPLC, discarding approximately the first 2m1 of filtrate to waste. The volume removed at each sampling time point was replaced with 4m1 pre-heated media.
Rivastigmine content of the samples was analysed by HPLC
as described below.
HPLC analysis Column: PUROSPHER ~ (RP-18) 5mm, 12.5 cm x 4.Omm i.d.
LiChroCart [(Cartridge), Merck, Germany] or equivalent.
Temperature: 40 ~ 1° C
Mobile phase: 1 litre of mobile phase was prepared by adding 670m1 of HPLC grade methanol to 330m1 of aqueous buffer (3.858 - 3.95g of ammonium carbamate (anhydrous form of carbonate) dissolved in 1 litre of deionised water). The mobile phase was filtered and degassed for 10 minutes with helium. The pH was adjusted to 9.2 as necessary with conc. ammonia.
Flow Rate: 1.7 ml/min.
Inj..ection Volume : 501 .
W Detection: 214nm Retention of active ingredient : t~,A .,13 z1 . 5min HPLC was calibrated with duplicate standards, each prepared by accurately weighing 20mg of rivastigmine tartrate reference standard (equivalent to 12.5mg Rivastigmine base) into a 500m1 volumetric flask. This was dissolved and diluted to 500m1 with medium, mixed well and an aliquot filtered through a Millipore Millex-HV Hydrophilic PVDF 0.45mm filter into a suitable vial for injection, discarding approximately the first 2m1 of filtrate to waste.
The calibration was accepted if:
1. The difference between the weight corrected peak response for the two rivastigmine standard solutions was not greater than 2.0%.
2. The coefficient of variation for five injections of a single rivastigmine reference solution was not greater than 2.0%.
Calculations The formulae given below (at 1 and 2) can be used to calculate the release of active agent from sample formulations with pH independent and pH dependent polymer coatings.
1. Formulation comprising only pH independent polymers For a formulation comprising only pH independent polymer, with samples taken at 0.5 hours, 1 hour, 2 hours, 4 hours and 6 hours:
A. Uncorrected amount of rivastigmine (free base) released ( in mg) MH - Asample x Wtstd X DF x P X F
Astd B. Correction factor (for each time point) 2 5 QH _ MH x VS
Vdiss C. The corrected hourly release of rivastigmine To.s Ro.s - Mo.s Ti R1 - M1 + Qo . s T2 Ra - Ma + Qi + Qo.s T4 R4 - M4 + Q2 + Q1 + Q0.5 Ts Rs - Ms + M4 + Qa + Qi + Qo . s D. The corrected amount of rivastigmine (free base) released Released = RH x 100 Potency Where:-H - sampling time intervals MH - mg of rivastigmine (uncorrected) released per hour Asamp ~ - response of sample Asia - response of standard DF - dilution factor = 500 - 1.0 Wsta - weight of standard (mg) V aiss - volume of dissolution medium (500m1) QH - correction factor (mg of rivastigmine free base) VS - volume of sample withdrawn at each interval (4m1) RH - corrected hourly release (mg) R - corrected % released for each interval Potency - mg/sample P - Correction factor for purity of standard (if less than 100%) F - 0.625 to convert rivastigmine tartrate to free base 2. Formulation comprising pH dependent polymers For a formulation comprising pH dependent polymer, with one sample taken from acid at 2 hours, and subsequent samples taken from phosphate buffer at two-hourly intervals:
A. _ Uncorrected amount of rivastigmine (free base) M
released (in mg):
Mx - AsamDle x Wtstd x DF x P x F
Astd B. Correction factor Q (for each time point):
Qx _ Mx x Vs Udies C. The corrected amount of rivastigmine R released at each time point T is given by:
Tz Rz - Ma T4 R4 _ M4 Q2 +
T6 R6 - M6 M4 +Qz +
T8 Ra - M$ Q6 + M4 +Q2 +
T10 R10 - M10 Q8 + Q6 + M4 + Q2 +
Tlz Rlz - M~z Mlo + Qa + Qs + M4 + Qz +
D. The correctedamount of rivastigmine (free base) released:
Released _ Rx x 100 Potency where:-H - sampling time intervals MH - mg of rivastigmine (uncorrected) released per hour Asamp ~ - response of sample Agtd - response of standard DF - dilution factor = 500 = 1.0 Wtsta - weight standard (mg) of V ass - volume dissolution medium (500m1) of QH - correctio n factor (mg of rivastigmine free base) VS - volume sample withdrawn at each of interval (4m1) RH - corrected release for each time interval (mg) R - corrected % released for each interval Potency - mg/sample P - Correction factor for purity of standard (if less than 100%) F - 0.625 to convert rivastigmine tartrate to free base Example 1: Preparation of instant release (IR) Rivastigmine multiparticulates.
A solution of hydroxypropyl methylcellulose was prepared by adding 100.08 of hydroxypropyl methylcellulose into 1.900k8 of purified water and continuing mixing for 45 minutes.
A suspension of Rivastigmine tartrate was prepared as follows. To 1106.68 of hydroxypropyl methylcellulose solution were added 265.78 of Rivastigmine tartrate. The mixture was stirred for 15 minutes to dissolve the drug.
27.78 of silicon dioxide were added to the solution and the mixture was stirred for 15 minutes.
A protective solution was prepared as follo~5s. To 682.98 of hydroxypropyl methylcellulose solution were added 17.18 of silicon dioxide and the mixture was stirred for minutes.
10 The Rivastigmine suspension was sprayed first onto 2.500k8 of 0.85-l.OOmm non-pareil seeds in a fluid bed apparatus (GPCG-3, Glatt) equipped with a Wurster 7"
chamber. After the equivalent of 5% Rivastigmine free base weight gain was layered onto the non-pareil seeds, 15 1.75% weight gain of the protective solution was applied onto the cores. The spray rate for drug layering was 3.2-4.8g/min*kg, the inlet temperature was 47-50°C and the cores were maintained at 34-38°C. The drug loaded instant release multiparticulates were cooled in the Glatt GPCG-3 for 20 minutes. The multiparticulates were screened to remove oversized beads and fine material.
Example 2: Preparation of sustained release (SR) Eudragit RS:RL (98:2) coated Rivasticrmine multi~articulates.
Rivastigmine instant release multiparticulates (prepared according to Example 1) were coated with Eudragit RS:
Eudragit RL (98:2) aqueous dispersion.
A Eudragit RS: Eudragit RL (98:2) aqueous dispersion was prepared as follows: 0.58 of Simethicone emulsion USP, 120.0g of DBS and 3608 of talc USP were added with mixing to 2.515kg of purified water. The mixture was stirred for 15 minutes in a high shear mixer at 6000 rpm. The suspension was added to 1.960kg of Eudragit RS 30D and 40.0g of Eudragit RL 30D (ammonio methacryla~e co polymers in the form of aqueous dispersions from Rohm Pharma, Germany) and stirred for 20 minutes.
A polymer weight gain of 12% was coated onto the Rivastigmine coated multiparticulates and in process samples were taken at 6, 8 and 10% polymer coating. The coated multiparticulates were cured in an oven at 40°C
for 40 hours, then screened to remove oversized multiparticulates and fine material.
Table 1 shows dissolution rates for sustained release multiparticulates. These profiles are illustrated in Figure 1.
Table 1 Eudragit RS: RL (98:2) DBS
released Time 6% 80 l00 12%
2 5 ( hours ) 0.5 55.9 23.0 3.4 N/T
1 80.1 61.4 32.2 2 96.4 91.0 69.1 4 97.7 94.6 90.5 6 99.2 97.7 96.6 Example 3: Preparation of delayed release (DR) Eudractit RS:RL (90:10) coated Rivastigmine multiparticulates.
A Eudragit RS: Eudragit RL (90:10) aqueous dispersion was prepared as follows: 0.5g of simethicone emu'Tsion USP, 120.0g of triethyl citrate and 3608 of talc USP were added with mixing to 2.515kg of purified water. The mixture was stirred for 15 minutes is a high sharer mixer at X000 rpm. The suspension was added to 1.800kg of Eudragit RS 30D and 2008 of Eudragit RL 30D (ammonio methacrylate co-polymers in the form of aqueous dispersions from Rohm Pharma, Germany) and stirred for 20 minutes.
The resulting combined dispersion was sprayed onto instant release multiparticulates prepared according to Example 1, using a fluid bed apparatus as used in Example 1. Spray rate was 3.5-15g/min*kg, the inlet temperature was 38-42°C and the cores temperature was 25-30°C. A
polymer coating of 40% polymer weight gain was coated onto the instant release multiparticulates and an in process sample was taken at 30% polymer coating. The multiparticulates were cured and screened as described in Example 2.
Examt~le 4: Pret~aration of delayed release (DR) Eudragit RS:RL (98:2) over-coated Rivastiamine multiparticulates.
Eudragit RS:RL (90:10)coated Rivastigmine multiparticulates (prepared according to Example 3) were coated with Eudragit RS: Eudragit RL (98:2) aqueous dispersion (prepared according to Example 2), using triethyl citrate as plasticiser.
A polymer weight gain of 20% was over-coated to the Eudragit RS:RL (90:10) coated Rivastigmine multiparticulates, and an in process sample-~vas taken at loo polymer coating. The multiparticulates were cured and screened as described in Example 2.
Example 5: Preparation of delayed release (DR) EudraQit RS:L (75:25) coated Rivastic~mine multiparticulates.
A Eudragit RS: Eudragit L (75:25) organic solution was prepared as follows: 4.650kg of isopropyl alcohol were stirred with 1258 of triethyl citrate and 3.750kg of Eudragit RS12.5 for 5 minutes. 2258 of talc (USP) were added and the mixture stirred for 15 minutes. 1.250kg of Eudragit L12.5 was added to the mixture and stirred for 30 minutes.
The resulting~solution was sprayed onto instant release multiparticulates prepared according to Example 1, using a fluid bed apparatus as used in Example 1. Spray rate was 5-8.5g/min*kg, and the inlet temperature was 38-40°C.
The instant release multiparticulates were maintained at 29-32°C. A polymer coating of 30% polymer weight gain was coated onto the instant release multiparticulates and an in process sample was taken at 20% polymer coating.
The multiparticulates were cured and screened as described in Example 2.
Table 2 shows dissolution rates for the multiparticulates prepared in Examples 3, 4 and 5. Sample profiles are illustrated in Figure 2.
Table 2 Example Example Example Eudragit Eudragit Eudragit RS: RS: RS: L
RL RL
(90:10) (98:2) (75:25) TEC TEC TEC
overcoat Time % released % released % released (hours) 30% 400 10% 20% 20% 30%
1 0 . 9 8 . 3 j~jT o 0 0 .
o 2 -- -- -- 0.4 0.0 3 26.4 20.7 0.8 -- --4 57.6 33.3 1.6 1.8 0.0 6 87.8 66.8 4.2 6.4 1.4 8 95.9 83.4 7.6 30.2 7.0 10 98.3 91.0 21.2 74.6 28.4 12 99.7 93.6 37.1 96.5 61.8 Example 6~ Manufacture of instant release (IR) Rivasticrmine minitablets.
Formulation details:
Material Rivastigmine 13.7 tartrate Sodium starch 10 glycolate Microcrystalline 74.05 cellulose Colloidal silicon 1.5 dioxide Magnesium stearate 0.75 The instant release minitablets were produced by direct compression using the following method 1. Add a similar quantity of the microcrystalline cellulose to the drug and bag blend tor~-1 minute.
2. Add the colloidal silicon dioxide and bag blend for a further 1 minute 3. Screen the mix through a 600mm sieve 4. Add the remaining microcrystalline cellulose, the drug/microcrystalline cellulose/colloidal silicon dioxide mix and the sodium starch glycolate to a V cone blender and mix for 15 minutes at l8rpm.
Add the magnesium stearate and mix for a further 5 minutes at 18 rpm Figure 3 shows a dissolution profile for instant release minitablets.
Example 7: Manufacture of sustained release (SR) Rivasticrmine minitablets.
Formulation details:
Material Rivastigmine tartrate 13.7 Hydroxypropyl cellulose 40 Microcrystalline 38.8 cellulose Colloidal silicon dioxide 1.5 Magnesium stearate 1 The Rivastigmine SR minitablets were produced by direct compression using the following method 1. Add a similar quantity of the microcrystalline cellulose to the drug and bag blend for 1 minute.
2. Add the colloidal silicon dioxide~and bag blend for a further 1 minute 3. Screen the mix through a 600mm sieve 4. Add the remaining microcrystalline cellulose, the drug/microcrystalline cellulose/colloidal silicon dioxide mix, and the hydroxypropyl cellulose to a V cone blender and mix for 15 minutes at l8rpm.
5. Add the magnesium stearate and mix for a further 5 minutes at 18 rpm Example 8: Coatincr of minitablets from Example 6 with the pIi independent polymer Eudracrit RS:RL (98:2).
A Eu-?ragit RS: RL (9R:2) aqueous dispersion was prepared as follows:
0.58 of simethicone emulsion USP, 128 of triethyl citrate and 368 of talc USP were added with mixing to 251.58 of purified water. The mixture was stirred for 15 minutes using a mixer at 1200rpm. This suspension was then added to 1968 of Eudragit RS30D and 4g of Eudragit RL30D
(ammonio methacrylate co-polymers in the form of aqueous dispersions from Rohm Pharma, Germany) and stirred for 20 minutes.
The resulting dispersion was sprayed onto minitablets as manufactured in step la, using a fluidised bed coater with Wurster column insert. The spray rate was 3.7-5.7g/
min, the inlet temperature was 30-39°C and the bed temperature 28-32°C. A coating of 20% poly~e'r weight gain was applied and the tablets dried within the fluidised bed coater for 15 minutes and then dried for 40 hours in an oven.
Figure 4 shows dissolution profiles for these minitablet formulations.
Example 9~ Coating of minitablets from Example 6 with the t~H dependent polymer Eudracrit S 12.5.
A Eudragit S 12.5 organic dispersion was prepared as follows 32g of dibutyl sebecate was added to 77g of purified water, this suspension was then added to 1.081kg of isopropyl alcohol and mixed for 5 minutes. 1.247kg of Eudragit S 12.5 was added into the solution and mixed for 5 minutes. Finally 63g of sterilised talc was added and the suspension mixed for 20 minutes.
The resulting dispersion was sprayed onto the sustained release minitablets from Example 6 using a fluidised bed coater with a Wurster column insert. The spray rate was 8.4-10.4g/min and the inlet temperature 38-47°C. The minitablets were maintained at approximately 33°C. A
coating of 20% polymer weight gain was coated onto the minitablets with an in-process sample being taken at 15%
polymer weight gain, the minitablets were dried for 15 minutes before removal from the fluidised bed coater.
Dissolution profiles for these minitablet formulations are shown in Figure 5.
Example 10~ Coencapsulation of multiparticulates with mini. tablets .
Sustained release Rivastigmine minitablets, and delayed release Rivastigmine multiparticulates, were formulated as detailed below and coencapsulated into hard gelatin capsules.
Minitablets:
Component mg/capsule Rivastigmine HTA 4.8 Methocel K100LV 14.0 Avicel FH101 15.3 Aerosil 200 0.5 Magnesium Stearate 0.4 Multiparticulates:
Component mg/capsule Rivastigmine HTA 4..8 HPMC 3cps * 1.6 Silicon dioxide 0.8 -N.P Seeds 52.8 Eudragit RS 8.9 Eudragit L 3.0 Triethyl citrate 2.4 Talc 4.8 Table 3 shows dissolution profiles for the individual components. These profiles are illustrated in Figure 6.
Table 3 Minitablets Multiparticulates 40~ Methocel 20~ Eudragit RS:L
IC100LV (75:2 TEC
Time ~ released % released (hours) 0.5 42.1 --1 - 72.7 0 2 83.3 0.4 3 __ --4 93.0 1.8 6 92.8 6.4 8 -- 30.2 10 -- 74 . 6 12 -- 96.5 Example 11: Coencapsulation of sustained release Rivastiamine multinarticulates and delayed release Rivastidmine multiparticulates.
Sustained release Eudragit RS:RL (98:2) coated Rivastigmine multiparticulates were coencapsulated with each of three different delayed release multiparticulates. Instant release multiparticulates were prepared as described in Example 1, and were then coated with Eudragit RS:L (75:25) at 100, Eudragit RS:L
(75:25) at 15%, and Eudragit RS:L (65:35) at 15%.
Compositions of the three different co-encapsulated formulations are set out below:
Batch 1 Composition mg/capsule Component SR DR
Rivastigmine (Base) 4.8(3.0) 4.8(3.0) HPMC 3cps 1.6 1.6 Silicon Dioxide 0.8 0.8 Non-Pareil Seeds 52.8 52.8 Eudragit RS (as solid)4.7 6.8 Eudragit RL (as solid)0.1 n/a Eudragit L (as solid)n/a 2.2 Triethyl Citrate 1.0 1.8 Talc 2.9 3.3 Simethicone Emulsion 0.1 n/a Size 3 Gelatin Capsuleone one Batch 2 Composition mg/capsule Component SR DR
Rivastigmine (Base) 4.8(3.0) 4.8(3.0) HPMC Sops 1.6 1.6 2 5 Silicon Dioxide 0.8 0.8 Non-Pareil Seeds 52.8 52.8 Eudragit RS (as solid)4.7 4.5 Eudragit RL (as solid)0.1 n/a Eudragit L (as solid)n/a 1.5 3 0 Triethyl Citrate 1.0 1.2 Talc 2.9 2.2 Simethicone Emulsion 0.1 n/a Size 3 Gelatin Capsuleone one Batch Composition mg/capsule Component SR DR
Rivastigmine (Base) 4.8(3.0) 4.8(3.0) HPMC 3cps 1.6 1.6 Silicon Dioxide 0.8 0.8 Non-Pareil Seeds 52.8 52.8 Eudragit RS (as solid)4.7 5.9 Eudragit RL (as solid)0.1 n/a Eudragit L (as solid)n/a 3.1 Triethyl Citrate 1.C 1.8 Talc 2.9 3.3 Simethicone Emulsion 0.1 n/a Size 3 Gelatin Capsuleone one
Thus there is a need for novel modes of administration of pharmaceutically active agents capable of delivering tailored release of active agents.
Summary of the Invention We have developed a method of formulating active ingredients to provide novel orally administrable pharmaceutical formulations or dosage forms giving delayed or sustained release of the active agent.
One object of the present invention is to provide sustained release formulations, capable of releasing active ingredient over a required time period. A further object of the present invention is to provide delayed release formulations capable of delivering a pulse of active agent, similar to that obtained with an immediate release formulation, after a suitable delay period.
A further object of the invention is to provide a dosage form capable of releasing active agent at two different release rates. In a preferred embodiment the dosage form is capable of releasing active agent in two distinct peaks, separated by an appropriate time period.
Typically the peaks will be separated by at least two hours, possibly at least five hours, possibly at least 8 hours.
Accordingly, the present invention provides a particulate oral dosage form comprising a pharmaceutically active agent, the dosage form also comprising a release modifying layer, the release modifying layer comprising a polymer having solubility properties predetermined to affect the rate of release of the active agent under enteric physiological conditions.
The particulate dosage form may be manufactured as a multiparticulate formulation. This may be a granulate, or alternatively a pellet or "non-pareil" type formulation, in which the active agent is applied to an inert support. The particulate dosage form may also be manufactured in a "minitablet" type formulation, in which the active agent is compressed into a minitablet with appropriate excipients.
Thus, in one embodiment, the pharmaceutically active agent is applied to an inert, particulate, pharmaceutically acceptable support. In a preferred embodiment the inert, particulate, pharmaceutically acceptable support comprises carbohydrate beads, such as non-pareil seeds (often referred to as neutral pellets, or sugar spheres).
The active ingredient may be sprayed onto the inert, particulate, pharmaceutically acceptable support from solution, preferably an aqueous solution. Alternatively, the active ingredient may be coated onto the inert, particulate, pharmaceutically acceptable support from suspension, for example, by means of a fluidised bed coating system such as a Wurster system. Tne active agent may be applied to the inert, particulate, pharmaceutically acceptable support alone or in combination with further pharmaceutically acceptable exc.i-pients .
In a further embodiment, the particulate dosage form may be manufactured as a "minitablet" formulation of the pharmaceutically active agent. Minitablets may be formed by the direct compression of active agent with fillers such as microcrystalline cellulose, lactose, dicalcium phosphate, lubricants such as magnesium stearate or stearic acid, disintegrants such as sodium starch glycolate and glidants such as colloidal silicon dioxide.
Minitablets may also be formed by wet granulation of the drug with suitable excipients in a fluidised bed.
These particulate dosage forms will typically initially constitute "immediate release" type formulations, whose release properties may be altered by application of suitable coatings, as will be described below. Typically the active agent will constitute 1 to 20%, preferably 3 to 100, of the total weight of the immediate release particulate dosage form prior to the application of any coating.
The particulate dosage form may also comprise a protective sealant.or barrier coat, applied to the particulate dosage form. Preferably, this protective sealant or barrier layer is soluble and does not substantially modify the release of the active drug under physiological conditions, but protects it during processing. In one embodiment, the protective coat is composed mainly of hydroxypropyl methylcellu'Tose. Other agents can be added to improve the processability of the sealant layer. The protective coat can be applied from solution, such as an aqueous solution, or suspension using a fluidised bed coater (for example, a Wurster system), or in a pan coating system.
Minitablet formulations may include excipients which affect the rate of dissolution of the minitablet, and thus the rate of release of the active agent. Such minitablet formulations may be regarded as "sustained release" type minitablets before any modifying coatings are applied. Their release properties may be further modified by application of release modifying coatings.
Thus, minitablets providing sustained release of the active agent may be formed by the direct compression or wet granulation of the drug with excipients, as described above, plus the inclusion of rate controlling excipients such as hydroxypropylcellulose, polyethylene glycolate and ethylcellulose, typically in a concentration of 20-80%.
The release profile of the active agent can be modified according to the present invention~by applying a modifying coating of material having predetermined dissolution properties to the particulate dosage form.
Such a modifying coating may be used to provide a sustained release profile or a delayed release profile for the active agent, and typically comprise soluble polymers (with solubility being pH independent or pH
dependent) that can modify the release of the drug.
For example, a "sustained release" type formulation may release between 2.5% and 25% of the active agent in 0.5 hours, between 25% and 70% of the active agent in 1 hour, between 65o and 95% of the active agent in 2 hours, and at least 90% of the active agent in 4 hours, as determined in standard USP method II dissolution assay, in phosphate buffer at pH 6.8 (as described later). Thus a typical sustained release formulation may provide approximately loo release of the active agent in 0.5 hours, approximately 50% release of the active agent in 1 hour, approximately 75% release of the active agent in 2 hours, and approximately 95% release of the active agent in 4 hours. The release profile required will vary depending on the active agent employed and the pharmacokinetic profile desired.
In preferred embodiments the modifying coating may comprise soluble or permeable acrylate polymers, e.g.
ammonio methacrylate polymers or co-polymers, or methacrylic acid polymers or co-polymers. The polymers can be used alone or in combination with each other.
Additionally or alternatively such modifying materials may be blended with active agent as a matrix ingredient.
The coatings can also include other agents to improve the processability of the coating. Examples of such agents include talc, silicon dioxide and glyceryl monostearate.
The quantity of such anti-caking agents used for preparing coatings for the dosage form is e.g. from about 2% to about 100% by weight, preferably 30 to 600, based on the total dry weight of the polymer.
The coatings can also include a material that improves the characteristics of the polymer material. Such materials are generally referred to as "plas~icisers" and include, for example, dibutyl sebacate (DBS), diethyl phthalate, citric acid esters, or triethyl citrate (TEC), stearates, polyethylene glycols and ethylene glycol.
Dibu-tyl sebacate or triethyl citrate are the preferred plasticisers. The amount of plasticiser to be used in the coating is preferably from about 10% to 50%, most preferably about 20%, based on the weight of the dry polymer.
The coating solutions can also include an anti-foaming agent. An example of such an agent is simethicone emulsion. The amount of anti-foaming agent to be used in the coating is preferably from less than 0.5% of the final coating solution.
The amount of coating to be used in preparing the dosage form will be determined by the desired delivery properties, including the amount of drug to be delivered, the time delay desired, and the size of the particles.
The coating polymers will typically be coated from 5 to 20% weight gain on the instant release particles, preferably 6-10% polymer weight gain. The polymer layer can be coated by any known method, including spray application. Spraying can be carried out using a fluidised bed coater (preferably using a Wurster system), or in a pan coating system.
The coated particles can be dried and/or cured after _g_ application of the polymer layers. "Curing" means that the particles are held at a controlled temperature for a time sufficient to provide stable release rates. Curing can be performed for example in an oven or in a fluid bed drier. Curing can be carried out at temperature within 25° and 50°C, preferably 35° to 45°C.
The particulate dosage form may, alternatively or adds-tionally, be coated with a modifying layer able to modify the release of the active agent, to form delayed release particles.
The process and the materials used to prepare a delayed release coating can be similar to those used to provide sustained release coatings, as described above. More particularly, however, we envisage a delayed release or sustained release coating comprising a blend of a relatively insoluble or impermeable polymeric material with a more soluble or permeable material, the choice of polymers and the proportions in the blend controlling the release rate. A particularly preferred embodiment. uses for the relatively permeable polymer a polymer whose permeability or solubility is pH dependent; in particular being more soluble or permeable in alkaline conditions than in acidic conditions. This enables passage of the coating through the stomach relatively undisrupted, for release of the active agent further along the gut. For sustained release the pH dependence of polymer solubility or permeability may not be needed. A pH dependent system may be used to provide a delay in initial drug release.
It may also be used to provide protection against acid degradation of acid labile drugs in the gut and/or maximise the concentration of drug available to _g-absorption sites in the intestine.
Film forming polymers which are swellable or soluble under appropriate conditions and suitable for oral formulation, are available commercially and=7cnown to the skilled person, e.g. Eudragit polymethacrylate coating systems from Rohm. Poly(meth)acrylates with varying proportions of ionic groups in the acrylate-forming moi~-ty, e.g. quaternary ammonium salt groups, can be used to provide correspondingly varying film permeabilities.
Eudragit L may be used to provide drug release in the duodenum/jejunum, and Eudragit S for release in the ileum.
One particular novel procedure proposed herein is to form a release-delaying coating from a blend of film-forming, swellable acrylate polymers of any suitable kinds as described herein, one of which is in aqueous dispersion (latex) and the other of which is in non-aqueous dispersion (latex), creating a characteristic and useful difference in film permeability behaviours of the two polymers in the layer.
The amount of coating to be used may be determined by the desired delivery properties, including the amount of drug to be delivered, the time delay desired, and the size of the particles. The modifying layer will typically provide 15 to 80% weight gain on the uncoated or sustained release particles, preferably 15 to 40% polymer weight gain on a first layer and possibly 5 to 30%
polymer weight gain on a subsequent layer. The first and subsequent layers may have identical or different compositions.
Increasing the amount of coating increases the distance the drug has to travel by diffusion through the swelled or permeabilised polymer film to be released into the surrounding medium, and therefore reduces the rate of drug release by diffusion. Decreasing the proportion of permeable component will give less opportunity for the drug to be directly solubilised by the dissolution medium and therefore may provide a longer lag time before drug release begins.
Typically, the particulate dosage forms will be encapsulated into individual doses. Administration is preferably in a "prophylactically effective amount" or a "therapeutically effective amount", as the case may be (although prophylaxis may be considered therapy), this being sufficient to show benefit to the individual. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of the condition to be treated. Prescription of treatment, e.g. decisions on dosage etc, is within the responsibility of general practitioners and other medical doctors, and typically takes accour~t of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed), 1980.
It is envisaged that one or more varieties of the particulate dosage forms may be encapsulated together.
The quantity of particles filled into any individual capsule will vary depending on the active agent to be administered, the specific activity of the active agent in the particular particulate dosage form, and the pharmacokinetic profile required. Any combination of the above described components may be encapsulated to obtain a desired release profile, and they may be Combined in various ratios or strengths. For example, uncoated neutral pellet ("non-pareil") type multiparticulates providing an initial release, and coated neutral pellet ("nan-pareil") type multiparticulates providing a delayed release, may be encapsulated together e.g. in a hard gelatine capsule, preferably using standard dual filling encapsulation equipment. Alternatively sustained or delayed release minitablets could be encapsulated with instant release non-pareil seeds. Depending on the formulations, any one of the possible component types may contribute to initial, sustained or delayed release elements of the overall pharmacokinetic profile provided.
Specific embodiments of the present invention will now be described in more detail by way of example, with reference to the accompanying Figures, in which:
Figure 1 shows dissolution profiles for sustained release multiparticulate formulations.
Figure 2 shows dissolution profiles for delayed release multiparticulate formulations.
Figure 3 shows dissolution profiles for sustained release minitablet formulations without a modifying coat.
Figure 4 shows dissolution profiles for sustained release minitablet formulations coated with Eudragit RS/RL
Figure 5 shows dissolution profiles for delayed release minitablet formulations.
Figure 6 shows dissolution profiles for co-encapsulated sustained release minitablets and delayed release multiparticulate formulations.
Experimental For formulations comprising pH dependent polymer, dissolution profiles were established by immersion of test formulation for two hours in O.O1M HC1, followed by immersion in pH 6.8 phosphate buffer. For formulations comprising only pH independent polymer, the immersion in acid was omitted, and test formulations were immersed in pH 6.8 phosphate buffer for the duration of the assay.
Aliquots of the dissolution buffers were removed at intervals and analysed for released rivastigmine by HPLC.
Buffers O.O1M HC1 was prepared by diluting 8.5m1 of concentrated HCl 1 litre with de-ionised water to give a solution of O.1M HCl. This was then diluted to O.O1M HCl with deionised water, and then degassed by sparging with helium at 1.2 litres/min for 20 minutes.
1 litre of phosphate buffer (pH6.8 ~ 0.05) was prepared by adding 250m1 of 0.2M potassium phosphate solution (27.228 of monobasic potassium phosphate(KH2P04).per litre distilled water) to 112m1 of 0.2M sodium hydroxide solution and diluting to 1000m1 with distilled water.
Phosphate buffer was degassed as above.
Dissolution Test formulation corresponding to 12.5m8 of rivastigmine base was placed into a clean dry dissolution basket assembly (USP Apparatus I, with 40 mesh baskets). The _13_ basket was attached to the apparatus shaft, lowered into a dissolution vessel containing 500m1 O.O1M HCl or phosphate buffer at 37.0 ~ 0.5°C, and rotated at 100rpm.
For pH dependent formulations, after two hours dissolution time, the O.O1M HCl was neutralised by addition of approximately 50m1 O.1N NaOH to the vessel, with mixing. The basket was then transferred to a second dissolution apparatus containing 500m1 phosphate buffer (pH 6.8).
At each time point, a 4m1 aliquot of dissolution buffer was removed and filtered through a Millipore Millex-HV
Hydrophilic PVDF 0.45mm filter into a suitable vial for analysis by HPLC, discarding approximately the first 2m1 of filtrate to waste. The volume removed at each sampling time point was replaced with 4m1 pre-heated media.
Rivastigmine content of the samples was analysed by HPLC
as described below.
HPLC analysis Column: PUROSPHER ~ (RP-18) 5mm, 12.5 cm x 4.Omm i.d.
LiChroCart [(Cartridge), Merck, Germany] or equivalent.
Temperature: 40 ~ 1° C
Mobile phase: 1 litre of mobile phase was prepared by adding 670m1 of HPLC grade methanol to 330m1 of aqueous buffer (3.858 - 3.95g of ammonium carbamate (anhydrous form of carbonate) dissolved in 1 litre of deionised water). The mobile phase was filtered and degassed for 10 minutes with helium. The pH was adjusted to 9.2 as necessary with conc. ammonia.
Flow Rate: 1.7 ml/min.
Inj..ection Volume : 501 .
W Detection: 214nm Retention of active ingredient : t~,A .,13 z1 . 5min HPLC was calibrated with duplicate standards, each prepared by accurately weighing 20mg of rivastigmine tartrate reference standard (equivalent to 12.5mg Rivastigmine base) into a 500m1 volumetric flask. This was dissolved and diluted to 500m1 with medium, mixed well and an aliquot filtered through a Millipore Millex-HV Hydrophilic PVDF 0.45mm filter into a suitable vial for injection, discarding approximately the first 2m1 of filtrate to waste.
The calibration was accepted if:
1. The difference between the weight corrected peak response for the two rivastigmine standard solutions was not greater than 2.0%.
2. The coefficient of variation for five injections of a single rivastigmine reference solution was not greater than 2.0%.
Calculations The formulae given below (at 1 and 2) can be used to calculate the release of active agent from sample formulations with pH independent and pH dependent polymer coatings.
1. Formulation comprising only pH independent polymers For a formulation comprising only pH independent polymer, with samples taken at 0.5 hours, 1 hour, 2 hours, 4 hours and 6 hours:
A. Uncorrected amount of rivastigmine (free base) released ( in mg) MH - Asample x Wtstd X DF x P X F
Astd B. Correction factor (for each time point) 2 5 QH _ MH x VS
Vdiss C. The corrected hourly release of rivastigmine To.s Ro.s - Mo.s Ti R1 - M1 + Qo . s T2 Ra - Ma + Qi + Qo.s T4 R4 - M4 + Q2 + Q1 + Q0.5 Ts Rs - Ms + M4 + Qa + Qi + Qo . s D. The corrected amount of rivastigmine (free base) released Released = RH x 100 Potency Where:-H - sampling time intervals MH - mg of rivastigmine (uncorrected) released per hour Asamp ~ - response of sample Asia - response of standard DF - dilution factor = 500 - 1.0 Wsta - weight of standard (mg) V aiss - volume of dissolution medium (500m1) QH - correction factor (mg of rivastigmine free base) VS - volume of sample withdrawn at each interval (4m1) RH - corrected hourly release (mg) R - corrected % released for each interval Potency - mg/sample P - Correction factor for purity of standard (if less than 100%) F - 0.625 to convert rivastigmine tartrate to free base 2. Formulation comprising pH dependent polymers For a formulation comprising pH dependent polymer, with one sample taken from acid at 2 hours, and subsequent samples taken from phosphate buffer at two-hourly intervals:
A. _ Uncorrected amount of rivastigmine (free base) M
released (in mg):
Mx - AsamDle x Wtstd x DF x P x F
Astd B. Correction factor Q (for each time point):
Qx _ Mx x Vs Udies C. The corrected amount of rivastigmine R released at each time point T is given by:
Tz Rz - Ma T4 R4 _ M4 Q2 +
T6 R6 - M6 M4 +Qz +
T8 Ra - M$ Q6 + M4 +Q2 +
T10 R10 - M10 Q8 + Q6 + M4 + Q2 +
Tlz Rlz - M~z Mlo + Qa + Qs + M4 + Qz +
D. The correctedamount of rivastigmine (free base) released:
Released _ Rx x 100 Potency where:-H - sampling time intervals MH - mg of rivastigmine (uncorrected) released per hour Asamp ~ - response of sample Agtd - response of standard DF - dilution factor = 500 = 1.0 Wtsta - weight standard (mg) of V ass - volume dissolution medium (500m1) of QH - correctio n factor (mg of rivastigmine free base) VS - volume sample withdrawn at each of interval (4m1) RH - corrected release for each time interval (mg) R - corrected % released for each interval Potency - mg/sample P - Correction factor for purity of standard (if less than 100%) F - 0.625 to convert rivastigmine tartrate to free base Example 1: Preparation of instant release (IR) Rivastigmine multiparticulates.
A solution of hydroxypropyl methylcellulose was prepared by adding 100.08 of hydroxypropyl methylcellulose into 1.900k8 of purified water and continuing mixing for 45 minutes.
A suspension of Rivastigmine tartrate was prepared as follows. To 1106.68 of hydroxypropyl methylcellulose solution were added 265.78 of Rivastigmine tartrate. The mixture was stirred for 15 minutes to dissolve the drug.
27.78 of silicon dioxide were added to the solution and the mixture was stirred for 15 minutes.
A protective solution was prepared as follo~5s. To 682.98 of hydroxypropyl methylcellulose solution were added 17.18 of silicon dioxide and the mixture was stirred for minutes.
10 The Rivastigmine suspension was sprayed first onto 2.500k8 of 0.85-l.OOmm non-pareil seeds in a fluid bed apparatus (GPCG-3, Glatt) equipped with a Wurster 7"
chamber. After the equivalent of 5% Rivastigmine free base weight gain was layered onto the non-pareil seeds, 15 1.75% weight gain of the protective solution was applied onto the cores. The spray rate for drug layering was 3.2-4.8g/min*kg, the inlet temperature was 47-50°C and the cores were maintained at 34-38°C. The drug loaded instant release multiparticulates were cooled in the Glatt GPCG-3 for 20 minutes. The multiparticulates were screened to remove oversized beads and fine material.
Example 2: Preparation of sustained release (SR) Eudragit RS:RL (98:2) coated Rivasticrmine multi~articulates.
Rivastigmine instant release multiparticulates (prepared according to Example 1) were coated with Eudragit RS:
Eudragit RL (98:2) aqueous dispersion.
A Eudragit RS: Eudragit RL (98:2) aqueous dispersion was prepared as follows: 0.58 of Simethicone emulsion USP, 120.0g of DBS and 3608 of talc USP were added with mixing to 2.515kg of purified water. The mixture was stirred for 15 minutes in a high shear mixer at 6000 rpm. The suspension was added to 1.960kg of Eudragit RS 30D and 40.0g of Eudragit RL 30D (ammonio methacryla~e co polymers in the form of aqueous dispersions from Rohm Pharma, Germany) and stirred for 20 minutes.
A polymer weight gain of 12% was coated onto the Rivastigmine coated multiparticulates and in process samples were taken at 6, 8 and 10% polymer coating. The coated multiparticulates were cured in an oven at 40°C
for 40 hours, then screened to remove oversized multiparticulates and fine material.
Table 1 shows dissolution rates for sustained release multiparticulates. These profiles are illustrated in Figure 1.
Table 1 Eudragit RS: RL (98:2) DBS
released Time 6% 80 l00 12%
2 5 ( hours ) 0.5 55.9 23.0 3.4 N/T
1 80.1 61.4 32.2 2 96.4 91.0 69.1 4 97.7 94.6 90.5 6 99.2 97.7 96.6 Example 3: Preparation of delayed release (DR) Eudractit RS:RL (90:10) coated Rivastigmine multiparticulates.
A Eudragit RS: Eudragit RL (90:10) aqueous dispersion was prepared as follows: 0.5g of simethicone emu'Tsion USP, 120.0g of triethyl citrate and 3608 of talc USP were added with mixing to 2.515kg of purified water. The mixture was stirred for 15 minutes is a high sharer mixer at X000 rpm. The suspension was added to 1.800kg of Eudragit RS 30D and 2008 of Eudragit RL 30D (ammonio methacrylate co-polymers in the form of aqueous dispersions from Rohm Pharma, Germany) and stirred for 20 minutes.
The resulting combined dispersion was sprayed onto instant release multiparticulates prepared according to Example 1, using a fluid bed apparatus as used in Example 1. Spray rate was 3.5-15g/min*kg, the inlet temperature was 38-42°C and the cores temperature was 25-30°C. A
polymer coating of 40% polymer weight gain was coated onto the instant release multiparticulates and an in process sample was taken at 30% polymer coating. The multiparticulates were cured and screened as described in Example 2.
Examt~le 4: Pret~aration of delayed release (DR) Eudragit RS:RL (98:2) over-coated Rivastiamine multiparticulates.
Eudragit RS:RL (90:10)coated Rivastigmine multiparticulates (prepared according to Example 3) were coated with Eudragit RS: Eudragit RL (98:2) aqueous dispersion (prepared according to Example 2), using triethyl citrate as plasticiser.
A polymer weight gain of 20% was over-coated to the Eudragit RS:RL (90:10) coated Rivastigmine multiparticulates, and an in process sample-~vas taken at loo polymer coating. The multiparticulates were cured and screened as described in Example 2.
Example 5: Preparation of delayed release (DR) EudraQit RS:L (75:25) coated Rivastic~mine multiparticulates.
A Eudragit RS: Eudragit L (75:25) organic solution was prepared as follows: 4.650kg of isopropyl alcohol were stirred with 1258 of triethyl citrate and 3.750kg of Eudragit RS12.5 for 5 minutes. 2258 of talc (USP) were added and the mixture stirred for 15 minutes. 1.250kg of Eudragit L12.5 was added to the mixture and stirred for 30 minutes.
The resulting~solution was sprayed onto instant release multiparticulates prepared according to Example 1, using a fluid bed apparatus as used in Example 1. Spray rate was 5-8.5g/min*kg, and the inlet temperature was 38-40°C.
The instant release multiparticulates were maintained at 29-32°C. A polymer coating of 30% polymer weight gain was coated onto the instant release multiparticulates and an in process sample was taken at 20% polymer coating.
The multiparticulates were cured and screened as described in Example 2.
Table 2 shows dissolution rates for the multiparticulates prepared in Examples 3, 4 and 5. Sample profiles are illustrated in Figure 2.
Table 2 Example Example Example Eudragit Eudragit Eudragit RS: RS: RS: L
RL RL
(90:10) (98:2) (75:25) TEC TEC TEC
overcoat Time % released % released % released (hours) 30% 400 10% 20% 20% 30%
1 0 . 9 8 . 3 j~jT o 0 0 .
o 2 -- -- -- 0.4 0.0 3 26.4 20.7 0.8 -- --4 57.6 33.3 1.6 1.8 0.0 6 87.8 66.8 4.2 6.4 1.4 8 95.9 83.4 7.6 30.2 7.0 10 98.3 91.0 21.2 74.6 28.4 12 99.7 93.6 37.1 96.5 61.8 Example 6~ Manufacture of instant release (IR) Rivasticrmine minitablets.
Formulation details:
Material Rivastigmine 13.7 tartrate Sodium starch 10 glycolate Microcrystalline 74.05 cellulose Colloidal silicon 1.5 dioxide Magnesium stearate 0.75 The instant release minitablets were produced by direct compression using the following method 1. Add a similar quantity of the microcrystalline cellulose to the drug and bag blend tor~-1 minute.
2. Add the colloidal silicon dioxide and bag blend for a further 1 minute 3. Screen the mix through a 600mm sieve 4. Add the remaining microcrystalline cellulose, the drug/microcrystalline cellulose/colloidal silicon dioxide mix and the sodium starch glycolate to a V cone blender and mix for 15 minutes at l8rpm.
Add the magnesium stearate and mix for a further 5 minutes at 18 rpm Figure 3 shows a dissolution profile for instant release minitablets.
Example 7: Manufacture of sustained release (SR) Rivasticrmine minitablets.
Formulation details:
Material Rivastigmine tartrate 13.7 Hydroxypropyl cellulose 40 Microcrystalline 38.8 cellulose Colloidal silicon dioxide 1.5 Magnesium stearate 1 The Rivastigmine SR minitablets were produced by direct compression using the following method 1. Add a similar quantity of the microcrystalline cellulose to the drug and bag blend for 1 minute.
2. Add the colloidal silicon dioxide~and bag blend for a further 1 minute 3. Screen the mix through a 600mm sieve 4. Add the remaining microcrystalline cellulose, the drug/microcrystalline cellulose/colloidal silicon dioxide mix, and the hydroxypropyl cellulose to a V cone blender and mix for 15 minutes at l8rpm.
5. Add the magnesium stearate and mix for a further 5 minutes at 18 rpm Example 8: Coatincr of minitablets from Example 6 with the pIi independent polymer Eudracrit RS:RL (98:2).
A Eu-?ragit RS: RL (9R:2) aqueous dispersion was prepared as follows:
0.58 of simethicone emulsion USP, 128 of triethyl citrate and 368 of talc USP were added with mixing to 251.58 of purified water. The mixture was stirred for 15 minutes using a mixer at 1200rpm. This suspension was then added to 1968 of Eudragit RS30D and 4g of Eudragit RL30D
(ammonio methacrylate co-polymers in the form of aqueous dispersions from Rohm Pharma, Germany) and stirred for 20 minutes.
The resulting dispersion was sprayed onto minitablets as manufactured in step la, using a fluidised bed coater with Wurster column insert. The spray rate was 3.7-5.7g/
min, the inlet temperature was 30-39°C and the bed temperature 28-32°C. A coating of 20% poly~e'r weight gain was applied and the tablets dried within the fluidised bed coater for 15 minutes and then dried for 40 hours in an oven.
Figure 4 shows dissolution profiles for these minitablet formulations.
Example 9~ Coating of minitablets from Example 6 with the t~H dependent polymer Eudracrit S 12.5.
A Eudragit S 12.5 organic dispersion was prepared as follows 32g of dibutyl sebecate was added to 77g of purified water, this suspension was then added to 1.081kg of isopropyl alcohol and mixed for 5 minutes. 1.247kg of Eudragit S 12.5 was added into the solution and mixed for 5 minutes. Finally 63g of sterilised talc was added and the suspension mixed for 20 minutes.
The resulting dispersion was sprayed onto the sustained release minitablets from Example 6 using a fluidised bed coater with a Wurster column insert. The spray rate was 8.4-10.4g/min and the inlet temperature 38-47°C. The minitablets were maintained at approximately 33°C. A
coating of 20% polymer weight gain was coated onto the minitablets with an in-process sample being taken at 15%
polymer weight gain, the minitablets were dried for 15 minutes before removal from the fluidised bed coater.
Dissolution profiles for these minitablet formulations are shown in Figure 5.
Example 10~ Coencapsulation of multiparticulates with mini. tablets .
Sustained release Rivastigmine minitablets, and delayed release Rivastigmine multiparticulates, were formulated as detailed below and coencapsulated into hard gelatin capsules.
Minitablets:
Component mg/capsule Rivastigmine HTA 4.8 Methocel K100LV 14.0 Avicel FH101 15.3 Aerosil 200 0.5 Magnesium Stearate 0.4 Multiparticulates:
Component mg/capsule Rivastigmine HTA 4..8 HPMC 3cps * 1.6 Silicon dioxide 0.8 -N.P Seeds 52.8 Eudragit RS 8.9 Eudragit L 3.0 Triethyl citrate 2.4 Talc 4.8 Table 3 shows dissolution profiles for the individual components. These profiles are illustrated in Figure 6.
Table 3 Minitablets Multiparticulates 40~ Methocel 20~ Eudragit RS:L
IC100LV (75:2 TEC
Time ~ released % released (hours) 0.5 42.1 --1 - 72.7 0 2 83.3 0.4 3 __ --4 93.0 1.8 6 92.8 6.4 8 -- 30.2 10 -- 74 . 6 12 -- 96.5 Example 11: Coencapsulation of sustained release Rivastiamine multinarticulates and delayed release Rivastidmine multiparticulates.
Sustained release Eudragit RS:RL (98:2) coated Rivastigmine multiparticulates were coencapsulated with each of three different delayed release multiparticulates. Instant release multiparticulates were prepared as described in Example 1, and were then coated with Eudragit RS:L (75:25) at 100, Eudragit RS:L
(75:25) at 15%, and Eudragit RS:L (65:35) at 15%.
Compositions of the three different co-encapsulated formulations are set out below:
Batch 1 Composition mg/capsule Component SR DR
Rivastigmine (Base) 4.8(3.0) 4.8(3.0) HPMC 3cps 1.6 1.6 Silicon Dioxide 0.8 0.8 Non-Pareil Seeds 52.8 52.8 Eudragit RS (as solid)4.7 6.8 Eudragit RL (as solid)0.1 n/a Eudragit L (as solid)n/a 2.2 Triethyl Citrate 1.0 1.8 Talc 2.9 3.3 Simethicone Emulsion 0.1 n/a Size 3 Gelatin Capsuleone one Batch 2 Composition mg/capsule Component SR DR
Rivastigmine (Base) 4.8(3.0) 4.8(3.0) HPMC Sops 1.6 1.6 2 5 Silicon Dioxide 0.8 0.8 Non-Pareil Seeds 52.8 52.8 Eudragit RS (as solid)4.7 4.5 Eudragit RL (as solid)0.1 n/a Eudragit L (as solid)n/a 1.5 3 0 Triethyl Citrate 1.0 1.2 Talc 2.9 2.2 Simethicone Emulsion 0.1 n/a Size 3 Gelatin Capsuleone one Batch Composition mg/capsule Component SR DR
Rivastigmine (Base) 4.8(3.0) 4.8(3.0) HPMC 3cps 1.6 1.6 Silicon Dioxide 0.8 0.8 Non-Pareil Seeds 52.8 52.8 Eudragit RS (as solid)4.7 5.9 Eudragit RL (as solid)0.1 n/a Eudragit L (as solid)n/a 3.1 Triethyl Citrate 1.C 1.8 Talc 2.9 3.3 Simethicone Emulsion 0.1 n/a Size 3 Gelatin Capsuleone one
Claims (14)
1. A dosage form containing pharmaceutically active agent in two or more different formulations having different respective release times for the pharmaceutically active agent under enteric conditions.
2. A dosage form according to claim 1 in which the different formulations contain the same pharmaceutically active agent.
3. A dosage form according to claim 1 or 2 in which one set formulation is an instant release formulation and another said formulation is a delayed release formulation.
4. A dosage form according to any one of the preceding claims in which one said formulation is a sustained release formulation and another said formulation is a delayed release formulation.
5. A dosage form according to claim 3 or claim 4 in which the delayed release formulation has the pharmaceutically active agent surrounding by a release-delaying coat of polymeric material.
6. A dosage form according to claim 5 in which the release-delaying coat comprises a blend of two polymers having different permeabilities.
7. A dosage form according to claim 6 in which a more soluble of the two polymers is an acrylate or acrylic acid polymer modified with ionic groups.
8. A dosage form according to claim 6 or claim 7 in which the more soluble of the two polymers has a pH-dependent permeability, being more soluble under alkaline conditions than under acidic conditions.
9. A dosage form according to any one of the preceding claims in which one or more of said different formulations is/are provided as a plurality of particulates, a plurality of the particulates of the respective formulation being contained in a unit dosage form.
10. A dosage form according to claim 9 which has a capsule containing said plural particulates.
11. A delayed release pharmaceutical dosage form comprising pharmaceutically active agent and a release modifying coating containing a blend of polymeric materials having different permeabilities, a more permeable of the polymeric materials having a pH-dependent permeability, being more permeable under alkaline conditions than under acidic conditions.
12. A delayed release dosage form according to claim 11 in which said more permeable polymeric material comprises an acrylate and/or acrylic acid polymer, modified with ionic groups such as quaternary ammonium groups.
13. A method comprising the preparation of a dosage form according to any one of claims 1 to 12.
14. A method of administering a delayed dose of pharmaceutically active agent, or plural temporally-spaced doses of pharmaceutically active agent, comprising administering a single dosage form according to any one of claims 1 to 12.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US15088099P | 1999-08-26 | 1999-08-26 | |
| US15089199P | 1999-08-26 | 1999-08-26 | |
| US60/150,880 | 1999-08-26 | ||
| US60/150,891 | 1999-08-26 | ||
| US60/151,211 | 1999-08-26 | ||
| US15121199P | 1999-08-27 | 1999-08-27 | |
| PCT/GB2000/003309 WO2001013898A2 (en) | 1999-08-26 | 2000-08-29 | Pharmaceutical formulations with different release times |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2380333A1 true CA2380333A1 (en) | 2001-03-01 |
Family
ID=27387049
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002380333A Abandoned CA2380333A1 (en) | 1999-08-26 | 2000-08-29 | Pharmaceutical formulations |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1206250A2 (en) |
| AU (1) | AU6715600A (en) |
| CA (1) | CA2380333A1 (en) |
| WO (1) | WO2001013898A2 (en) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8071128B2 (en) | 1996-06-14 | 2011-12-06 | Kyowa Hakko Kirin Co., Ltd. | Intrabuccally rapidly disintegrating tablet and a production method of the tablets |
| US9358214B2 (en) | 2001-10-04 | 2016-06-07 | Adare Pharmaceuticals, Inc. | Timed, sustained release systems for propranolol |
| US6663888B2 (en) | 2001-12-14 | 2003-12-16 | Eurand Pharmaceuticals Ltd. | Pulsatile release histamine H2 antagonist dosage form |
| WO2004034959A2 (en) * | 2002-09-18 | 2004-04-29 | Elan Corporation, Plc | Multiparticulate modified release composition comprising beraprost |
| MY148805A (en) | 2002-10-16 | 2013-05-31 | Takeda Pharmaceutical | Controlled release preparation |
| MXPA05004422A (en) * | 2002-10-25 | 2007-11-22 | Collegium Pharmaceutical Inc | Pulsatile release compositions of milnacipran. |
| US8367111B2 (en) | 2002-12-31 | 2013-02-05 | Aptalis Pharmatech, Inc. | Extended release dosage forms of propranolol hydrochloride |
| ES2241478B1 (en) * | 2004-02-13 | 2006-11-16 | Lacer S.A. | PHARMACEUTICAL PREPARATION FOR THE SUSTAINED RELEASE OF A PHARMACEUTICALLY ACTIVE PRINCIPLE. |
| US8747895B2 (en) | 2004-09-13 | 2014-06-10 | Aptalis Pharmatech, Inc. | Orally disintegrating tablets of atomoxetine |
| US9884014B2 (en) | 2004-10-12 | 2018-02-06 | Adare Pharmaceuticals, Inc. | Taste-masked pharmaceutical compositions |
| CA2584957C (en) | 2004-10-21 | 2015-08-25 | Eurand Pharmaceuticals Limited | Taste-masked pharmaceutical compositions with gastrosoluble pore-formers |
| US9161918B2 (en) | 2005-05-02 | 2015-10-20 | Adare Pharmaceuticals, Inc. | Timed, pulsatile release systems |
| US8865197B2 (en) | 2005-09-06 | 2014-10-21 | Israel Oceanographic And Limnological Research Ltd. | Food formulation for aquatic animals with integrated targeted delivery of bioactive agents |
| TW200711823A (en) * | 2005-09-30 | 2007-04-01 | Primax Electronics Ltd | Laminating device and laminating method for use in same |
| WO2011067667A2 (en) | 2009-12-02 | 2011-06-09 | Eurand Pharmaceuticals Limited | Fexofenadine microcapsules and compositions containing them |
| KR101990951B1 (en) * | 2015-04-27 | 2019-06-20 | 주식회사 네비팜 | A sustained releasing Pharmaceutical Composition comprising Rivastigmine |
| CN114159391B (en) * | 2021-12-10 | 2023-05-05 | 卓和药业集团股份有限公司 | Cabalatine bitartrate dry suspension and preparation method thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5158777A (en) * | 1990-02-16 | 1992-10-27 | E. R. Squibb & Sons, Inc. | Captopril formulation providing increased duration of activity |
| US5286497A (en) * | 1991-05-20 | 1994-02-15 | Carderm Capital L.P. | Diltiazem formulation |
| US5326570A (en) * | 1991-07-23 | 1994-07-05 | Pharmavene, Inc. | Advanced drug delivery system and method of treating psychiatric, neurological and other disorders with carbamazepine |
| IL141762A0 (en) * | 1998-10-01 | 2002-03-10 | Novartis Ag | New oral formulations |
-
2000
- 2000-08-29 WO PCT/GB2000/003309 patent/WO2001013898A2/en not_active Application Discontinuation
- 2000-08-29 AU AU67156/00A patent/AU6715600A/en not_active Abandoned
- 2000-08-29 EP EP00954802A patent/EP1206250A2/en not_active Withdrawn
- 2000-08-29 CA CA002380333A patent/CA2380333A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| AU6715600A (en) | 2001-03-19 |
| WO2001013898A3 (en) | 2001-05-25 |
| EP1206250A2 (en) | 2002-05-22 |
| WO2001013898A2 (en) | 2001-03-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7781448B2 (en) | Once daily dosage forms of trospium | |
| EP2265261B1 (en) | Drug delivery systems comprising weakly basic drugs and organic acids | |
| CA2380333A1 (en) | Pharmaceutical formulations | |
| US20030157169A1 (en) | Controlled release dosage form of [R-(Z)]-alpha-(methoxyimino)-alpha-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile monohydrochloride | |
| EP0929301A2 (en) | Controlled release dosage form of r-(z)]-alpha-(methoxyimino)-alpha-(1-azabicyclo 2.2.2]oct-3-yl)acetonitrile monohydrochloride | |
| JP2003507416A (en) | Pharmaceutical preparations | |
| US20040228918A1 (en) | Granule modulating hydrogel system | |
| MXPA06004017A (en) | Once daily dosage forms of trospium |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |