JP2003507416A - Pharmaceutical preparations - Google Patents

Abstract

  (57) [Summary] The present application discloses a novel pharmaceutical formulation adapted to delay the release of a pharmacologically active substance. Delayed release drug formulations are those in which the active ingredient, which can be in microparticle or tablet form, is encapsulated in a delayed release coat containing a polymeric material having predetermined swelling / permeation properties. In particular, blends of acrylate and / or acrylic acid polymers modified by ionic groups are used. In a preferred embodiment, a polymer having a pH dependent permeability is used as the more permeable coating element. Delayed release formulations are constructed as a single dosage form together with immediate release or sustained release dosage forms, so that a unit dosage form (preferably an oral dosage form) effectively administers two doses to the patient at different times. it can.

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention relates to pharmaceutical formulations and methods of administration thereof, and more particularly to orally administrable formulations capable of providing a desired pharmacokinetic profile for a pharmacologically active substance.

BACKGROUND Many pharmacologically active substance of the invention are metabolized by metabolic system of a mammal. Regardless of the dosing regimen, the pharmacokinetic profile of the active ingredient and its interaction with the subject's metabolic system must be taken into account in order to obtain the required pharmacokinetic profile and bioavailability of the drug. I have to. It may be desirable to achieve a slow sustained release rate of the pharmacologically active substance. This is ideal if a single administration or dose of the active substance is required to act for an extended period of time, especially if the metabolism or degradation of the drug does not significantly reduce its bioavailability. Is.

However, metabolism or degradation can significantly reduce the bioavailability of many drugs. In such cases, the method of administration must be devised to overcome the problems associated with drug metabolism. The metabolism of certain active substances can be saturable.
In this case, it is possible to deliver a therapeutically acceptable amount of the active ingredient to the target tissue or organ with a pulse of the active ingredient sufficient to saturate the relevant metabolic or degradative pathways.

[0004] After a certain lag time, it is desirable to produce a single dosage form capable of releasing a pulse of active agent as provided by immediate release formulations. The combination of one or more of such dosage forms with an immediate release and / or sustained release formulation allows the patient to be provided with a number of staggered pulses of active agent in a single dosage formulation. Such a combination has the significant advantage of reducing the need for multiple dosing regimens and thus improving patient compliance, for example.

Thus, there is a need for new modes of administration of pharmacologically active substances that can be released and delivered on demand.

SUMMARY OF THE INVENTION The present inventors have developed a method of formulating active ingredients to provide novel orally administrable pharmaceutical formulations or dosage forms which provide delayed or sustained release of the active agent.

One object of the present invention is to provide a sustained release formulation which is capable of releasing the active ingredient over the required period of time. Another object of the present invention is to provide a delayed release formulation capable of delivering a pulse of active agent similar to that obtained by an immediate release formulation after a suitable lag period.

A further object of the invention is to provide a dosage form which is capable of releasing the active substance at two different release rates. In a preferred embodiment, the dosage form is capable of releasing the active substance at two distinct peaks at appropriate time intervals. Typically the peaks are separated by at least 2 hours, optionally at least 5 hours, or at least 8 hours.

Accordingly, the present invention provides a granular oral dosage form comprising a pharmacologically active substance, which dosage form comprises a release modifying layer, which release modifying layer under intestinal physiological conditions. Of a soluble polymer that is predetermined to affect the release rate of

Granular dosage forms can be manufactured as multilayer particle formulations. It can be a granulate, or a pellet or "non-pareil" type formulation. In this case, the active substance is applied to the inert support. Granular dosage forms can also be prepared as "mini-tablet" type formulations. In this case, the active substance is compressed with suitable excipients into minitablets.

For example, in some embodiments, the pharmacologically active agent is applied to a pharmaceutically acceptable inert particulate support. In a preferred embodiment, the pharmaceutically acceptable inert particulate support comprises carbohydrate beads such as non-pareil seeds (often referred to as neutral pellets or sugar spheres).

The pharmaceutically acceptable inert particulate support can be sprayed with the active ingredient from a solution, preferably an aqueous solution. Alternatively, the pharmaceutically acceptable inert particulate support can be sprayed with the active ingredient from a suspension using, for example, a fluid bed coating system such as the Wurster system. The active substance may be applied to the pharmaceutically acceptable inert particulate support either alone or in combination with another pharmaceutically acceptable excipient.

In yet another embodiment, the particulate dosage form can be manufactured as a “mini-tablet” type formulation of the pharmacologically active agent. Minitablets include active substances such as fillers such as microcrystalline cellulose, lactose, dicalcium phosphate, lubricants such as magnesium stearate or stearic acid, disintegrants such as sodium starch glycolate, and colloidal silicon dioxide. It can be molded by direct compression with a glidant. Mini-tablets can also be formed by wet granulating the drug with suitable excipients in a fluid bed.

These particulate dosage forms are typically first constructed as an “immediate release” formulation, and their release characteristics can be modified by the application of suitable coatings, as described below. it can. Typically, before application of the coating, the active agent constitutes 1-20%, preferably 3-10%, of the total weight of the immediate release particulate dosage form.

Further, the particulate dosage form can include 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 agent under physiological conditions,
Protects actives during processing. In certain embodiments, the protective coat consists primarily of hydroxypropyl methylcellulose. Other agents can be added to improve the processability of the sealant layer. The protective coat can be applied from a solution, such as an aqueous solution, or a suspension, using a fluid bed coater (eg, Wurster system) or by a pan coating system.

The minitablets may include excipients which influence the dissolution rate of the minitablets and thus the release rate of the active substance. Such minitablets can be considered as "sustained release" minitablets prior to any modified coating. These release characteristics can be further modified by applying a release modifying coating. Thus, mini-tablets providing sustained release of the active substance may contain the drug, in addition to the excipients mentioned above, typically in concentrations of 20-80%, such as hydroxypropyl cellulose, polyethylene glycolate and ethyl cellulose. It can be molded by adding a rate controlling excipient and directly compressing or wet granulating.

The release profile of the active substance can be modified according to the invention by applying to the particulate dosage form a modified coating of a material having a predetermined dissolution profile. Such modified coatings can be used to give the active agent a sustained or delayed release profile and can typically modify the release of the drug (solubility is pH independent or dependent). ) Including a soluble polymer.

For example, a "sustained release" formulation is 2.5-2% of the active agent in 0.5 hours as measured by the standard USP Method II dissolution assay in phosphate buffer at pH 6.8 (as described below).
5% 25% to 70% of active substance in 1 hour, 65% to 95% of active substance in 2 hours, and 4
It releases at least 90% of the active substance over time. Thus, a typical sustained release formulation would have about 10% of active material at 0.5 hours, about 50% of active material at 1 hour, about 75% of active material at 2 hours, and about 95% of active material at 4 hours. To release. The required release profile will vary depending on the active agent used and the desired pharmacokinetic profile.

In a preferred embodiment, the modified coating can comprise a soluble or permeable acrylate polymer, such as an ammonio methacrylate polymer or copolymer, or a methacrylic acid polymer or copolymer. The polymers can be used alone or in combination with one another. Additionally or alternatively, such modifying materials may be blended with the active substance as a matrix component.

The coating may also include other agents to improve the processability of the coating. Examples of such agents include talc, silicon dioxide and glyceryl monostearate. The amount of such anticaking agent used to prepare the dosage form coating is, for example, about 2 based on the total dry weight of the polymer.
To about 100% by weight, preferably 30 to 60% by weight.

The coating can also include substances that improve the properties of the polymeric material. Such substances are commonly referred to as "plasticizers", for example dibutyl sebacate (DB
S), diethyl phthalate, citric acid ester or triethyl citrate (TEC)
, Stearate, polyethylene glycol and ethylene glycol. Dibutyl sebacate and triethyl citrate are the preferred plasticizers. The amount of plasticizer used in the coating is preferably about 10 based on the weight of dry polymer.
~ 50%, most preferably about 20%.

Defoamers can also be included in the coating solution. An example of such a drug is a simethicone emulsion. The amount of defoamer used in the coating is preferably less than 0.5% of the final coating solution.

The amount of coating used in preparing the dosage form depends on the amount of drug to be delivered,
It is determined by the desired delivery characteristics, including the desired lag time and particle size. The coating polymer is typically coated onto the immediate release particles for a 5-20% weight gain, preferably a 6-10% polymer weight gain. The polymer layer can be coated by any known method, including spraying. Spraying can be carried out using a fluid bed coater (preferably the Wurster system) or in a pan coating system.

The coated particles can be dried and / or cured after application of the polymer layer. “Curing” means maintaining the particles at a controlled temperature for a time sufficient to provide a stable release rate. Curing can be done in an oven,
Alternatively, it can be carried out in a fluidized bed drier within the range of 25 to 50 ° C, preferably 35 to 45 ° C.

Alternatively or in addition, the particulate dosage form can be coated with a modifying layer that can modify the release of the active agent to form delayed release particles.

The steps and materials used to prepare the delayed release coating can be similar to those used to provide the sustained release coating described above. But,
More specifically, we include a blend of a relatively insoluble or impermeable polymeric material with a more soluble or permeable material, and control the release rate by the choice of polymer and proportion within that blend. , Delayed release or sustained release coatings are envisioned. In a particularly preferred embodiment, the relatively permeable polymer is a polymer whose permeability or solubility is pH dependent, and which is more soluble or permeable especially under alkaline conditions than under acidic conditions. This allows the coating to pass through the stomach relatively undisintegrated and further release the active agent along the intestinal tract. The pH dependence of polymer solubility or permeability is not required for sustained release. pH-dependent systems may be used to provide a delayed initial drug release. In addition, this system can also be used to provide protection against acid degradation of acid labile drugs in the gastrointestinal tract and / or to maximize the concentration of drug available at the site of absorption in the intestine. .

Film-forming polymers that are swellable or soluble under suitable conditions and are suitable for oral formulations are commercially available and known to those skilled in the art. For example, Rohm Eudrag
There is it polymethacrylate coating system. Poly (meth) acrylates with varying proportions of ionic groups in the acrylate-forming moiety, such as quaternary ammonium groups, can be used to correspondingly alter the membrane permeability. Eudragit L can be used for drug release in the duodenum / jejunum and Eudragit S for drug release in the ileum.

One particular novel approach presented herein is to blend any suitable type of film-forming, swelling acrylate polymer as described herein, one of which is an aqueous dispersion ( Latex) and the other is a non-aqueous dispersion (latex)
To form a characteristic and useful difference in the membrane permeability behavior between the two polymers in this layer.

The amount of coating used can be determined by the desired delivery characteristics, including the amount of drug to be delivered, the desired time delay, and particle size. The modified layer typically provides a 15-80% weight gain on uncoated or sustained release particles, preferably a 15-40% polymer weight gain on the first layer, and optionally on the next layer. Results in a 5-30% polymer weight gain. The first layer and the next layer may have the same composition or different compositions.

Increasing the amount of coating increases the distance that the drug must diffuse and travel through the swollen or permeabilized polymeric coating in order to be released into the surrounding medium, thus diffusing The drug release rate is reduced. Reducing the proportion of permeable component reduces the chance that the drug will be directly solubilized by the solvent and thus the lag time before the release of the drug is initiated.

Granular dosage forms are typically encapsulated in individual doses. Preferably, the dose will be “prophylactically effective” or “therapeutically effective” as the case may be (although prophylaxis may be considered therapeutic), which is sufficient to effect each individual. Is the amount. The actual dose, and rate and time-course of administration, will depend on the nature and severity of the condition being treated. Prescription of treatment, eg decisions on dosage etc, is within the discretion of the physician and typically will include the disease to be treated, the individual patient's condition, the site of delivery, the method of administration and other factors well known to the physician. Taken into account. Examples of the techniques and protocols described above can be found in Remington's Pharmaceutical Sciences, 16th Edition,
See Osol, A. (eds.), 1980.

It is envisioned that one or more different granular dosage forms may be encapsulated together.
The amount of particles loaded into an individual capsule will vary depending on the active agent administered, the specific activity of the active agent in the particular particulate dosage form, and the pharmacokinetic profile required. Any combination of the above components can be encapsulated to achieve the desired release profile and they can be combined in various proportions and concentrations. For example, preferably using standard double-fill encapsulation equipment, eg, in hard gelatin capsules, in uncoated neutral pellet (“non-pareil”) type multilayer particles that provide initial release and in coatings that provide delayed release. Multilayer particles of the nature pellet (“non-pareil”) type can be encapsulated together.
Alternatively, sustained or delayed release mini-tablets can be encapsulated with immediate release non-pareil seeds. Depending on the formulation, one of the possible ingredient types is
It can contribute to the provision of an initial, sustained or delayed release component of the overall pharmacokinetic profile.

Specific embodiments of the present invention will be described in further detail with reference to the accompanying drawings.

Experimental In the case of formulations containing pH-dependent polymers, the dissolution profile was determined by immersing the test formulation in 0.01 M HCl for 2 hours and then in a pH 6.8 phosphate buffer. For formulations containing only pH independent polymer, the soaking in acid was omitted and the test formulations were soaked in phosphate buffer at pH 6.8 during the assay time. Aliquots of lysis buffer were removed at timed intervals and analyzed by HPLC for released rivastigmine.

Buffer To prepare 0.01 M HCl, 8.5 ml concentrated HCl was diluted with 1 liter deionized water to prepare a 0.1 M HCl solution. Then dilute it to 0.01 M HCl with deionized water,
It was then degassed by sparging with helium at 1.2 l / min for 20 minutes.

250 ml of 0.2 M potassium phosphate solution (27.22 g of monobasic potassium phosphate (KH ₂ PO ₄ ) for 1 liter of distilled water) was added to 112 ml of 0.2 M sodium hydroxide solution, and 1000 ml of distilled water was added. 1 liter of a phosphate buffer (pH 6.8 ± 0.05) was prepared by diluting the solution. The phosphate buffer was degassed as above.

A test formulation corresponding to 12.5 mg of dissolved rivastigmine base was placed in a clean and dry dissolution basket assembly (USP Apparatus I with a 40 mesh basket). The basket was attached to the shaft of the device, submerged in a lysis vessel containing 500 ml of 0.01 M HCl or phosphate buffer at 37.0 ± 0.5 ° C and spun at 100 rpm.

For pH-dependent formulations, 0.01 M HCl was neutralized after a dissolution time of 2 hours by adding and mixing about 50 ml of 0.1 N NaOH to the vessel. Next, phosphate buffer (pH 6.8)
The basket was transferred to a secondary dissolver containing 500 ml.

At each time point, a 4 ml aliquot of lysis buffer was removed and filtered through a Millipore Millex-HV Hydrophilic PVDF 0.45 mm filter into a suitable container for analysis by HPLC. About 2 ml of the first filtrate was discarded as waste. The volume removed at each sampling time was replenished with 4 ml of preheated medium.

Samples were analyzed for rivastigmine content by HPLC as described below.

HPLC analytical column: PUROSPHER® (RP-18) 5 mm, 12.5 cm × 4.0 mm ID LiChroCart [(Cartridge), Merck, Germany] or equivalent Temperature: 40 ± 1 ° C. Mobile phase: HPLC grade 670 ml of methanol in aqueous buffer (dissolve 3.85 g to 3.95 g of ammonium carbamate (anhydrous form of carboxylate) in 1 L of deionized water) 330
1 L of mobile phase was prepared by adding to ml. The mobile phase was filtered and degassed with helium for 10 minutes. The pH was adjusted to 9.2 with concentrated ammonia as needed.

Flow rate: 1.7 ml / min Injection volume: 50 μl UV detection: 214 nm Retention time of active ingredient: t _{RENA 713} ≧ 1.5 min A calibration curve for HPLC was prepared using two standards. 500 for each
Prepared by accurately weighing 20 mg rivastigmine tartrate reference standard (equivalent to 12.5 mg rivastigmine base) in a ml volumetric flask. This was dissolved in solvent, diluted to 500 ml, mixed well and an aliquot was filtered through a Millipore Millex-HV Hydrophilic PVDF 0.45 mm filter into a suitable container for injection. About 2 ml of the first filtrate was discarded as waste.

A calibration curve is accepted if: 1. Difference between weight-corrected peak responses for two rivastigmine standard solutions
Did not exceed 2.0%. 2. Coefficient of variation of 5 injections for one Rivastigmine reference solution did not exceed 2.0%.

Calculations The mathematical formulas (1 and 2) shown below can be used to calculate the release of active agent from sample formulations with pH independent and pH dependent polymer coatings.

1. Formulations Containing Only pH-Independent Polymers For formulations containing only pH-independent polymers, for samples taken at 0.5 h, 1 h, 2 h, 4 h and 6 h: Uncorrected amount of released rivastigmine (free base) (mg):

[Equation 1] B. Correction factor (for each time point):

[Equation 2] C. Corrected rivastigmine release over time:

[Equation 3] D. Corrected amount of released rivastigmine (free base):% released = _RH x 100 / wherein H = sample acquisition time interval _MH = released rivastigmine (uncorrected) mg / hour A _samp = sample response A _std = Response of standard product DF = Dilution factor = _500/500 = 1.0 W _std = Weight of standard product (mg) V _diss = Volume of solvent (500 ml) Q _H = Correction factor (rivastigmine free base mg) V _s = Volume of sample taken at each time point (4 ml) R _H = Release (mg) corrected hourly R% = Relative% released corrected each time Potency = mg / Sample P = Regarding the purity of the standard Correction factor (when less than 100%) F = 0.625 (to convert rivastigmine tartrate to the free base)

2. Formulations Containing pH Dependent Polymers For formulations containing pH dependent polymers, one sample was removed from the acid at 2 hours
For samples taken from the phosphate buffer every 2 hours thereafter: A. Uncorrected amount of released rivastigmine (free base) M (mg):

[Equation 4] B. Correction factor Q (for each time point):

[Equation 5] C. Corrected amount of Rivastigmine R released at each time point T:

[Equation 6] D. Corrected amount of released rivastigmine (free base):% released = _RH x 100 / wherein H = sample acquisition time interval _MH = released rivastigmine (uncorrected) mg / hour A _samp = of sample Response A _std = Response of standard product DF = Dilution factor = _500/500 = 1.0 W _std = Weight of standard product (mg) V _diss = Volume of solvent (500 ml) Q _H = Correction factor (rivastigmine free base mg ) V _s = Volume of sample taken at each time point (4 ml) R _H = Release (mg) at each corrected time% R = Corrected release% at each time Potency = mg / Sample P = Purity of standard Correction factor for less than 100% F = 0.625 (to convert rivastigmine tartrate to the free base)

Example 1 Preparation of Immediate Release (IR) Rivastigmine Multilayer Particles 100.0 g of hydroxypropylmethylcellulose was added to 1.900 kg of purified water, 4
A hydroxypropyl methylcellulose solution was prepared by continuing mixing for 5 minutes. A suspension of rivastigmine tartrate was prepared as follows. To 1106.6 g of hydroxypropylmethylcellulose solution, 265.7 g of rivastigmine tartrate
Was added. The mixture was stirred for 15 minutes to dissolve the drug. To this solution was added 27.7 g of silicon dioxide and the mixture was stirred for 15 minutes. A protective solution was prepared as follows. To 682.9 g of the hydroxypropylmethylcellulose solution, 17.1 g of silicon dioxide was added and the mixture was stirred for 15 minutes. In a fluidized bed apparatus (GPCG-3, Glatt) equipped with a Wurster 7 "chamber, the rivastigmine suspension was first sprayed onto 2.500 kg of 0.85-1.00 mm non-pareil seeds. After obtaining a bulking layer corresponding to 5% of stigmine free base, it was loaded with 1.75% with protective solution on the core, spraying rate for drug layering was 3.2-4.8 g / min * kg, The inlet temperature is 47 to 50 ° C, and the core temperature is 34 to 38
Maintained at 0 ° C. The drug loaded immediate release multilayer particles were cooled in the Glatt GPCG-3 for 20 minutes. The multilayer particles were sieved to remove oversize beads and fine material.

[0048] EXAMPLE 2 Eudragit RS: RL (98: 2) coated sustained release of the (SR) rivastigmine (prepared according to Example 1) a multilayer particle preparation Eudr the rivastigmine immediate release multilayer particles
Coated with agit RS: RL (98: 2) aqueous dispersion. Eudragit RS: RL (98: 2) aqueous dispersion was prepared as follows. 0.5 g of simethicone emulsion USP, 120.0 g of DBS and 360 g of talc USP were added to 2.515 kg of purified water while mixing. The mixture was stirred for 15 minutes on a high shear mixer at 6000 rpm.
This suspension was mixed with Eudragit RS 30D 1.960 kg and Eudragit RL 30D 40.0 g (Rohm P
Ammonio methacrylate copolymer in aqueous dispersion from Harma, Germany) and stirred for 20 minutes.

The rivastigmine coated multilayer particles were coated to a polymer loading of 12% and samples were removed during the process at 6, 8 and 10% polymer coating. The coated multilayer particles were cured in an oven at 40 ° C. for 40 hours and then sieved to remove oversized multilayer particles and fine material.

Table 1 shows the dissolution rate for sustained release multilayer particles. These profiles will be described with reference to FIG.

[Table 1]

Example 3 Eudragit RS: RL (90:10) coated delayed release (DR) rivastigmine poly
Preparation of Layered Particles Eudragit RS: RL (90:10) aqueous dispersion was prepared as follows. 0.5 g of simethicone emulsion USP, 120.0 g of triethyl citrate and 360 g of talc USP were added to 2.515 kg of purified water while mixing. Mix the mixture in a 6000 rpm high shear mixer 1
Stir for 5 minutes. This suspension was added to 1.800 kg of Eudragit RS 30D and 200 g of Eudragit RL 30D (ammoniomethacrylate copolymer in aqueous dispersion from Rohm Pharma, Germany) and stirred for 20 minutes.

The resulting mixed dispersion was sprayed onto the immediate release multilayer particles prepared according to Example 1 using a fluidized bed apparatus as used in Example 1. Spraying speed is 3.5-1
5 g / min x kg, inlet temperature was 38-42 ° C, core temperature was 25-30 ° C. Immediate release multilayer particles were coated with a polymer coat with a polymer loading of 40% and samples were removed during the process at 30% polymer coating. The multilayer particles were cured and then sieved as described in Example 2.

Example 4 Preparation of Delayed Release (DR) Rivastigmine Multilayer Particles Overcoated with Eudragit RS: RL (98: 2) Eudragit RS: RL (90:10) using triethyl citrate as the plasticizer. Eudrag coated rivastigmine multilayer particles (prepared according to Example 3)
It was coated with an RS: RL (98: 2) aqueous dispersion (prepared according to Example 2).

Eudragit RS: RL (90:10) -coated rivastigmine multilayer particles were overcoated so that the amount of the polymer added was 20%, and a sample was taken out during the process at the time of 10% polymer coating. The multilayer particles were cured and then sieved as described in Example 2.

Example 5 Preparation of delayed release (DR) rivastigmine multilayer particles coated with Eudragit RS: L (75:25) Eudragit RS: Eudragit L (75:25) organic solution was prepared as follows. . Isopropyl alcohol 4.650 kg to triethyl citrate 125 g and Eudragit RS12
.5 stirred with 3.750 kg for 5 minutes. Add 225 g of talc (USP) and mix 15
Stir for minutes. 1.250 kg of Eudragit L12.5 was added to this mixture and stirred for 30 minutes.

The resulting solution was sprayed onto the immediate release multilayer particles prepared according to Example 1 using a fluidized bed apparatus as used in Example 1. Spray rate is 5 to 8.5 g / min
* kg, inlet temperature was 38-40 ℃. The immediate release multilayer particles were maintained at 29-32 ° C. A polymer coat was coated on the immediate release multilayer particles to a polymer loading of 30% and samples were taken during the process at 20% polymer coating. The multilayer particles were cured and then sieved as described in Example 2.

Table 2 shows dissolution rates for the multilayer particles prepared in Examples 3, 4 and 5. The sample profile will be described with reference to FIG.

[Table 2]

Example 6 Preparation of Immediate Release (IR) Rivastigmine Mini Tablets Formulation Details:

Immediate release mini-tablets were prepared by direct compression using the following method.
1. Add the same amount of microcrystalline cellulose to the drug and bag blend for 1 minute. 2. Add colloidal silicon dioxide and bag blend for an additional 1 minute. 3. Sift the mixture through a 600 mm sieve. 4. The remaining microcrystalline cellulose, drug / microcrystalline cellulose / colloidal silicon dioxide mixture, and sodium starch glycolate are placed in a Type V corn blender and mixed at 18 rpm for 15 minutes. Add magnesium stearate and mix for another 5 minutes at 18 rpm. FIG. 3 shows the dissolution profile for immediate release minitablets.

Example 7 Preparation of Sustained Release (SR) Rivastigmine Mini Tablets Formulation Details:

Rivastigmine SR mini tablets were produced by direct compression using the following method. 1. Add the same amount of microcrystalline cellulose to the drug and bag blend for 1 minute. 2. Add colloidal silicon dioxide and bag blend for an additional 1 minute. 3. Sift the mixture through a 600 mm sieve. 4. The remaining microcrystalline cellulose, drug / microcrystalline cellulose / colloidal silicon dioxide mixture, and hydroxypropyl cellulose are placed in a Type V corn blender and mixed for 15 minutes at 18 rpm. 5. Add magnesium stearate and mix for another 5 minutes at 18 rpm.

[0062] Example 8 pH of mini tablets of Example 6 independent polymer Eudragit RS: RL (98: 2 ) by Koti ring Eudragit RS: RL (98: 2 ) an aqueous dispersion was prepared as follows . Simethicone emulsion USP 0.5 g, triethyl citrate 12 g and talc US
P 36 g was added to 251.5 g of purified water while mixing. The mixture was stirred for 15 minutes using a 1200 rpm mixer. This suspension is mixed with Eudragit RS 30D 196 g and Eudragit
4 g of RL 30D (ammoniomethacrylate copolymer in aqueous dispersion from Rohm Pharma, Germany) was added and stirred for 20 minutes.

The resulting dispersion was sprayed onto mini-tablets as prepared in step 1a using a fluid bed coater equipped with a Wurster column. Spray rate is 3.7 to 5.7
g / min, inlet temperature 30-39 ° C, bed temperature 28-32 ° C. Polymer increase
Coated to 20%, the tablets were dried in a fluid bed coater for 15 minutes and then in an oven for 40 hours. Figure 4 shows the dissolution profile for these mini tablets.

Example 9 Coating of Mini-Tablets of Example 6 with pH Dependent Polymer Eudragit S 12.5 An Eudragit S 12.5 organic dispersion was prepared as follows. 32 g of dibutyl sebacate was added to 77 g of purified water, and then this suspension was added to 1.081 kg of isopropyl alcohol and mixed for 5 minutes. Eudragit S12.5 in this solution
1.247 kg was added and mixed for 5 minutes. Finally, 63 g of sterilized talc was added and the suspension was mixed for 20 minutes.

The resulting dispersion was sprayed onto the sustained release minitablets of Example 6 using a fluid bed coater equipped with a Wurster column. Spraying speed is 8.4 to 10.4 g / min,
And the inlet temperature was 38-47 ° C. Mini tablets were maintained at about 33 ° C. The minitablets were coated to a polymer loading of 20% and at the time of 15% polymer coating the in-process sample was removed and the minitablets were dried for 15 minutes before being removed from the fluid bed coater. The dissolution profile for these mini tablets is shown in FIG.

Example 10 Simultaneous Encapsulation of Multilayer Particles and Mini-Tablets Sustained release rivastigmine minitablets and delayed release rivastigmine multilayer particles were formulated as detailed below and co-encapsulated in hard gelatin capsules. .

Mini tablets: Ingredient mg / capsule Rivastigmine HTA 4.8 Methocel K100LV 14.0 Avicel PH101 15.3 Aerosil 200 0.5 Magnesium stearate 0.4

Multilayer particles: Ingredient mg / capsule Rivastigmine HTA 4.8 HPMC 3cps * 1.6 Silicon dioxide 0.8 NP seed 52.8 Eudragit RS 8.9 Eudragit L 3.0 Triethyl citrate 2.4 Talc 4.8

Table 3 shows the dissolution profile for the individual components. These profiles will be described with reference to FIG.

[Table 3]

Example 11 Simultaneous Encapsulation of Sustained-Release Rivastigmine Multilayer Particles and Delayed-Release Rivastigmine Multilayer Particles Three delayed-release extended release rivastigmine multilayer particles coated with Eudragit RS: RL (98: 2). Co-encapsulated with each of the multilayer particles. Immediate release multilayer particles were prepared as described in Example 1 and then 10% Eudragit RS: L (75:25).
, Eudragit RS: L (75:25) 15% and Eudragit RS: L (65:35) 15%.

The composition of the three simultaneous encapsulation formulations is shown below.

[Brief description of drawings]

[Figure 1]   FIG. 6 shows the dissolution profile for sustained release multilayer particle formulations.

[Fig. 2]   FIG. 7 shows the dissolution profile for delayed release multi-layered particle formulations.

FIG. 3 shows the dissolution profile for sustained release mini-tablets without modified coat.

FIG. 4 shows the dissolution profile for Eudragit RS / RL coated sustained release mini-tablets.

[Figure 5]   FIG. 5 shows the dissolution profile for delayed release mini tablets.

FIG. 6 shows dissolution profiles for co-encapsulated sustained release minitablets and delayed release multilayer particle formulations.

─────────────────────────────────────────────────── ─── Continued front page    (31) Priority claim number 60 / 151,221 (32) Priority date August 26, 1999 (August 26, 1999) (33) Priority claiming countries United States (US) (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, LS, MW, MZ, SD, SL, SZ, TZ, UG , ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, C A, CH, CN, CR, CU, CZ, DE, DK, DM , DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, K E, KG, KP, KR, KZ, LC, LK, LR, LS , LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, R U, SD, SE, SG, SI, SK, SL, TJ, TM , TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Fanning, Neil             County west ireland             Mies, Athlone, Monxland Lee             Industrial Estate, Ellanf             Armature, Technologies             (No address) (72) Inventor Palmer, Fiona             County west ireland             Mies, Athlone, Monxland Lee             Industrial Estate, Ellanf             Armature, Technologies             (No address) (72) Inventor Stark, Paul             County west ireland             Mies, Athlone, Monxland Lee             Industrial Estate, Ellanf             Armature, Technologies             (No address) F-term (reference) 4C076 AA37 AA41 AA54 AA64 AA67                       BB01 CC01 DD29A DD41C                       EE09H EE10H EE13H EE31A                       EE32A EE38A FF31 FF33                       FF68

Claims (14)

[Claims] 1. A dosage form comprising a pharmacologically active substance in two or more different formulations, each having a different release time under intestinal conditions for said pharmacologically active substance. 2. The different pharmaceutical preparations contain the same pharmacologically active substance.
Dosage form according to. 3. A dosage form according to claim 1 or 2, wherein one said formulation is an immediate release formulation and another said formulation is a delayed release formulation. 4. A dosage form according to any one of claims 1 to 3, wherein one said formulation is a sustained release formulation and another said formulation is a delayed release formulation. 5. The dosage form according to claim 3 or 4, wherein the delayed release formulation has a pharmacologically active agent surrounded by a delayed release coat of polymeric material. 6. The dosage form of claim 5, wherein the release-retarding coat comprises a blend of two polymers having different permeability. 7. The dosage form of claim 6, wherein the more soluble of the two polymers is an ionic group modified acrylate or acrylic acid polymer. 8. The method according to claim 6, wherein the more soluble one of the two polymers has pH-dependent permeability and is more soluble under alkaline conditions than under acidic conditions. The described dosage form. 9. The one or more of the different formulations are provided as a plurality of particles, the plurality of particles of each formulation being retained in one unit dosage form.
A dosage form according to any one of claims 8 to 8. 10. The dosage form of claim 9, which is a capsule containing the plurality of particles. 11. A delayed release dosage form comprising a pharmacologically active substance and a modified release coat comprising a blend of two polymeric materials having different permeability, wherein the polymeric material is permeable to said permeable dosage form. The above delayed release dosage form, wherein the larger one has a pH-dependent permeability and is more permeable under alkaline conditions than under acidic conditions. 12. The delayed release dosage form of claim 11, wherein the more permeable polymeric material comprises an acrylate and / or acrylic acid polymer modified with an ionic group such as a quaternary ammonium group. 13. A method comprising the preparation of a dosage form according to any one of claims 1-12. 14. A method of administering a delayed single dose of a pharmacologically active substance or multiple doses of a pharmacologically active substance at timed intervals, the method according to any one of claims 1 to 12. Such a method comprising administering a single dosage form.