JP4357422B2 - Method for producing microcapsule preparation having enhanced taste masking ability and high dissolution rate - Google Patents

Description

  The present invention relates to the field of microencapsulation of active ingredients. A novel method for obtaining microcapsule formulations with enhanced taste masking and optimal dissolution profiles is described.

  Achieving effective encapsulation of the active ingredients is important for the manufacture of a variety of compositions. Microencapsulation techniques are used when the active ingredient particulates must be individually coated with an external coating.

  The microencapsulation method consists of coating a micro drug core (fine particles) with a polymer layer. Polymer layering can be achieved by various techniques, in particular by microencapsulation by phase separation (or coacervation), which has been demonstrated to yield very reliable coated microparticles (M. Calanchi), “Taste Masking of oral formulations”, Pharmaceutical Manufacturing International, pp.139-141, 1996; L. Dobetti, S. Deluge, (L Dobetti, S. De Luigi), “Development in Microencapsulation”, Pharmaceutical Manufacturing and Packaging Sourcer, p. 39-40, December 1998).

  The microcapsules are manufactured in order to achieve the purpose, unlike the conventional drug coating technique in that individual microparticles to be individually coated must be obtained in a size of, for example, about 500 μm or less. Need to avoid agglomeration.

  In the pharmaceutical field, microencapsulation of the active ingredient produces in particular multiparticulate pharmaceutical compositions such as, for example, syrups, immutable or transient suspensions, chewable tablets or fast melting tablets. Applied for. Microencapsulation is especially used to mask the taste of drugs characterized by bitterness, throatiness, saltiness, and local tongue paralysis.

  Microencapsulation is also used to adjust the drug release profile after administration. In principle, taste masking and controlled release functions are both obtained by increasing the thickness of the microcapsule wall. As a result, it is easy to produce taste-masked sustained-release microcapsules, whereas it is difficult to obtain taste-masked rapid-release microcapsules. Nevertheless, this immediate release form is particularly well suited for drugs with an unpleasant taste that must be delivered immediately into the stomach for pharmacokinetic and pharmacodynamic reasons: unacceptable Antibiotics that often give possible taste (eg penicillin, cephalosporin, carbapenem, penem, penum, aminoglycoside, macrolide, ketolide, tetracycline, quinolone, etc.) are typical examples, and these antibiotics are It must be delivered and absorbed immediately into the stomach in order to require strong taste masking while at the same time ensuring that the action begins quickly and avoiding disturbances by the gut microbiota.

  A second example is an anti-inflammatory or analgesic. This type of drug often requires taste masking to avoid bitterness or sore throat, but at the same time, rapid absorption is essential to ensure rapid analgesia.

  A third example is a drug characterized by a narrow absorption port. These drugs require immediate release near the first part of the gastrointestinal tract to ensure proper bioavailability.

  For the purpose of obtaining good taste masking, ethyl cellulose is preferred and most widely used as the sealing polymer. The polymer is characterized by an effective sealing ability and is easily layered on drug microparticles; in addition, the polymer is a very safe excipient with no toxicity issues. However, ethylcellulose-coated microparticles cannot simultaneously achieve good taste masking and a high dissolution rate in the stomach. To overcome this problem, attempts were made to reduce the thickness of the microcapsule wall (ie, using a smaller amount of encapsulated polymer), but taste masking can no longer be achieved with thinner coatings, This is not a good solution. As an alternative to ethylcellulose, for example, the use of coating polymers with high solubility in the stomach is equally inadequate: in fact, these polymers are thicker to achieve levels similar to the taste masking of ethylcellulose. Requires a coating with The result is very low titer microcapsules: these microcapsules require bulky dosage forms, for example large tablets or capsules, and are therefore very problematic from the point of patient acceptance It becomes. Furthermore, for ethylcellulose, it is more difficult to obtain individual small sized coated microparticles, and polymers with higher solubility have the problem of particle aggregation during the coating process.

  At present, there are no microencapsulation methods that can produce small microcapsules while at the same time ensuring good taste masking, rapid onset of action, and high titer.

  The present invention discloses a microencapsulation method characterized in that the drug core is coated with a first layer of ethylcellulose and the resulting microcapsules are coated with an acrylic polymer layer. The resulting microcapsules show high titer, optimal taste masking and guarantee immediate release in the stomach. Therefore, the present invention allows for the manufacture of superior pharmaceutical dosage forms, particularly where immediate delivery into the stomach is required even when administration is required in the form of a reconstitutable suspension. Useful for certain drugs with an unpleasant taste.

The first object of the present invention is as follows:
a. Coating the fine drug particles with an ethyl cellulose layer;
b. Further, the step a. A method for producing a microcapsule containing a drug, characterized by the step of coating a product of

  Although the method is particularly suitable for agents that have an unpleasant taste and require immediate delivery into the stomach, any agent obtained in particulate form can be the subject of the method. For the purposes of the present invention, the term “medicament” also includes mixtures of two or more thereof.

  Individually coated microcapsules are obtained from step a. The coating step a. Is accomplished by microencapsulation techniques known in the art. Of these, microencapsulation by phase separation (also known as microencapsulation by coacervation) is preferred.

Known phase separation methods are outlined below, but are not limited thereto. Step sequence (i) Dispersion: Create a two-phase system in which a liquid phase (eg, ethylcellulose solution of cyclohexane) and a solid phase (drug particles) are present simultaneously; (ii) Phase separation: Coacervation inducer (eg, eprene ( A third phase is formed by the action of an ethylene polymer) such as epolene. This phase, called coacervate, refers to a highly concentrated polymer solution in a solvent that diffuses over the surface of the suspended drug core. As a result, coacervate droplets aggregate and cover the drug core with a continuous phase (gel phase) of the membrane. Reduced total free interfacial energy, caused by a reduction in the surface area of the coating material in droplet aggregation, promotes polymer film accumulation; (iii) Curing: liquid polymer film cools suspension to room temperature (Iv) Separation: The microcapsules are separated from the liquid medium by coagulation. The supernatant can then be removed and the microcapsules can be washed with fresh solvent to remove the residue of the phase separation agent. Finally, the microcapsules were filtered, dried and screened.

  Another known technique that can be applied to perform step a. Is fluid bed coating. In this case, the ethylcellulose coating can be achieved by spraying onto the pharmaceutical core of either an organic solution or aqueous dispersion of the polymer. This choice depends strictly on the chemical and physical properties of the core to be coated.

  If the subsequent step b is also carried out by fluidized bed coating, all the steps are particularly advantageous in that they can be carried out in the same reactor by simply changing the coating solution when moving from step a. To step b. is there.

  The product of step a. Is an ethylcellulose microcapsule containing the drug. The resulting microcapsules preferably have a drug / ethylcellulose weight ratio of 1: 1 to 30: 1, more preferably 3: 1 to 15: 1. In this specification, the weight ratio of drug / ethylcellulose is PR (phase ratio).

In order to apply a further coating of acrylic polymer (step b), it is preferred to use a spray coating technique: according to this embodiment, the microcapsules obtained in step a. Or spray the suspension. The solvent used to form this solution or suspension is preferably an acidic aqueous solvent, an aqueous alcohol solvent, an organic solvent, or a mixture thereof. When using a hydroalcoholic solution, the following weight percent composition, calculated on the total weight of the solution:
Acrylic polymer: 4 to 20%, preferably 7 to 20%,
Alcohol (eg ethanol): 30-94%, preferably 40-75%,
Water: 0-40%, preferably 10-35%,
Finely divided inorganic substance (for example, talc): 2 to 20%, preferably 5 to 9%,
It is preferable to contain.

  Acrylic polymers can be layered indifferently during one or more layering steps: in the latter case, a multilayer acrylic coating is obtained.

  The product of step b preferably has an acrylic polymer content comprised between 5% and 40% by weight, the optimal region of the polymer being 10-25%; the acrylic polymer used in step b is Selected from among acrylic polymers for pharmaceutical use: the acrylic polymers are known in the pharmaceutical art and are usually linear and branched and / or cross-linked of acrylic acid and / or methacrylic acid The polymer selected should be soluble under acidic pH (eg 1 g is soluble in 1N HCl); as a representative example of these polymers, Eudragit E (methacrylic) Class of products including, but not limited to, cation copolymers based on dimethylaminoethyl acrylate and neutral methacrylates) It is not a thing.

  A further object of the present invention is a microcapsule obtained by the method described above. According to the method of the present invention, taste-masked small microcapsules (containing 20-800 μm as the weight median particle size, preferably 100-400 μm, and having a titer (ie, mg drug per gram of the final product of step b) of 400- And can release at least 80% of the drug contained in the microcapsules within 30 minutes, preferably 10 minutes in a simulated gastric fluid test or acid medium. A high level of titer provides smaller tablets or capsules (ie, including a small amount of coating polymer) without changing drug content, thus making it more acceptable to patients and pharmaceutically advantageous features It is. The reduction in the amount of coating polymer includes the further advantage that the composition can be dissolved in water without forming a thick viscous solution around the drug core: this means that the diffusion and action of the drug starts quickly. Established even easier. The resulting microcapsules show the advantage of improved buoyancy in water, i.e. do not form aggregates, do not float on the surface of the suspension medium and do not adhere to the side of the glass: The capsules do not require a separate wet treatment with a surfactant, such as is required in the case of ethylcellulose microcapsules.

  Furthermore, the resulting microcapsules exhibit the ability to retain taste masking function when suspended in a neutral or basic aqueous medium. In many cases, the use of a resuspended dosage form requires ease of administration and efficiency (eg, a dosage form as a single dose bag and an extemporaneous suspension dry powder).

  The above-described microcapsules that simultaneously achieve high taste masking / high titer / high dissolution rate are novel and represent a further object of the present invention. In addition, these microcapsules can be prepared in pharmaceutically suitable dosage forms (eg, instantly suspended dry powder, tablets, mini-tablets, microcapsule-containing capsules, single dose bags, in the presence of appropriate pharmaceutical excipients. , Fast disintegrating tablets, syrups, etc.).

  The methods and microcapsules of the present invention can be used for a variety of taste masking of active ingredients that have a bitter or non-bitter taste and require immediate release. Active ingredients useful in the present invention include antibiotics and antibacterial agents (eg, ketolides); antiviral agents, analgesics, anesthetics, eating disorders, anti-arthritic agents, anti-asthmatic agents, anticonvulsants, anti-epileptic agents Agent, antidiabetic agent, antidiarrheal agent, antihistamine agent, anti-inflammatory agent, antiemetic agent, antitumor agent, antiparkinsonian agent, antipruritic agent, antipsychotic agent, antipyretic agent, antispasmodic agent, H2 antagonist, cardiovascular agent, antiarrhythmic agent , Antihypertensive, ACE inhibitor, diuretic, vasodilator, hormone, hypnotic, immunosuppressant, muscle relaxant, parasympathomimetic, parasympathomimetic, stimulant, sedative, anti-migraine, Contains antituberculosis drugs and tranquilizers. In general, taste masking is necessary because the active agents associated with this methodology have a bitter taste or another unpleasant taste.

  The present invention will now be described with reference to the following experimental examples, without limiting functionality.

Experimental equipment 5 L microencapsulation reactor Air stirrer / propeller Wave protection Constant temperature bath Shelf dryer Fluid bed

Materials Caffeine Theophylline Fluoxetine Ethylcellulose Polyethylene Cyclohexane Eudragit E
Micronized talc ethanol Purified water

Method Description Phase Separation 3000 g of cyclohexane is poured into a 5 L jacketed stainless steel reactor. A certain amount of the drug ethylcellulose and polyethylene was then added with gentle agitation ensured by the helix.

  Next, the stirring speed was increased to 500 rpm. The system was then heated to 80 ° C. so that the ethylcellulose was soluble in cyclohexane.

  The final microcapsules were dried in an electric furnace at 40 ° C. overnight and sieved with a 500 μm screen.

Fluidized bed coating A certain amount of the resulting microcapsules as described in the paragraph above is a Glatt GPCG 1 equipped with a 4 '' Wurster insert, plate type B, spray nozzle 1.0 mm.
Fill the fluid bed and the following qualitative composition:
Eudragit (registered trademark) E100
Micronized talc ethanol The coating suspension with purified water was sprayed.

Subsequently, a second layer of coating suspension was applied. The final product was sieved through a 500 μm screen. The resulting coating level was calculated as the theoretical weight increase of the microcapsules.
Residual cyclohexane, residual ethanol, and residual polyethylene remained within pharmaceutically acceptable limits.

Analysis method Elution rate method (i):
USP paddle 900 mL or 500 mL, 0.1 N HCl or pH 1.2 buffer, 50 or 100 rpm, 37 ° C.
Samples were collected a predetermined number of times within at least 30 minutes.
Publish data at 10 and 30 minutes.

Evaluation of taste masking (TM)
Obtained by perceptual judgment.
A certain amount of microcapsules was evaluated as at or after suspension in a suitable aqueous medium.

Particle size distribution (PSD)
Performed by sieving analysis using an automatic sieving method. Octagonal digital (Endecott type) with a sieve.

Optical microscopy (PSD)
It was performed with an Ortolux microscope and a Zeiss Axioscopic 2 microscope.

Experimental principle Three experimental sets were used.
In the first set, only the coating (ie ethyl cellulose) was applied.
In the second set, only the acrylic polymer layer was applied.
In the third set, drug fine particles were first coated with an ethylcellulose layer and further coated with an acrylic polymer layer as described in the present invention.

result

From the evaluation of the above results, the following is clear:
When the coating level is low, the elution rate is very fast but taste masking is unacceptable. When the coating level is high, the taste masking function is significantly improved, but the release profile is too slow and unacceptable. Furthermore, the titer drops dramatically. Even with high coating levels (dissolution rate is significantly reduced), in some cases taste masking is unacceptable. This is thought to be related to the larger surface area of the drug used.
-The application of ethyl cellulose allows a particle size distribution that is acceptable even at high rates.

From the evaluation of the above results, the following is clear:
The application of acrylic polymers does not significantly affect the release in stimulated gastric juices, even at a high rate, but does not guarantee the required taste masking and applies low levels of acrylic polymers. However, the particle size distribution was unacceptable due to the aggregation phenomenon.
To overcome this drawback, batch coatings of B2 and B3 were applied at very low spray rates, but this was a time consuming process and became not economically compatible with the industrial application of this technology.
Despite the use of the above conditions, the particle size distribution was not considered completely satisfactory due to residual aggregates. In any case, the taste masking function was not sufficient.

From the evaluation of the above results, the following is clear:
-Even when suspended in a liquid medium, the application of two layers allows the microcapsules to properly mask the taste, further guarantees immediate release, and significant aggregation of the microcapsules Can also be avoided.
-Furthermore, since all coating amounts are relatively low, the possibility of obtaining an appropriate titer is guaranteed.

Caffeine, a microscopic image of lot B1 described in the experimental section showing a clear aggregation phenomenon. Theophylline, particle size distribution of microcapsules of the invention (Lot C2). Microscopic image of lot C3 representing fluoxetine, a microcapsule of the invention. Microscopic image of lot C1 representing caffeine, a microcapsule of the invention.

Claims (10)

a. Coating the drug fine particles with an ethyl cellulose layer;
b. Said step a. With an acrylic polymer layer; A method for producing a microcapsule containing a drug, comprising the step of further coating the product of :
Step b. The coating in is applied by spraying the solution or suspension of the acrylic polymer onto the particles obtained in step a.
The following weight percent components, where the solution or suspension is calculated relative to the total weight of the solution:
Acrylic polymer: 4-20%,
Alcohol: 30-94%,
Water: 0-40%
Finely divided inorganic substance: 2 to 20%,
The manufacturing method which is a hydroalcoholic solution containing this . Step a. The method for producing microcapsules according to claim 1, wherein the coating in is applied by phase separation microencapsulation or fluidized bed coating. The hydroalcoholic solution or suspension has the following weight percent components calculated relative to the total weight of the solution:
Acrylic polymer: 7-20%,
Alcohol: 40-75%,
Water: 10-35%,
Finely divided inorganic substance: 5 to 9%,
The manufacturing method of the microcapsule of Claim 1 or 2 containing this. The method for producing microcapsules according to claim 1 or 3 , wherein the alcohol is ethanol and the inorganic substance is talc. Step a. Product having a drug / ethylcellulose weight ratio (phase ratio) of 3: 1 to 15: 1, and said step b. Product has a 10 to 25% by weight of acrylic polymer content, the method of producing microcapsules according to any one of claims 1 to 4. Step b. Drug taste-masked microcapsules obtained, the weight median particle size of 20～800Myu m, has a titer of 400~950mg / g, it was included in the microcapsules within 30 minutes in acidic aqueous medium in the at least 80% can be released, a method of producing microcapsules according to any one of claims 1 to 5. The microcapsule containing the chemical | medical agent obtained by the manufacturing method of the microcapsule of any one of Claims 1-6 . The microcapsule according to claim 7 , which is in a pharmaceutically administrable form. 9. The micro of claim 8 , wherein the pharmaceutically administrable form is selected from dry powder for immediate suspension, tablets, mini-tablets, capsules containing microcapsules, single dose bags, fast disintegrating tablets, syrup. capsule. The microcapsule according to any one of claims 7 to 9 , wherein the drug is selected from penicillin, cephalosporin, carbapenem, penem, penum, aminoglycoside, macrolide, ketolide, tetracycline, quinolone.