DE2164019A1 - Process for the manufacture of drug microcapsules by means of atomization evaporation - Google Patents

Description

Brentford, Middlesex, UK

"Process for the manufacture of drug microcapsules by means of atomization evaporation "

Priority: 23-12.1970, Great Britain, No. 61 304/70

The invention relates to a method for producing medicament microcapsules.

It is common to determine the physiochemical properties of a drug by coating the drug particles with a coating of a different material. Properties, that can be changed in this way are taste, texture, solution behavior, activity, flowability and compressibility.

A large number of drugs cannot be administered orally or they show physical in this form of administration or chemical adverse properties. For example, some drugs have such an unpleasant taste that the patient is reluctant to take the prescription. Some drugs cannot be given orally because they are having

209832/1135

Received onJjt

216A019

the hag sap react and become inactive, or because they if they are too concentrated, damage the bowel tract. Others react with the air during storage thereby lose a large part of their activity. Some drugs may not work in because of their adverse properties Tablets are compressed, although they are of course administered as less easy-to-dose syrups or solutions or as more expensive capsules can be.

. So far, various methods have been used to eliminate this

P. Tried difficulties. Essentially, the drug particles are coated with waxy polymer products or resins so that the unpleasant properties of the drug are masked when the drug is administered. However, some of these methods are expensive or ineffective, and in the majority of cases they can only be used on fairly large particles, for example with a diameter larger than IOC μ _{ .

Such methods are spray drying (see US Pat. Nos. 2,805,977 and 3,146,167) and spray freeze drying "(see U.S. Patents 3,080,292 and 3,137,630), the conversion in US Pat Fluidized bed (see US Pat. No. 3,015,128) and flocculation (see UvS-PS 3 242 051 and 3 341 466). Many of those made in this way However, particles are poorly coated and the process is therefore uneconomical. Removal is a number of common practices not developed to production maturity and in general only to preparations with delayed drug release or only applicable to particles larger than 100µ in diameter.

209832/1135

bath

_ 3. Received on..§All

'216 A

The task of the invention was therefore to find an effective method for Umhüllung.von particles with a diameter smaller than air; 100 nm, but also over 100 μ _} can be found.

The invention accordingly relates to a method of production of drug microcapsules, which is characterized is that a drug in the solution of a practically water-insoluble coating agent, which is an electrostatic Has attraction for the drug, is suspended in a homogeneous or heterogeneous organic solvent, which has a dielectric constant that is less than 35 E,

^: in which the coating agent is more soluble than the drug, and that the solvent is slowly evaporated from this drug suspension to form a coating.

The method according to the invention is a nebulization evaporation which is applicable to acidic, basic or amphoteric drugs of low water solubility, for example less than 10 percent, and is suitable for masking the taste of drugs, controlling their delivery rate and improving their flowability. The method is based on the evaporation of droplets from a suitable suspension of the medicament in an organic solvent containing the dissolved coating agent. The first thing is absorption and. the mutual attraction between the suspended particles and dou coatings is effected by electrostatic anaiehunp. Dot Üoür.'rH'.g then forms through the slow .evaporation fJG.'j iJuspcns iorjößpruhnc.-belü in such a conditional house!., RittiJfj only a few 'i'ei iojiuri2ur>ai; i: nen; .) tos se meet.

209832/1135

BATH ORIGINAL

The drug should be significantly less soluble in the heterogeneous or homogeneous solvent than the coating agent. In addition, the dielectric constant of the solvent should have such a value that the ionization of the ionic. see and the potential ionic groups of the drug and the coating agent takes place, but not so large that it comes to an undesirable complete salt formation between the drug and the coating agent. Such Löjsungsmittelsysterne normally have a dielectric constant that is less than 25 D, preferably less than 10 ^E, ·

The solvent should be non-toxic and pharmaceutically acceptable; the complicated washing and / or drying of the capsules in order to remove the last traces of the solvent is then no longer necessary. Solvent systems having such characteristics are: methanol, ethanol, propanol, isopropanol and like alcohols, which have six or fewer carbon atoms, acetone, methyl acetate, methyl and ethyl esters, Chlorofornuuethylenchlorid, ethylene dichloride, tetrachlorethylene and trichlorethylene ψ.

The drug can be acidic, basic or amphoteric and one or more ionizable or strongly polarizable groups . to have. Examples of such compounds are insoluble penicillins or their insoluble salts, e.g. ampicillin ((X-aminobenzylpenicillin), hydroxyampicillin, calcium flucloxacillin, Magnesium flucloxacillin, benzathine cycloxacillin; insoluble barbiturates, such as allobarbitone, aprobarbitone, butabarbitone, Calcium cyclobarbitone, heptabarbitone, and insoluble suI

209832/1135

BATH ORIGINAL

and
phonamides, such as sulfadimidine / ephedrine or theophylline, codeine

and morphine.

Penicillins are particularly suitable for the invention Process of atomization evaporation.

The coating agent can be a resin, a polymer or a mixture of the two and is chosen so that in the suspension of the medicament in a solution of the coating agent one there is electrostatic attraction between the coating agent and the drug. Accordingly, when encasing a basic An acidic or amphoteric coating agent is selected for a medicament, a basic or an acidic medicament amphoteric coating agent and, in the case of an amphoteric drug, a basic, acidic or amphoteric coating agent.

The electrostatic attraction between the coating agent and the drug can be due to the absorption of ions or charged Solvent molecules in one or both components or by the induced polarization and partial ionization of the Drug and the coating agent arise in the solution. The first precipitation occurs through the electrostatic attraction of the coating agent on the surface of the medicament. As soon as this nucleation has occurred, there will be more Coating layers held in place by other physical forces, e.g. Van der Waals forces. The type of coating agent in the process according to the invention depends on the use of the end product.

209832/1135

For example, the coating should be sufficient to mask taste be insoluble and impermeable in water to prevent rapid dissolution of the drug in a neutral aqueous medium, however, it should quickly dissolve in gastric juice and become permeable in order to release the drug for absorption.

Suitable coating agents for masking the taste of sour, Amphoteric or acidic drug salts contain one or more of the following polymers: Dimethylaminoethyl methacrylate or other esters of methacrylic acid, poly-P vinylacetaldiethylaminoacetate, 2-methyl-5-vinylpyridine methacrylic acid, Methacrylate copolymer, cellulose acetate, ol-dibutyl-ß-hydroxypropyl ether and ethyl cellulose.

Suitable coating agents for masking the taste of in acid soluble basic, amphoteric or salts of basic drugs consist of cellulose acetate phthalic acid esters, hydroxypropylmethyl cellulose phthalic acid esters, Polyvinyl acetate, shellac, sandarak resin or anionic, made from methacrylic acid or methacrylic acid esters synthesized, polymers. r

If a slow release of the drug in the digestive tract is required, the coating must be sparingly soluble. He exists then from one of the following polymers: shellac, sandarak resin, ethyl cellulose, cellulose acetate phthalic acid ester or from an anionic polymer synthesized from methacrylic acid or methacrylic acid esters.

209832/113 5

received

In the method according to the invention of wrapping a medicament the suspension of the Medicament in the dissolved coating agent through a nozzle or a centrifugal disk in the form of fine droplets in a room, in which the solvent evaporates, dispersed. The dispersing is preferably carried out so that the in one Droplets moving in the air flow or falling under the influence of gravity rarely collide. The temperature and the solvent vapor pressure within the room is adjusted so that the solvent is slowly enough out of the Droplets evaporate, so that a more even and preferably a hole-free coating is created on the particle surface.

The microcapsules of the drug are then removed from the room. One can also take precautions to avoid the solvent to regain.

The particle size distribution in the spray mist should be small, the diameter of the droplets can be smaller than 100 μ .

The particles remain in the room until an even coating of the drug and complete evaporation of the Solvent is reached. The time required for this and the physically on eggs;? ο juice of the product v / earth by factors, like the 'J'eileijoi size of the lever, the concentration, the physical and chemical properties and weight of the »coating agent ::; and the drug, the feed rate the surf υ ion, the speed of the droplet sediiüent at ion, dio'i-eiauoratur, the type and vapor pressure of the solvent im liauiii, booinfiußst.

209832/1135 BATH ORIGINAL

The boiling point of the solvent should be high enough to allow rapid evaporation of the solvent from the droplets to prevent. Rapid evaporation causes the formation of rigid crusts on the liquid-air interface, which prevent evaporation of the solvent and lead to a coating that has holes and pores.

The concentration of the drug and the weight of the coating agent influence the particle size distribution of the spray mist by changing the viscosity and the surface tension of the suspension. Likewise, the Einspeisge- \ affects speed of the suspension in the atomizer or in the due-- se the particle size distribution of the fog. In both cases ! leads to a decrease in the particle size distribution of the mist

a larger droplet surface and thus a higher one Evaporation rate of the solvent.

The rate of evaporation of the falling droplets can be controlled by a stream of air. A stream of air in the upper areas of the room and against the direction of the sedimenting droplets increases the concentration gradient of the solvent vapor from the droplet surfaces and facilitated the evaporation of the solvent. A stream of air decreased in the same direction as the sedimenting droplets this concentration gradient, the evaporation rate of the solvent at the liquid / gas interface is less.

209832/1 135

BAQrÖFöGINAL

The rate of evaporation of the solvent can be increased by Check the temperature and / or the solvent vapor pressure in the room. For example, certain areas of the room can be heat or cool and blow additional solvent vapor into the room at various points. Preferably should be the introduction of solvent vapor or other gases that reduce the rate of evaporation of the solvent control, do not significantly increase the number of particle collisions, as this leads to the formation of aggregates and lumps can lead, which then sediment more quickly in the lower areas of the room.

Fig. 1 shows in longitudinal section a system for the inventive Atomization evaporation. An atomizer (1) is arranged at the top of a tower (2) 7.3 m high and 3.3 m in diameter, whose inner walls (3) are lined with polyethylene. The atomizer consists of a centrifugal disc ! Steel (4) driven by a motor (5) with 20,000 revolutions or less per minute. The suspension (6) to be dispersed is poured into a funnel (7) above the disk (4) filled. It is stirred with a stirrer (ö) and through a glass tube (9) fed into the center of the disc (4). The feed speed is controlled by a tap (10) and adjusted so that the solvent evaporates completely before the particles are on the polyethylene film (11) Fall of the bottom of the tower. There they are collected and, if necessary, brought to a plate dryer, where anything else may still be adhering Solvent evaporates.

209832/1136

BATH ORIGINAL

- ίο - received on. "£ Jii £

The following examples illustrate the invention. ".

Example 1 A suspension of the composition

Ample illin-trihydr at., -

(of-aminobenzy! penicillin) ^δ

Eudragit E.

(Dimethylaminoethyl methacrylate). ^G

Tetrachlorethylene. ■. 500 ml

is in the funnel of the atomization-evaporation described above s plant introduced. The atomizer disc rotates at 5000 rpm. The resulting droplets become horizontal dispersed and then fall under the influence of gravity through the tower down, which has a temperature of about 10 C. In the process, all of the solvent evaporates and forms polymer microcapsules around the drug. The product is collected at the bottom of the tower and at barely any temperature Dried on plate dryers for 3 hours.

The powder obtained is smooth and tasteless and consists of spherical microcapsules with a diameter of less than 60 μ. · ■

B e i s ρ i e. "2 bii: 21 each

The following suspensions are prepared and, as described in Example 1, prepared from microcapsules. The suspensions are poured into the nebulizer with r.iriam Durciicatz of 200 and 400 ml pru minute a ^ espoj s t. J) Jt-; Ami η hl dar Zusn!. ::.: Enstöofäo of the falling droplets is, determined by the microscope, insignificant. The powder is dried "JO minutes a :: i Boden dos Tower" by circulating warm air.

209832/1136 BAD ORIGfNAL

- »- received _Λτ

The final particle size depends on the operating speed of the atomizer from «In general, a mean particle size of less than 50 ^ u is achieved. The particle size distribution of the products from Example 16, 1 and 6 is summarized in Table I:

Example 2

Magnesium Flücloxacillin 75 g

(Magnesium salt of 2- / 2 ^f -Chlor-6'-

fluorophenylZ-S-methyl ^ -isoxalyl-

penicillirjs)

Eudragit E 75 g

(Dimethylaminoethyl methacrylic acid ester)

Tetrachlorethylene 500 ml

Example 3-

Benzathine cycloxacillin 50 g

(Ν, Ν'-dibenzylethylenediamine salt of

3_0-chlorophenyl-5-methyl-4-isoxazolyl-

penicillin)

Eudragit E 50 g

Tetrachlorethylene 500 ml

Example 4-

Sulphadimidine _ 50 g

(2- / j) -amino in azolsulphonamidqy-4,6-dimethy3.pyrimidine)

Eudragit E 20 g

Ethyl cellulose 30 g

Technical methanol '100 ml

Votraehloräthylen 500 ml

209832/1135 BAD ORIQjNAt

example Benzathine cycloxacillin 5 50 G Sankyo AEA
(Polyvinyl acetal diethylaminoacetate) ■ 50 G acetone 125 ml Tetrachlorethylene 375 ml

Example 6

.Magnesiuraflucloxacillin. 50 g

Sankyo A.E.A. . 50 g

Acetone '. 125 ml '

Tetrachlorethylene 375 ml

Example 7

Ampicillin trihydrate 50 g

Sankyo A.E.A. 50 g

Acetone. 125 ml

Tetrachlorethylene 375 ml

Examples

Anti-malarial agent 50 g

(4-, 6-Mamino-1,2-dihydro-2,2-dimethyl-1,1- (3,4-dichlorobenzyloxy) -1,3,5-triazine hydrochloride)

M.P.A. -RE. 50 g

(2-methyl-5-vinylpyridine methacrylic acid / Methacrylic acid ester copolymer)

Propanol (1) 200 ml

Tetrachlorethylene 300 ml

209832/1 135

Example 9 Sulphadimidine x 60 g

Gelva
(Polyvinyl acetate) example SuIphadimidine 10 40 G Trichlorethylene CAP
(Cellulose acetate phthalic acid ester) 500 ml acetone Propanol (I) - 75 G *
example 25th G Sulphadimidine 11 250 ml Eudragit Retard L. 25-0 ml 60 G 40 G

(anionic polymer from methacrylic acid and methacrylic acid esters)

Propanol (2), 500 ml

Example 12

Magnesium flucloxacillin 50 g

Sankyo A.E.A. . 10 g

Ethyl cellulose - 40 g

Trichlorethylene '375 ml

Acetone '125 ml

209832/1135

Example 13

Benzathine cycloxacillin 30 g

Sankyo A. E. A.. 10 g

Ethyl cellulose x 20 g

Tetrachlorethylene 225 ml

Acetone 75 ml

Propanol (2) 150 ml

Example 14

^ Anti-malarial agent 25 g

Shellac '' 50 g

Propanol (1) 500 ml

Example 15

¹ anti-malarial agent 25 g

Shellac (19 percent with sodium hydroxide 5Oe

neutralized) -> 6

Propanol (1) ■ 500 ml

Example 16

Anti-malarial agents. 25 g

Shellac (36 percent with .sodium hydroxide

neutralized) 50 g

Propanol (1) 500 ml

■ B e i s. Ρ i e 1 17

Anti-malarial agents. 25 g

Sandarak resin. 50 g Propanol (2). 500 ml

209832/1135

21 6A019

Example 18 Sulphadimidine 60 g

Eudragit Retard S 40 g

(Anionic polymer from methacrylic acid and methacrylic acid esters ^

Propanol (2) 500 ml

Example ^ 19

Sulphadimidine Example 20 Anti-malarial agents Example 21 Sulphadimidine 75 g C.A.P. C.A.P. Ethyl cellulose 75 g Acetone. < acetone Tetrachlorethylene ' 375 ml Propanol (1) Propanol (1) Technical methanol 375 ml 75 g 78 g 375 ml .375 ml 50 g 50 g 500 ml 100 ml

2 0.9832 / 1 135

- ¹⁶ - received

Table I. the Particle size
in μ 16 Products from example 16, 6th Particle size distribution 6th 60 ■ 0 5 1 and percent
5 50 0 10 40 0 Particles (on each
Percent rounded up) . 10 30th 10 Example no. 15th 20th 20th ' 1 20th 10 60 O 25th 0 10 5 15th 10 10 25th 25th 25th

The Lösegescliwindigkeit of drug-microcapsules and untreated drugs in distilled water at 25 ⁰ C is shown in Fig. 2, the dissolution rate in hydrochloric acid 0,047n in Fig. 3 and 4.

The dissolution rate of drugs is untreated ^v large in both solutions, the rate of dissolution of the coated drug is slowed in distilled V / ater. FIG. 3 shows that the rate of dissolution of drug microcapsules which were produced for taste masking (Examples 1 to 12) is high in simulated gastric juice. Pig. Figure 4 shows that the rate of leaching of microcapsules made for slow release of the drug is small in simulated gastric juice.

The concentration of the untreated drugs in these trials was smaller than the saturation value. The crystals dissolved

209832/1135

BADORiGtNAt

therefore in both solvents quickly and completely within a few minutes.

Except for the products that are made for a rapid release of the drug in simulated gastric juice, was the rate of dissolution of the microcapsules, with the same weight of active material as in the tests with untreated Medication, small. -The speeds were determined by the amount of polymer in the microcapsule matrix. In some In some cases, relatively high polymer concentrations (greater than 50 percent) were necessary in order to quickly dissolve the coated Avoid drug.

The taste of the drug microcapsules was better than that of untreated powders. Microcapsules with improved taste, administered as a single dose, tasted significantly better than similar ones Suspensions of the untreated material.

20 9 832/1135 BAD

Claims (8)

- 18 patent claims 1. Process for the production of drug microcapsules, characterized in that a medicament in the solution of a practically water-insoluble coating agent, that has an electrostatic attraction for the drug, in a homogeneous or heterogeneous organic Solvent is suspended, which has a dielectric constant that is less than 35 E, in which the coating material · L is tel soluble than the drug and the solvent from the drug suspension to form a coating is evaporated slowly. 2. The method according to claim 1, characterized in that the suspension of the drug in the coating agent as fine Droplets are sprayed through an atomizer nozzle or a centrifugal disc in a ^ aum in which such a temperature and such a solvent vapor pressure prevails, that the solvent is slowly forming from the droplets W of a uniform and hole-free coating evaporates. 3. The method according to claim 1 and 2, characterized in that the drug is a sparingly soluble acidic, basic or amphoteric semi-synthetic penicillin or its salt and that is the dielectric constant of the solvent is less than 25 E. 4. The method according to claim 1 to 3, characterized in that the drug is a water-soluble isoxazolylpenicillin swore or its salt is. 209832/1 135 BATH ORIGINAL - 19 - 5. The method according to claim 1 to 4, characterized in that the ^ the solvent of at least one C-,. -alcohol or a C-z ^ c-ketone, or a C ~ c-ester or a C-, p-halogenated Hydrocarbon ". 6. The method according to claim 1 to 5, characterized in that a basic drug with an acidic or amphoteric Polymer and / or resin, an acidic drug with a basic or amphoteric polymer and / or resin, or a amphoteric drug is coated with a basic, acidic or amphoteric polymer and / or resin, 7. The method according to claim 6, characterized in that the coating agent of methacrylic acid dimethylaminoethyl ester, 2-methyl-5-vinyl methacrylic acid / methacrylic acid ester copolymer, Polyvinyl acetaldimethylaminoacetate, cellulose acetate phthalic acid ester, polyvinyl acetate and / or anionic polymers consists of methacrylic acid and methacrylic acid ester ^ optionally with the addition of methyl or ethyl cellulose. 8. The method according to claim 1 to 7, characterized in that microcapsules with a diameter of at most 100 nm getting produced. 209832/1135