NO126299B - - Google Patents

Description

Procedure for coating penicillins.

The present invention relates to a method by coating

ning of penicillins. The invention relates in particular to a method for coating penicillins with a mixture containing or consisting of ethyl cellulose and a pharmaceutically usable wax.

Penicillins have been used with considerable success in treatment

of bacterial infections in humans. Unfortunately, certain of the penicillins, and especially the isoxazole types of penicillins, e.g. oxacillin, cloxacillin, dicloxacillin and flucloxacillin as well as nafcillin and to some extent also ampicillin and hetacillin have been shown to have a strongly pronounced bitter taste. The taste has been difficult to mask by simply adding flavorings or sweeteners to the orally administrable preparations. This problem is in it

substantially have been lost by coating penicillins with coating materials of the type described here. The aim of the present invention is thus to arrive at palatable penicillin for oral administration in the treatment of bacterial infections in humans.

The antibacterial preparations prepared from penicillins and obtained by the present invention are suitable for oral administration to humans. They are palatable, and the amount of penicillin contained in the preparations is absorbed by the human gastrointestinal system upon oral administration at essentially the same rate and time interval as corresponding preparations containing uncoated penicillins. This property of preparations containing coated penicillins was completely unexpected on the basis of the teachings that can be derived from various patents. When treating bacterial infections, it is advantageous to quickly achieve a blood level value for penicillin that is sufficient for bacterial infections to be combated.

It is known from the U.S. Patent Document No. 2902^07 to coat potassium penicillin with wax to mask the bitter taste, and from U.S. Pat. patent no. 32<*>+7065 it is known to coat ascorbic acid particles with a mixture of ethyl cellulose and wax in order to obtain a free-flowing powder which lacks the unpleasant taste otherwise associated with ascorbic acid. Finally, it's from the U.S. patent document no. 2921883 known a coating for pharmaceuticals consisting of a mixture of ethyl cellulose and a lipoid hydroxyl group-containing material consisting of fatty alcohols, esters of glycol or glycerol with higher fatty acids, esters of a higher hydroxyl fatty acid with a lower aliphatic alcohol or esters of a polyhydric fatty alcohol with a lower aliphatic acid. This coating maintains a release of the drug in the digestive tract, so that there is not a rapid but a slower release of the drug.

The coated penicillins • produced by the present method can be administered in preparations in solid and liquid form, e.g. such as tablets, capsules, powders or pills, granules, syrups, elixirs and suspensions.

The method used for coating the penicillins is known, for example, from U.S. patent documents no. 2805977 and no. 2921833 as well as French patent document no. 1289^30.

In the following, the terms include oxacillin (3-phenyl-5-methyl-h-isoxazolylpenicillin), cloxacillin-1 3-(3-chlorophenyl)-5-methyl-M- isoxazolylpenicillin], dicloxacillin-[3-(2,6- dichlorophenyl)-5-methyl-^--isoxazolylpenicillin] and flucloxacillin-i 3-(2-chloro-6-fluorophenyl)-5-methyl-M-isoxazolylpenicillin] the free acid forms and the non-toxic,

pharmaceutically usable, cationic salts of such penicillins as well as the anhydrates and hydrates of these penicillins. The production and properties of these compounds are, among other things, described in the U.S. patents No. 2996501, No. 3239507 and No. 3317389.

As used herein, the term nafcillin (2-ethoxy-1-naphthylpenicillin) includes the free acid form and the non-toxic, pharmaceutically acceptable, cationic salts of penicillin and the anhydrates and hydrates thereof. The production and properties of these compounds are, among other things, described in the U.S. patent no 3157639.

Ampicillin is the common name for D-(-)-α-amino-benzylpenicillin. The term ampicillin as used herein includes the free acid, i.e. the amphoteric form, the anionic salts with acids,

such as hydrochloric acid, and cationic salts with bases, such as sodium hydroxide, and anhydrates and hydrates of this penicillin type. The production of these and their properties are, among other things, described in the U.S. patents No. 29856^8, No. 31M-0282, No. 3lW+<>>+5, No. 31576^0 and No. 3l8o862.

Hetacillin is the general name for 7-(2,2-dimethyl-5-oxo-U-phenyl-1-imidazol-idinyl)-penicillanic acid with the structural formula:

The term hetacillin as used herein includes the free acid

as stated above, and the non-toxic, pharmaceutically useful, cationic salts of the acidic carboxylic acid group, and the non-toxic, pharmaceutically useful acid addition anionic salts, i.e. salts of basic nitrogen and the anhydrates and hydrates of this penicillin type. The manufacture of these and their properties are described in Belgian Patent No. 6<1>f285l and U.S. Pat. patent No. 319880U-.

The waxes that can be used when coating together with ethyl cellulose are water-insoluble, pharmaceutically applicable waxes including paraffin wax, mineral wax, ceresin wax, Utah wax, montan wax, carnauba wax, Japan wax, myrtle wax, linseed wax, candelilla wax, sugarcane wax, spermaceti whale wax, beeswax, Chinese wax, shell wax, castor wax and similar waxes. A single type of wax or a mixture of wax types can be used. A preferred type of wax is sperm whale wax, and a preferred mixture of waxes is sperm whale wax and castor wax.

The penicillin's coating must contain ethyl cellulose and a pharmaceutically usable wax to achieve the desired properties, but other coating materials can be introduced into this, e.g. hydrogenated peanut oil, cetyl alcohol, hydrogenated vegetable oil, etc.

The following combinations of coating materials are particularly well applicable: ethyl cellulose-beeswax-castor wax-cetyl alcohol, ethyl cellulose-castor wax-hydrogenated peanut oil, ethyl cellulose-paraffin wax and ethyl cellulose-spermaset whale wax-castor wax-paraffin wax.

According to the invention, a method is provided by coating an orally administrable, synthetic penicillin: ampicillin, hetacillin, nafcillin, oxacillin, cloxacillin, dicloxacillin or flucloxacillin or salts or mixtures thereof, and the method is characterized by the fact that micronized particles of the penicillin are suspended in a solution containing ethyl cellulose and a pharmaceutically usable wax in an inactive, volatile, organic solvent, after which the suspension is spray-dried and the coated penicillin particles produced thereby are recovered.

When carrying out the method, a suspension of very small particles of the penicillin is sprayed in a solution containing ethyl cellulose and a pharmaceutically usable wax in an inactive, volatile, organic solvent or in a mixture of solvents by spraying the suspension into a heated, non-reactive, gaseous medium to remove the solvent. The suspension is brought into contact with the gaseous medium in the form of finely divided droplets. The term "micronized" denotes a particle size of no more than 30 µm.

The solvent used to dissolve the coating material is evaporated and removed during spray extraction. The solvent must therefore be volatile and at the same time unreactive towards the coating material and the penicillin. Other properties of the solvent are not of significant importance, and a whole range of solvents can be used for this purpose. It will be clear to the person skilled in the art which solvents he can use, and suitable solvents include methylene chloride, chloroform, cyclohexane, carbon tetrachloride, methyl ethyl ketone and acetone, methylene chloride being a preferred solvent.

The temperature of the gaseous medium into which the suspension of penicillin and the coating materials is sprayed is not de-

significant meaning. However, it must be sufficiently high that practically all the solvent will be removed, but not so high that a splitting of the penicillin will occur. It will be clear to the person skilled in the art that the upper and lower temperature limits will depend on such process variables as the supply rate for the suspension and the time the suspension stays in the heated area. With lower supply rates and longer residence times, a lower temperature will thus be sufficient to remove the significant amount of the solvent. At higher feed rates and shorter residence times, higher temperatures will be necessary. It has been shown that a temperature between 115 and 125°C, preferably approx.

120°C is a suitable working temperature.

The coated penicillin particles used in de.oral antibacterial preparations can contain from 7 parts by weight of coating material per part by weight of penicillin to 9 parts by weight of penicillin per weight part cover material. The coated penicillin particles preferably contain 1-3 parts by weight of coating material per weight-

part penicillin, preferably 3 parts by weight of coating material per

part by weight of penicillin. The cover preferably contains 1-3 wt.

parts of wax or wax mixture per part by weight ethyl cellulose. The over-

drawn penicillin particles should not have a size greater than U-0 mesh (U.S. standard sieves), and particles with a size not greater than 150 mesh (U.S. standard sieves) are preferred.

According to a preferred embodiment, dicloxacillin is coated

with ethyl cellulose and spermaceti whale wax. When producing the coated dicloxacillin, a suspension consisting of dicloxacillin, ethyl cellulose, spermaceti wax and methylene chloride is sprayed into air at a temperature of approx. 120°C. Ethyl cellulose and sperm whale

wax is preferably present in the suspension in a ratio of

respectively 1 part by weight per part by weight sodium dicloxacillin and 2 parts by weight

per part by weight sodium dinloxacillin. The solvent methylene chloride is preferably present in a ratio of between 7.5 and 15 l/kg sodium dicloxacillin, ethyl cellulose and spermaceti whale wax. The suspension's flow rate is regulated so that the correct evaporation of the methylene chloride is achieved.

In the description, and especially in the examples, hetacillin-free acid is taken as standard with an efficiency of 1000 mcg/mg, and when other salts are used, the weight is that which gives an equivalent amount of activity, i.e. 1096 mg potassium hetacillin is activity equivalent to 1000 mg hetacillin-free acid. The ratio is stoichiometric.

As for ampicillin with a standard activity of 1000 mcg/mg, anhydrous ampicillin is used and the ampicillin trihydrate here has an effectiveness of 865 mcg/mg.

As for dicloxacillin, the standard is the free acid with

an activity of 1000 mcg/mg, and the sodium salt is thus 920 mcg/mg.

In compositions, an overflow is often used in this area

of e.g. 10% of each of the active ingredients compared to the stated efficiency.

In the examples given below, the use of a single antibacterial substance in the tablets is indicated. The oral, antibacterial preparations described here have all the proven therapeutically useful results that are achieved with other oral preparations of the penicillins specified, e.g. dicloxacillin. They can thus be used for regulating infections or combating such infections which are particularly susceptible to specified penicillins, e.g. dicloxacillin, susceptible organisms that cause infectious diseases in the respiratory system. Ampicillin and hetacillin preparations are effective against Gram-positive and many Gram-negative organisms. In addition, oxacillin, dicloxacillin, flucloxacillin, nafcillin and cloxacillin preparations are particularly effective against Gram-positive bacteria, including especially those resistant to benzylpenicillin.

The preparations are administered in the same dosage form as other orally administrable preparations containing the same penicillin types, e.g. dicloxacillin. Thus, preparations for children can be administered with a daily dose of approx. 50 mg ampicillin or cloxacillin or oxacillin or 25 mg hetacillin or nafcillin or 12.5 mg flucloxacillin or dicloxacillin per kg body weight per day in 3 or h-different doses. For adults, the preparation can be administered so that the patient receives a daily dose of approx. 1 g ampicillin, cloxacillin, hetacillin or nafcillin, 2 g oxacillin or 500 mg dicloxacillin or flucloxacillin in 3 or h doses in a dosage unit form of e.g. 125, 250 or 500 mg penicillin. Oral suspensions containing approx. 50 - approx. 125 mg penicillin and preferably approx. 60 - 70 mg penicillin per teaspoonfuls are suitable dosage forms. When it comes to particularly serious infections, the above-mentioned doses can be doubled.

Example 1

Spryte coating of sodium dicloxacillin with a mixture of ethyl cellulose and spermaceti whale wax

Description of manufacture

1) Sperm set whale wax was dissolved in approx. 8 liters of methylene chloride. The reading was carried out in a 20 liter glass or stainless steel container using a mixer. It was not necessary - with any heat treatment. 2) Ethyl cellulose in small portions was added to the mixed clear solution while stirring. The whole thing was stirred until a clear solution with a relatively high viscosity was formed. 3) Sodium dicloxacillin was then added in small portions with stirring, and a milky suspension was formed. h) The resulting solution was filtered through three layers of cheesecloth to remove any contaminating particles. 5) The remainder of the methylene chloride (7 liters) was added with stirring and the dicloxacillin sodium was completely dispersed. No lumps or agglomerates occurred in the dispersion. 6) A so-called "Nerco-Niro laboratory model sprbyte user" was used in the following way: a) . The electric heater was set to 2 or 3 until the air intake was approx. 130°C.

b) When equilibrium is achieved:,

air inlet: 115- - 120°C,

air outlet: 50 - 55°C.

c) The turbine atomizer was set over a "Teflon" gasket and compressed air was supplied until the atomizer gauge read 6 kg/cm p.

A maximum compressed air pressure of approx. <*>+5 - 5.0 kg,

and the turbine rotated at a speed of ^'0,000 revolutions per minute. 5 minutes were used to achieve equilibrium in the chamber for the start of liquid addition to the selenium. d) The liquid supply to the turbine was started from a 2 liter separating funnel connected to the turbine with a short piece of "Teflon" pipe.

The supply rate was 60-80 ml per minute.

e) The process was regulated by maintaining the following usage conditions throughout the process:

air inlet: 115 - 120°C,

air output: 60 - 70°C.

f) The atomizer was stopped and the electric heating unit turned into position for blowing out. The apparatus was allowed to stand; in this' position .i. 5

minutes before the cover layer was lifted off.

g) The cover layer was lifted off using a hydraulic lifting device and the product collected from the walls. h) It was not expected that the product would stick to the walls of the chamber by means other than electrostatic forces.

i) The product was dried in a vacuum oven for 1 12 hours at room temperature. The methylene chloride residue was less than 0.5%.

j) The free-flowing, coated dicloxacillin sodium product was allowed to pass through a h-0 mesh screen and collected.

Example 2

Sprbyte coated dicloxacillin sodium for oral suspension

62. 5 mg/ 5 ml (coating of ethyl cellulose-. spermaceti whale wax)

This figure represents the dicloxacillin effect and includes a 10% excess. The following formula was used to calculate the amount of coated sodium dicloxacillin used:

Description of manufacture

1) All ingredients were mixed, except for the sprbyte-coated sodium dicloxacillin and the kaolin, with approx. 1/3 sucrose in a

.suitable mixing unit. It was mixed for 30 minutes.

2) The mixture was added to the remaining amount of sucrose, and kaolin was added. It was mixed for 30 minutes. 3) The excess sodium dicloxacillin was added to the mixture. the thing under 2), cg it was mixed for 30 minutes.

h) The mixture was filled into bottles. For use for the application, a sufficient volume of distilled water up to

60.0 ml. A suspension was thereby formed with 10% above the stated effectiveness of 62.5 mg of sodium dicloxacillin activity per 5 ml.

Example 3

Spray coating of sodium dicloxacillin with a mixture of ethyl cellulose. sperm whale wax and castor wax

Note: The preparation must be kept at a temperature of 20 - 25°C to prevent wax from precipitating from the solution.

Description of manufacture

aggregate dissolved in the methylene chloride in a suitable stainless steel container. If necessary, steam was used as a heat source to keep the temperature at approx. 25°C and to facilitate the dissolution of the castor

adult.

2) To the clear solution formed, ethyl cellulose was added in small portions while stirring until a clear, viscous solution was formed. 3) To this solution sodium dicloxacillin was added in small portions with stirring, and the mixture was continued until a milky white suspension was formed. This was free of lumps and agglomerates.

h) The solution was filtered, possibly through three layers of cheesecloth,

to remove polluting particles.

5) The resulting dispersion was transferred to a "Graco" pump and spray gun apparatus (Monarch model). The pump was connected to a supply line for compressed air which was circulated through the dispers

tion for at least 5 minutes by manually regulating the air pressure at 60 kg. 6) The "Graco" spray gun was adapted to tip /t^DLN-C1150 (0.026 cm). 7) A "Nerco-Niro" laboratory test reactor was completely assembled, except for the air-driven atomizing turbine, and the following temperature equilibrium was obtained:

Intake air: 115 - 120°C

Exhaust air: ^5 - 50°C

8) The opening was removed from the sprinkler breaker side, and the spray gun was inserted and activated to maintain constant sprinkler exchange. 9) The spray gun was occasionally inspected to see if lumps had formed, which were removed if necessary, and the tip was cleaned if necessary. 10) The product was collected and dried in a vacuum oven for 12 hours at room temperature. The methylene chloride residue was less than 0.5$. 11) The free-flowing, coated dicloxacillin sodium product was passed through a ho mesh sieve and collected.

Example h

Sprbyte coated sodium dicloxacillin powder for oral suspension, 62.5 mg/5 ml (coating ethylcellulose-sperm whale oil-castor wax

<*>This number denotes the dicloxacillin effect and here beyond an excess of 10%. To calculate the amount of coated sodium dicloxacillin used, the following formula was used:

Description of manufacture

1) All ingredients were mixed together, except for the sprbyte-coated sodium dicloxacillin and the kaolin, with approx. 1/3 sucrose in a suitable mixing unit. It was mixed for 30 minutes. 2) The remaining portion of sucrose and kaolin was added to the mixture. It was mixed for 30 minutes. 3) The spray-coated sodium dicloxacillin was added to the mixture and it was mixed for 30 minutes.

h) The material was filled into bottles.

When used as a medicine, a sufficient amount was added

volume of distilled water so that the volume of the material was 60.0 ml. A suspension was thereby formed with 10% above the indicated one

effect of 62.5 mg sodium dicloxacillin effect per 5 ml.

Example 5

Sprbyte coating of sodium dicloxacillin with a mixture of ethyl cellulose, castor wax, beeswax and cetyl alcohol

Note: This preparation must be kept at a temperature of 20 - 25°C for

to prevent wax from precipitating from the solution.

Description of manufacture

1) Castor wax, beeswax and cetyl alcohol were dissolved in methylene chloride in a suitable stainless steel container using a mixing unit. If necessary, steam was used as a heat source to keep the temperature at approx. 25°C and to facilitate the melting of castor wax. 2) Ethyl cellulose was added to the resulting clear solution in small portions with continued stirring until a clear, viscous solution was formed. 3) Sodium dicloxacillin was added in small portions while stirring. This was continued until a milky, white suspension was formed which was free of lumps and agglomerates. h) The solution was filtered through 3 layers of cheese cloth to remove contaminating particles. 5) ' The dispersion was transferred to a "Graco" pump spray gun apparatus (Monarch model). The pump was connected to a compressed air supply, and the dispersion was circulated with this for at least 5 minutes while manually regulating the air pressure to 30 kg.

6) The spray gun was attached to tip DLN-C1150 (0.0275 cm).

7) A "Nerco-Niro" laboratory test exchanger was completely assembled, except for the air-driven atomizing turbine, and the following temperature equilibrium was obtained:

inlet air: 115 - 120°C

outlet air: ^5 - 50°C

9) The gun was regularly inspected to see if any lumps had formed which were removed if any, and the tip was cleaned. 10) The product was collected and dried in a vacuum oven for 12 hours at room temperature. The methylene chloride residue was less than 0.5%. 11) The free-flowing, coated dicloxacillin sodium was allowed to pass through a ^0 mesh screen and collected.

Example 6

Sprbyte coated sodium dicloxacillin for oral suspension, 62.5 mg/5 ml (coating of ethyl cellulose-beeswax-castor wax-cetyl alcohol

This figure relates to the dicloxacillin effect with an excess of 10%. The following formula was used to calculate the amount of coated sodium dicloxacillin:

Description of manufacture

1) All ingredients were mixed, except for the sprbyte-coated sodium dicloxacillin and the kaolin, with approx. 1/3 sucrose in a suitable mixing unit. It was mixed for 3 minutes. 2) The mixture was added to the remaining part of the sucrose, after which kaolin was added and the whole was mixed for 30 minutes. 3) The sprbyte-coated sodium dicloxacillin was added to the mix-

the thing and the whole thing mixed for 30 minutes.

*+j The material was filled into bottles.

For patient use: A sufficient volume of distilled water was added until the total volume was 60.0 ml. A suspension with 10% above the stated effectiveness of 62.5 mg sodium dicloxacillin activity per 5 ml.

Example 7

Spryte coated sodium dicloxacillin with a mixture of ethyl cellulose, castor wax, hydrogenated peanut oil, hydrogenated vegetable etc. and sesame oil

Note: This preparation must be kept at a temperature between 20 and 25°C to prevent the waxes from being precipitated from the solution.

Description of manufacture

The ethyl cellulose, castor wax, hydrogenated peanut oil, hydrogenated vegetable oil and sesame oil were dissolved in 7.575 liters of methylene chloride at room temperature. Then the micronized sodium dicloxacillin was added and dispersed, and the whole was mixed until the material was uniform, after which the material was filtered through 3 layers of cheese cloth to remove contaminating particles. The test was carried out by using the apparatus and the method described in example 5, using an air inlet temperature of 115 - 120°C and an air outlet temperature of h5 - 50°C. The coated product was dried in a vacuum oven at room temperature for 12 hours, passed through a high mesh sieve and collected.

Example 8

Spryte-coated sodium dicloxacillin for oral suspension, 62.5 mg/5 ml. (Coating of ethylcellulose-castor wax-hydrogenated vegetable oil-sesame oil-hydrogenated peanut oil

<*>This number indicates the dicloxacillin potency plus an excess of 10%. The following formula was used to calculate the amount of extracted dicloxacillin sodium used:

Description of manufacture

1) All ingredients were mixed, except for the spray-coated sodium dicloxacillin and the kaolin, with approx. 1/3 of the amount of sucrose in a suitable mixing unit for 30 minutes. 2) The mixture was added to the remaining saccbarose part, and kaolin was added and the whole was mixed for 30 minutes. 3) The spray-coated sodium dicloxacillin was added to the mixture and the whole mixed for 30 minutes.

h) The material was filled into bottles.

For patient use, a sufficient amount of volume was added

^distilled water until a total volume of 60.0 ml was obtained. A suspension was thereby formed with 10% above the stated effectiveness of 62.5 mg sodium dicloxacillin action per 5 ml.

Example 9

Spryte coating of sodium dicloxacillin with a mixture of ethyl cellulose. spermaceti whale wax and castor wax

Note: This preparation was kept at a temperature of 20 - .25°C

to maintain castor wax solubility. A lower temperature will inevitably lead to precipitation of the wax. It is recommended to use steam as a heat source.

Description of manufacture

The ethyl cellulose, spermaceti wax and castor wax were dissolved in 15 liters of methylene chloride at room temperature. Next, the micronized sodium dicloxacillin was added and dispersed, and the whole was mixed until the material was homogeneous, after which the material was filtered through 3 layers of cheese cloth to remove any contaminating particles. It was spray-dried using the apparatus and method described in example 1, using an air inlet temperature of 115 - 120°C and an air outlet temperature of 60 - 70°C. The coated product was dried in a vacuum oven for 12 hours at room temperature.

The spray-coated sodium dicloxacillin prepared above was used as a dry mixture for an aqueous oral suspension using the method indicated in example h.

Example 10

Spryte coating of ampicillin trihydrate with a mixture of ethyl cellulose. spermaceti whale wax and castor wax

Description of manufacture

The ethyl cellulose, spermaceti wax and castor wax were dissolved in 9.0 liters of methylene chloride at room temperature. Then the micronized ampicillin trihydrate was added and dispersed. It was all converted until homogeneity was achieved and filtered through 3 layers of cheese cloth to remove any contaminating particles. It was sprayed using the apparatus and method described in example 9, using an air inlet temperature of 125 - 135°C and an outlet temperature of 50 - 70°C. The coated ampicillin trihydrate was spread on trays and dried for 12 hours at room temperature and then passed through a high mesh sieve and collected.

A comparison was made between the blood level/erdies during oral administration of suspensions containing coated dicloxacillin and the blood level values during oral administration of corresponding suspensions containing uncoated dicloxacillin. An investigation was also carried out to determine the blood level values for penicillin in humans. The results of the survey are set out below in tables I and II:

For the sake of comparison, the control suspension was prepared using the method set out in Example 2 while uncoated dicloxacillin was used instead of coated dicloxacillin.

5 ml of each of the suspensions was administered orally to each of 12 patients, and the resulting blood level values were measured respectively 1/2, 1, 2, 3 and h hours after administration.

It appears from the tables that the suspensions where coated dicloxacillin was used gave blood level values that could be compared with those obtained with suspensions where uncoated dicloxacillin was used.

Claims (1)

Process for coating an orally administrable, synthetic penicillin: ampicillin, hetacillin, nafcillin, oxacillin, cloxacillin, dicloxacillin or flucloxacillin or salts or mixtures thereof, characterized in that micronized particles of the penicillin are suspended in a solution containing ethyl cellulose and a pharmaceutically usable wax in an inactive, -volatile, organic solvent, after which the suspension is spray-dried and the resulting coated penicillin particles are recovered.