CA2085342A1 - Stable aqueous drug suspensions - Google Patents

Stable aqueous drug suspensions

Info

Publication number
CA2085342A1
CA2085342A1 CA 2085342 CA2085342A CA2085342A1 CA 2085342 A1 CA2085342 A1 CA 2085342A1 CA 2085342 CA2085342 CA 2085342 CA 2085342 A CA2085342 A CA 2085342A CA 2085342 A1 CA2085342 A1 CA 2085342A1
Authority
CA
Canada
Prior art keywords
drug
microspheres
coating
matrix
micrometers
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA 2085342
Other languages
French (fr)
Inventor
Milton R. Kaplan
Chel W. Lew
Catherine S. Lamb
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KALMO ENTERPRISES Inc
Original Assignee
KALMO ENTERPRISES, INC.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US53818390A priority Critical
Priority to US538,183 priority
Application filed by KALMO ENTERPRISES, INC. filed Critical KALMO ENTERPRISES, INC.
Publication of CA2085342A1 publication Critical patent/CA2085342A1/en
Application status is Abandoned legal-status Critical

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1617Organic compounds, e.g. phospholipids, fats
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005Wall or coating material
    • A61K9/5015Organic compounds, e.g. fats, sugars
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5026Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0087Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches

Abstract

Finely divided drug particles are coated with a lipid or bioadhesive polymer to form microspheres (226) having a particle size of about 550 micrometers or less, and coated with two or more enteric coatings, at least one of which is water insoluble, to form microcapsules. The resultant microcapsules can be suspended in an aqueous solution to form stable oral doses of the drug.

Description

WO91/19486 PCl'/US91/04198 ~,.'`.', 1 2~342 STABLE AQUEQUS DRUG SUSPENSIONS
This invention relates to aqueous suspensions of encapsulated drugs having improved stability and process for making such suspensions.
BACKGROUND OF THE INVENTION
Drugs such as amoxicillin, ampicillin, penicillin V and erythromycin are antibacterial drugs which are available for oral dispensation in a gelatin capsule containing a specified dosage amount of the drug. For patients who have difficulty swallowiny capsules, e.g., the very young and the very old, the drugs can be suspended in an aqueous solution, such as a sugar-type syrup. However, the drugs are quite unstable in water, even when stored at temperatures of about 4C, and very unstable at room temperature. Thus the drug solutions or suspensions have a very short shelf life, even at }ow temperatures. Further, they have an unpleasant taste which makes them unpalatable.
E3eta-lactam antibiotics are orally inactive, and must be combined with an enhancer to promote their absorption into the body of the patient. Such enhancers are known, for example see US Patent 4,525,339, and include aliphatic fatty acids or acid glycerides. The fatty acids are generally C2 to Cl8 fatty acids, which can be straight or branched chain, saturated or unsaturated, their mono--, di- or triglycerides or mixtures thereof, and can also be partial or total esters of propylene W O 91/19486 P ~ /US91/04198 ~,3~34~ ` i glycol, polyethylene glycol and carbohydrates of C2 to C1z fatty acids and pharmaceutically acceptable esters and ethers of said glycerides. Encapsulating the drug in the enhancer is known also.
It would be desirable to be able to formulate these drugs so that they would be stable to long te~m storage, i.e., for up to about 18 months, even at room temperature in liquid form. In order to do that, the drug would have to be coated uniformly and completeIy with a water-impervious coating. Further, in order for the drug to stay suspended in an aqueous solution or emulsion for administration in liquid form, the particle size of the coated drug particles would have to be very small, on the order of 1500 micrometers or less; otherwise the drug particles would settle out o~ the solution or suspension, and the dosage would be inaccurate.
A suitable coating or encapsulant material must be impervious to water, but must dissolve in the stomach or other appropriate portion of the digestive tract, depending on the drug to be administered and the dosage required, for absorption by the patient. Coatings having particular solubility characteristics can be used to provide controlled or delayed release o~ the drug in the patient.
Un~ortunately, no one encapsulant coating is known to date that is effective to carry out all o~ these objectives. Thus there is a need to be able to apply more than one encapsulant WO9l/19486 2 0 g ~ 3 ~ ~CT/V~9l/04198 material, successively and uniformly, over very small particle size granules of the drug to be administered. The preparation of small microspheres, i.e. having a particle size less than about 500 micrometers, microspheres containing the drug and then encapsulating them in a series of encapsulants,that would provide enhancement, taste masking, controlled release and protection from moisture would be highly desirable.
SUMMARY OF THE INVENTION
We have found that microspheres comprising drug par~icles which have a particle size of up to about 550 microns, coated with a matrix material of a lipid or a bioadhesive polymer, can be encapsulated uniformly and completely within mu}tiple coatings, at least one of which is impervious to moisture, to produce microcapsules which are insoluble in water at about neutral pH, but which are soluble at acid pH. The microcapsules have a maximum particle size of about 1500 micrometers so they will stay suspended in an a~ueous solution. The microcapsules can be tailored to have other features, such as successive layers of encapsulants having differing solubility characteristics.
The microspheres are made using high speed rotation, e.g., a rotatiny disc method, that forms uniform, spherical particles of the required size. The microspheres are encapsulated with two or more coatings having differing solubility characteristics. The resultant water impervious WO91/19486 ~ PCT/US91/04198 ~ 73~

microcapsules can be admixed with aqueous solutions to form stable suspensions or mixtures that have a long shel~ life in a concentration to provide dosage amounts of the drug that can be taken orally.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is a cross sectional view of a high speed rotating disc system for preparing the microspheres of the invention.
Figure 2 is a cross sectional view of a centrifugal extrusion apparatus also used for preparing the microspheres and microcapsules of the invention.
Figure 3 is a cross sectional view of an air suspension chamber for encapsulating the microspheres of the invention;
DETAILED DESCRIPTION OF THE INVENTION
The microspheres and microcapsules described in this invention can be prepared using a variety of methods, including but not limited to, a rotating disc system, spray drying, a centrifugal extrusion nozzle devicet an air susp~nsion cooler, phase separation and solvent evaporation. In the ~ollowing paragraphs some of the procedures that can be used to prepare the microcapsules described hereinafter are set forth in detail. Variations will be known to those skilled in the art.
Microspheres of the de~ired particle siza, i.e., less than 550 micrometers, and pre~erably between about 250 to 500 j ~ 20~53~2 micrometers, can be made using a high speed rotating disc system as shown in Figure 1.
Referring to Figure 1, the high speed rotating disc system 10 comprises an emulsion feed tube 12 which is situated over and feeds onto a rotating disc 14. The disc 14 is rotated by means of a motor 16. The disc 14 and the motor 16 are enclosed in a chamber 18. The chamber 18 serves to dry or cool and solidify the microspheres and to collect them in a collection area 20. The chamber 18 is also fitted with a filter lo 22 and an exhaust system 24. The disc 14 is situated some distance above the collection area 20 to allow time for solidification of the microspheres.
In operation, a slurry of the solid drug particles, which are finely divided below about 100 micrometers, and a suitable matrix, e.g., a lipid or bioadhesive composition, is fed to the feed tube 12 and dropped onto the rotating disc 14. ~roplets or microspheres are thrown out from the periphery of the disc 14 due to the centrifugal forces developed by the high speed rotation of the disc 14, and fall by gravity to the collection area 20 of the chamber 18. The small spherical liquid droplets or microspheres are dried/cooled and solidified during this free fall, and are then collected. If desired, the microspheres can be sieved to collect a desired particle size distribution.
For a disc about 4 inches in diameter rotating at about 2000 rpm, and a drug particle size of a~out 50 micro~eters, the WO91/19486 PCT/~S9~/041g8 3 ~ 6 majority of the resultant microspheres have a particle size of about lOS to 500 micrometers. Control of the rotational speed of the disc 14 provides control over the size and size distribution of the microspheres.
Alternatively, and particularly suitably for hot melt matrix materials, microspheres can be formed in a centrifugal extrusion apparatus 110 as shown in Figure 2. Referring to Figure 2, the feed mixture or slurry o~ drug particles in the heated matrix material is fed through the center tube of a concentric feed tube 112 by means of a seal (not shown) to a rotating head 114 fitted with one or more nozzles 116. A
rotating shaft 118 rotates the head 114 at high speed by means of a motor 119. A mechanical stirrer ~not shown) can be used in the ~eed tank (not shown) prior to pumping through the feed tube 112 to provide continuous stirring o~ the drug particles in the hot melt matrix. As the head 114 rotates, the slurry of the drug in the matrix material flows through the inner orifice of the nozz~e, creating a stream of the drug particles - uniformly dispersed in the molten matrix material. This extruded rod breaks into individual particles due to the high speed rotation o~ the head 114. The coated drug particles are cooled and solidify to form the desired microspheres as they free fall into the collection area 120. The size of the resultant microspheres can be controlled and is dependent upon the feed rate~ the speed of rotation of the head 114 and the WO9l/19486 PCT/US91/~4198 -~ 7 20~33~
size of the nozzle openings. Microsphere particle siæes o~ from about 250 to 500 micrometers can be made readily.
In order to form the microcapsules of the in~ention, the microspheres as prepared above are encapsulated in one or more water impervious coatinqs.
The microcapsules can be prepared using the apparatus as shown in Figure 2, except using an additional feed line into the head 114. The slurry of the drug particles in the heated matrix mat~rial is fed through the center tube of the 10 concentric ~eed tube 112. The desired encapsulant material and any additive~ are fed through a separate feed line to the outer tube 113 of the feed tube 112 to the head 114. The additional feed line is provided to supply the encapsulant material, e g., a water i~pervious polymer dissolved in a solvent, as well as 15 any optional materials desired such as colorants, flavorings, surfactants and other additives as desired. The slurry of the drug particles in the matrix material is fed along with the encapsulant material, to the head 114. The rotation of the head 114 causes the encapsulant or encapsulant mixture to flow 20 through the outer orifice of the nozzle and the drug slurry to flow through the inner arifice o~ the nozzle, creating a rod of the drug slurry encased in a sheath of the encapsulant matarials. I~ an organic solvent is used in the encapsulant, it i8 vaporized and can be collected through the exhaust (not 25 shown) ~or disposal or recycled as desired.

~a~ 3~ 8 ~~`

The microcapsules of the invention can also b~ made in a modified air susp~nsion coater apparatus as shown in-Figure 3.
The air suspension coater 210 comprises a chamber 212 fitted with an air distribution plate 216 through which an air atream passes. A feed line 220 for supplyiny the encapsulant material is connscted to a hydraulic or pneumatic nozzle 224 which atomizes the encapsulant material into small droplets which coat the microspheres.
In operation, the microspheres to be coated 226 are fed through an entry port 228 in the chamber 2~2. An air stream supplied by means of a blower is fed into the chamber 212 and ; passes through the air distribution plate 216 to carry the microspheres smoothly past the head 224 ~or coating with encapsulant, and then up and over a coating partition 230 where the coated microspheres are dried and cooled during free fall back outside the coating partition 230 to begin another cycle past the nozzle 224. The nozzle 224 is designed to atomize the coating material to allow a uniform, thin coating to be applied. In the course of multiple passes of the microspheres past the nozzle 224, the encapsulant material uniformly coats the microspheres to the desired thickness. By changin~ the encapsulant feed to the nozzle 224, successive layers of desired encapsulant compositions are applied~ Control of the air volume and temperature, atomizing conditions and rate of 2S application ensures a high degree of uniformi~y of the coatings IA ' ~ ' i 9 20853~2 .
from batch to batch. Further, the closed system of the apparatus 210 provides excellent control of the conditions within the coater.
The drugs useful herein can be varied, but those particularly useful include antibacterial drugs including erythromycin or erythromycin ethyl succinate, and the penicillins, their salts, esters and hydrates, such as amoxicillin trihydrate, ampicillin trihydrate, penicillin V
potassium and the like. These drugs are unstable in water. The drugs are supplied in solid form. If the drug is upplied in a larger particle size than de~ired, it can be milled to the appropriate particle size prior to coating with a lipid coating.
As used herein, the term lipid includes fatty acids, whether saturated or unsaturated, such as monobasic aliphatic carboxylic acids which form esters with glycerol or other alcohols to make fats, oils, waxes and other lipids. Also included are the esters and ethers of glycerides, the esters formed by reaction of the fatty acids with glycerol, such esters ~ormed ~rom pharmaceutically acceptable weak acids such as tartaric acid and its diacetyl derivative, acetic acid, ascoxbic aaid and citric acid, or one having a monophosphate group to yield the mono-phosphate ester. Suitable ethers are formed by reaction of the mono- or diglyceride with a functionally reactive lower alkyl, alkenyl, alkynyl, aryl or WO91/19486 3~, 1 o PCT/USgl/04l98 i `"`,, substituted aryl group to produce the corresponding pharmaceutically acceptable ethar, as is known in the art.
Polyhydric alcohols such as octanol or a carbohydrate polyol, e.g., sucrose, are also useful in the present invention.
The matrix material can also be a bioadhesive polymer that will provide a delayed release of the drug. ~he bioadhesive polymer attaches to the stomach lining or mucin coating of the stomach, where it hydrates and is absorked, thereby releasing the drug particles.
Suitable bioadhesive polymers include adhesive materials such as gelatin, polycarbophil polymers, and Chitosan, commercially available from Protan of Norway. These matrix materials provide a delivery system which may provide a lon~
ating dosage ~orm by providing a reduced rate of emptying of the drug in the stomach, improve bioavailability of the drug, improve therapy, and increase the contact time of the drug in the desired absorption area.
The microspheres are made into microcapsules by means of one or more enteric coatings. The enteric coatings can be tailored to have the drug absorbed in the body as desired, but at least one layer o~ enteric coating must be water insoluble at normal pH. Most antibio~ics are meant to be absorbed in the intestinal tract, and thus must be protected from the high acid content gastric fluid of the stomach. Thus successive coatings may be insoluble in highly acid environments, i.e., pH below 1,,'" .' ' . ' ' WO9~/19486 PCT/US9l/04~98 fr~~l 1 1 2~53~

about 5, but soluble in less acid environments, i.e. pH about 5.5 to 7.5 or higher~
Examples of known enteric coating materials useful herein include cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, shellac, methacrylic acid and methacrylic acid esters and zein. Partially hydrogenated vegetable oils, stearic acid, hydrogenated tallow triglycerides, food grade metal stearates, tallow and mixtures thereof, and the like are used as lipids, carriers and modifiers for the microspheres. Suitable partially hydrogenated vegetable oil material is commercially available as Durkee 17 and Durkee KLX from Van den Burgh. Emersol 6349 stearic acid is commercially available from Emory Industries. Hydroqenated tallow triglycerides are commercially available as Grocol 600-E from A. Gross and Co. Suitable tallow flakes are commercially avaiIable from Anderson Clayton/Hank Products, Inc. A series of methacrylic acid or methacrylic acid esters commercially available as EudragitT~ coatings, trademarks of Rohm Pharma GmbH of Westerstadt, West Germany, have varying degrees of esterification, and are soluble at varying pH. ~hus drugs which are meant to be absorbed in the small intestine will be encapsulated in a first enteric coating that is insoluble in water but soluble in acidic environment, e.g., the sto~ach, and a second enteric coating which is insoluble in the ~ 12 low pH gastric fluid of the stomach, but æoluble in the less acid environment of the small intestine. For example, EudragitT~ E-100 is insoluble at neutral pH but soluble at a pH
less than 5.5; EudragitT~ 1-100-55 and L-30D are soluble at pH
greater than 5.5. Metal stearates incorporated into these shell materials can increase water repellency. Other enteric coatings are known which are less soluble and can provide release of the drug over time, as will be known to those skilled in the art.
To provide both water impermeability, protection of the drug in the stomach and release in the intestine, and delayed release in the intestine, a series of enteric coatings will be applied to the microspheres. The outer layer will be water insoluble at normal pH, but will dissolve in the stomach (pH
less than 5.5~. The next layer will be insoluble at low pH in the stomach, but will dissolve and release the drug in the intestine (pH greater than 5.5). A third layer can provide delayed release until the drug enters the upper gastrointestinal tract, where the pH is higher again.
The enteric coatings are dissolved in an organic solvent, suitably one appxoved for medicinal use, such as acetone, methylene chloride, or the lower alcohols such a ethanol, or mixtures of such solvents, and applied to the microspheres as above. The organic solvents are removed by evaporation during the processing of the microcapsules.

.

, .

~ 3 2~53q~

The amount of coating applied to the microspheres is not critical, and can vary from 5 to 30% by weight o~ the microcapsule. It is important that the enteric coating be applied uniformly over the microsphere to ensure that the microspheres are protected from moisturel and that a given dosage of the drug will be released by the coatings at the appropriate portion and time in the digestive tract. Too thick-a coating will delay dissolution of the coating and release of the drug.
The enteric coatings can a1so contain conventional additives such as suspending agents, emulsifying agents, essential oils, preservatives, flavoring or coloring agents and the like, as i5 known to one skilled in the art. Such additi~es can retain a desired texture, retard hydration or dehydration of the microsphare ingredients, and provide a uniform color and appearance.
The invention will be further described in the following examples, but the invention is not meant to be li~ited to the details thereof. In tha examples, percent is by weight.
The actual erythromycin and ery~hromycin ethyl succinate content of the microspheres was determined by high pressure liguid chromatography (HPLC).
Actual amoxicillin trihydrate content in the microspheres was determined using an iodimetric titration method, see Code `3 . of Federal Regulations: Food and Drugs, Vol 21, Chap 1 Part 436.204 (1988), 291.

Using the rotating disc apparatus of Figure 1, a slurry containing 30.0% of Erythromycin USP, 44.1 % of Emersol 6349, 18.9~ of Durkee 17 and 7.0% of aluminum stearate EA was heated to 180F and fed to the disc maintained at a temperature of 160~F.
The resultant microspheres had a particle size ' 10 distribution of 4.3% particles of less than 105 microns; 84.9 : particles of 105-250 microns; and 10.8~ particles of 250-355 micrometers.
~n assay of the microspheres having a particle size of 250~355 micrometers determined the actual Erythromycin content to be 20.9%.

The procedure of Example 1 was followed except varying the matrix composition and temperature. In these Examples, 30.0% of Erythromycin was employed. The data summarizing the matrix composition, the matrix temperature, particle size and weight % distribution obtained and the actual Erythromycin content in the microspheres are summarized below in Table I~ In the Table, D17 represents Durkee 17 E6349 represents Emersol 6349, G 600-E represents Grocol 600-E; Zn St represents food grade zinc stearate; Mg St represents food grade magnesium WO91/lg486 P~T/~S91/Q4198 , 15 2Q8334~

stearate: Al St represents food grade aluminum stearate; and A
84K represents Atmul 84K.

~ ~ ;

' WO 91/194~6 PCT/VS91/04198 3~, 16 ~. `i ' e ~ O ~O

L~

o~
,1 ~ q O q O q q q ul q ~ q ~J q ~ :
L~ ~ ~J o u~ o ~ u~ o ul o o u~ o u~ o It~ o E ~¦ ~ u~ u-) o o o o o v c: ~ o ~ o V~ ~ o U~
c I~ o ~ ~ d ~ ~`

.' ~ c ~ ~ ~t ~ K ~ ~ C K
o o ~o ~ t`i r~ o ~ I~ oo 1~ ~) ~ o ~1 n a ~
- .

WO 91/1~486 P~/US91/04198 ~7 2~a~2 ~`

U
U`~
~ o V rC
e ~

o oo O O ~ x o~
--K ~ o ~ r~r~ ~ o~ ~ ~ ~ co ~D

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O O O u~ ~ O U~0~ O O O

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.

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r~ ~ or~ r~ ~ I~

o o ~ ~o oo o o o o - ~ - o r~ o 1 _~
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All of the microspheres were satisfactory.

: 5 The procedure for Examples 2-13 was followed except using 23% of Erythromycin. The data are summarized in Table II below, where the symbols are the same as for Table I.

WO 9l/19486 PCI'/US91/0~198 i~, 1 9 ~S3~2 ~BL~ II

Pa~ticle MatrlY Te~np. Size, Weight E~ le Co~po~ltiQIl~ DF Micromet~rs X
1456.0Z E6349 190 105-250 15.9 ~- 14.0X G600-E 250-355 63.5 7.0% Zn St 35S-500 20.6 1552.5X E6349 190 105-250 39.9 17.5% D17 250-355 60.1 7.0% Z~ St 1670.0% D17 190 105-250 23.9 7.0X Zn St 250-355 76.1 1756.0X E6349 190 105-250 30.4 ; 14.0% G600-E 250-355 59.8 7.0X Al St 3S5-500 9.8 1852.5% E6349 190 105-250 67.1 17.5X D17 250-355 32.5 7.0X Al S t 1970.0% D17 190-200 C105 8.2 7.0X A1 St 105-250 46.9 250 355 44.9 2056.0% E6349 190 105-2S0 67.0 14.0X G600-E 250-355 33.0 7.0% Mg St 2152.5% E6349 190 105-250 58.9 17.5X D17 250-355 41.1 7.0 Mg St 2270.0X D17 190 105-250 10.4 7.0% Mg St 250-355 71.4 355-500 18.2 . ` :. ' , - ' ' ;, ' ' . . .

WO91/19486 ~ PCT/U591/~4198 ~S~ ~ ~' 20 All of the microsp~eres were satisfactory.

Using the apparatus of Figure 2 at a head speed of 2000 rpm, a head temperature of 190F and a shell composition temperature of 180F, a slurry of the drug in a matrix material was encapsulated with a single layer of various encapsulant compositions to produce microcapsules. Equal amounts by weight of the drug slurry and encapsulant were employed; thus the theoretical amount of Erythromycin was 15% in the microcapsules, which were sieved to collect a particle size of 250-500 micrometers for analysis. The data are summarized in Table III below where the symbols are the same as for Table I
and N 060 represents Neutrene 060 triglycerides.

W O 9l/19486 PCT/US9l/04198 , .

2 1 2~ 2 :
T~BL~ III
,`
Encapsulant Slurry Actual X
Example Com~osition Comso~ition Erythr mq~_n :
23 90Z D17 Ex3 8.7 lOX Zn St :.
24 80% E6349 EY3 9.5 80% E6349 ~s2 5.4 20% G600-E

26 100% D17 EY2 6.1 `:
27 90% D17 Ex2 5.6 10% Zn St 28 90% D17 Ex2 6.1 10% M8 St 29 lOOX D17 Ex3 90% D17 Ex3 lOX Mg St 31 80% E6349 56.0X E6349 6.7 20X N060 14.0X N060 30% Erythro~ycin 32 100% D17 56.0X E6349 14.0% ~060 30% Erythromycln 33 90% D17 56.0Z E6349 10% Zn St 14.0% ~060 30% Eryehromycin 34 90% D17 56.0% E6349 10% Mg St - 14.0% ~60 30X Erythromyci~

WO91/lg486 PCT/~S91/04198 ~ b~ 22 ` ~'~.,'~.!
.

Using the apparatus of Figure 3, the microspheres - prepared as in Examples 1-22 were encapsulated with two or more layers of various encapsulant co~positions to produce microcapsules. The enteric coatings were dissolved in a solvent mixture, as shown, to which was optionally added a dyestuff, FD&C ~l Lake Blue, or FD&C #6 Lake Yellow. EudragitT~ E-lO0 provides stability in liquid suspension and in the mouth, ~pH
about 7) and is soluble in the stomach tpH less than 5.5).
EudragitT~ L-100-55 will provide protection in the stomach and release the drug in the intestinal tract (pH over 5.5).
The data relating to the application o~ the coatings are summarized in Table IV below.

. . .

WO 91/19486 PCI/US9~/04198 i 23 2 ~ 3 ~ 2 '1 C N `O ~ 1~ ~ U'l N O O O ~CI P') ~
O ~--1 ~ N N N ~ ~ ~ N ~ , N e~ N
:E

O O O O O O . O O O O O O O O
r~ _~
O _ ~:) '# . O O O O O O O O O O o o _~ O O O
V _ ~J N N
.C ~
O~

3 o oo ~ o o o o o o o o o o o o o o o o o o o o o O ~ `O ~ ~ ~ N ~JN N N N ~ N N N N N N N N ~i N N

~ U ~ .
O ~ ~I O ~`I O O O O O O O O O O O O O O O O O O O O O O O
O ~ ~ 1 ~ N 1~ N ~ t~N N t~ 1 N t~ ~`I N ~ ~`J
U
V ~
~ ~ O
C~ 00 C
_1 .
~V~
0 0 ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~

O~
~ a ~ ~ ~ ~ ~ ~ ~ x ~ ~ ~ ~ ~
K
~: .

q 1~ O _I Nt~) ~ It~ `O 1~

.

W O 91/19486 P ~ /US91/~4198 24 ~.;

The data relating to the amount of the coatings applied is given below in Table V. where the result was obtained from a measurement of the amount of shell solution per weight of microsphere sample used during the coating process. The resultant microcapsules were in the 250 to 500 micxometer size range.

.

;

.

U'O 91/19486 PCT/US91/04198 I .ç~ 25 TABLE v 2 ~ 3 ~ 2 Weight x Shell E~camPle Inner ~Outer 36 14 . 013 . 9 43 13 . O13 . 3 44 13 . O13 . 8 13.013.2 46 13 . 013 . 1 47 13 . 013 . 6 .

Microcapsule samples made as in Examples 35-47 were evaluated for stability in simple syrup solution by storing for l and 4 weeks under accelerated shelf-life conditions at 37C.
The amount of antibiotic found in the syr~p was determined. The data are summarized below in Table VI.

W O ~1/19486 2 7 PCT/US9~/04198 " 1: .
: . TABLE VI 2 Q 3 a 3 ~ ~

Mlcrocapsules, X Release X Relea~e mD1e1 week 4 week~

<1.0* 6.2 36 0.11 2.4 : 37 <1~0* 2.5 ; 38 <1.0~ 2.5 39**<1.0* 3.0 ~-97 2.6 41 0.74 2.0 42 1.3 2.9 43 0.76 3.1 44 0.74 2.0 0.81 2.2 : 46 0.74 1.9 47~*0.64 1.6 Estlmated ~* rhese samples were then ~haken a~ 37C for 48 hours. The X release for Example 39 wa~
3.6%; the X release for Example 47 wa~ 1.8Z.

WO91/19486 28 PCT/US91/~4198 f ~ ~
3~
It is apparent that the microcapsules of the invention are stable in aqueous solution for long periods of time, even under accelerated temperature conditions.
EXAMpT~ 49 PART A. Microspheres were made following the procedure of Example 1 u~ing 40.0% of erythromycin ethyl succinate within a 69% Durkee 17 matrix. The matrix temperature was 235F.
The product contained 39.4% of particles 106-250 micrometers in size; and 60.4% of particles 250-355 micrometers in size;
The actual amount of the antibiotic found in the microspheres was 3I.2%.
PART B. The procedure of Example 35 was followed to make microcapsules of the microspheres of Part A. The first coating was made using EudragitT~ L-3OD and a second coating of Eudragit~ E-lOO using a solvent mixture of 72.0 parts of methylene chloride and 24.0 parts of ethanol. The microcapsules contained 20.0~ of erythrocmycin ethyl succinate.

The procedure of Example 1 was followed to prepare microspheres except that the drug employed was amoxicillin trihydrate in varying amounts. The data on microsphere preparation is summarized below in Table VII.

~ W O 91/194B6 PC~r/US9~/04198 ~ ; 2 9 2 0 8 53 ~
v 0 ~ o V ~ V
~ ~ ~ .
E~ ~ ~ .
1:: L V
_~ _ U ~
X L O O O O O O
r~
X

V
0~ O ~ O ~ O
K o u~ ~t o r~ ~ o o~ o C~
~ ~ ~ U~ o U~ U~ o U~ o U'~
P1 ~ ~, E , 1, ~ ~, ~, , N ~ o ~n o o `D o ~o o o o u ~ o ~ o u~ In D O O O O O O
~ ~ r~ o o _ o o E~ ~ _ o~ , .
.Y

C~
~ ~ V ~ o o ~ U~
0 i~
a c: Q ~
13 ~ K K K K o K o o oo r~ o ~ ~
q~ o ~o ~o 'D

Eil o ~ t U~
X ~ U'~

- WO91/194B6 P~T/US91/04198 ~ . 30 The microspheres as in Examples 50-55 were encapsulated following the procedure of Example 35. The data relating to the encapsulations are summarized in Table VIII below:

~,, ;
i , WO ~1/19486 PCl[/US91/0~198 3 l 2~353~2 o~ o ` ,~
I ~1 1 1~
o o o o O _~ ~ _1 ~: ~
o o o o ,~ L O O O O O
V C ~ ~ ,~

vl o ¢l O
~ O O O O O O O O
.C ~-t ~ ~ ~ ~J ~ ~ ~
:~~1 ~CO~ O O
L '~I ~ O O
.,1 ~
3 w X ~J~
e o~ c ~ ~ ~ ~ ~ ~
~ 14 ~: ~4~
a oo C
_ W' _ E o O K ~ ~ 1~ u~

~;
E ~o r~ o , ~ u~

. .

WO91/19486 ~ PCT/US91/04198 ~ ~ 32 ¢ !

EXA~PT.F. 6 1 - The microcapsule samples made as in Example 56 using the microspheres as made in Example 50 were evaluated in simple - syrup solution by storing for one, four and eleven weeks under accelerated shelf life conditions at 37C. The amounts of antibiotic found in the syrup after vigorous shaking is as follows: 0.0% release after one week; 3~1% release after four weeks and 26.5~ reiease after eleven weeks.
It is apparent that the microspheres of the invention can be encapsulated with multiple coatings as desired using the processes of the invention. The resultant microcapsules are small in size, are water impervious, and can be tailored so that the drug is protected in aqueous solutions, and can be released as desired, and when desired, to optimize the drug's e~ectlveness. The invention also provides a means of dispensing a water unstable drug in an aqueous solution that is stable and which can be stored at room temperature for extended periods of time.

Claims (18)

1. A microcapsule comprising a microsphere core particle comprising a solid drug particle in a matrix of a lipid or bioadhesive polymer encapsulated in two or more enteric coatings, at least one coating being impervious to water, said microcapsules having a particle size of 1500 micrometers or less.
2. A microcapsule according to claim 1 wherein said drug is selected from the group consisting of erythromycin or erythromycin ethyl succinate.
3. A microcapsule according to claim 1 wherein said drug is a penicillin.
4. A microcapsule according to claim 3 wherein said drug is selected from the group consisting of ampicillin, amoxicillin, and penicillin V, their salts and hydrates.
5. A microcapsule according to claim 1 wherein said matrix is a lipid.
6. A microcapsule according to claim 1 wherein said matrix is a bioadhesive polymer.
7. A microcapsule according to claim 1 wherein said one coating is insoluble in water at neutral pH and soluble in fluid having a pH of less than 5.5.
8. A microcapsule according to claim 7 wherein a second coating is soluble in fluid having a pH of more than 5.5.
9. A microcapsule according to claim 1 wherein the microsphere core particle comprises a solid drug particle in a bioadhesive polymer matrix encapsulated in two or more enteric coatings, at least the outer coating being impervious to water.
10. A microcapsule according to claim 1 having a particle size of from about 250 to about 550 micrometers.
11. A microcapsule according to claim 1 wherein said microsphere has a particle size of from about 105 to about 500 micrometers.
12. A microcapsule according to claim 1 wherein said microsphere has a particle size of from about 250 to about 355 micrometers.
13. A method of making microspheres which comprises a) admixing solid drug particles having a particle size of less than 500 micrometers with a matrix of a lipid or a bioadhesive polymer to form a slurry, b) forming microspheres having a drug core and a matrix coating thereon having a particle size of between about 105 to 500 micrometers, and c) solidifying said microspheres.
14. A method according to claim 13 wherein said forming comprises dropping said slurry onto a disc rotating at high speed whereby said slurry is divided into droplets.
15. A method according to claim 13 wherein said forming comprises extruding a drug particle slurry in a matrix material of a liipid or bioadhesive polymer through a nozzle rotating at high speed.
16. A method of making microcapsules which comprises encapsulating the microspheres of claim 10 with two or more enteric coatings, at least the outer one of which is water insoluble.
17. A method according to claim 16 wherein the outer coating is water insoluble at neutral pH but is soluble in a fluid at a pH

below 5.5 and the inner coating is soluble in a fluid having a pH over 5.5.
18. A stable medication comprising a sugar syrup containing a suspension of the microcapsules of claim 1.
CA 2085342 1990-06-14 1991-06-13 Stable aqueous drug suspensions Abandoned CA2085342A1 (en)

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US5160742A (en) * 1991-12-31 1992-11-03 Abbott Laboratories System for delivering an active substance for sustained release
SE9201930D0 (en) * 1992-06-24 1992-06-24 Astra Ab Gastric antibacterial treatment
AT403988B (en) * 1994-05-18 1998-07-27 Lannacher Heilmittel Solid oral sustained-release
AU719137B2 (en) * 1996-05-07 2000-05-04 Mayne Pharma International Pty Ltd Taste masked liquid suspensions
AUPN969796A0 (en) 1996-05-07 1996-05-30 F.H. Faulding & Co. Limited Taste masked liquid suspensions
DE19648576C2 (en) 1996-11-23 1999-08-12 Lohmann Therapie Syst Lts Lozenge modified release of active ingredients in the gastrointestinal tract
DE19706979A1 (en) * 1997-02-21 1998-08-27 Lindopharm Gmbh Combination preparation for orally administered erythromycin
US6197331B1 (en) 1997-07-24 2001-03-06 Perio Products Ltd. Pharmaceutical oral patch for controlled release of pharmaceutical agents in the oral cavity
DE19741114C2 (en) * 1997-09-12 2002-10-24 Riemser Arzneimittel Ag Moisture Stable and enteric dosage form for fish
EA200001109A1 (en) * 1998-05-20 2001-06-25 ДЗЕ ЛИПОСОМ КОМПАНИ, Инк. New particles, the composition thereof and method of treating with their application
SI20244A (en) * 1999-05-19 2000-12-31 LEK, tovarna farmacevtskih in kemičnih izdelkov, d.d. Melt granulation
EP1333807A4 (en) * 2000-10-13 2005-06-29 Advancis Pharmaceuticals Extended release erythromycin derivatives
EP1390024A4 (en) * 2001-05-11 2010-02-17 Merrion Res Iii Ltd Isostearic acid salts as permeation enhancers
US20030124196A1 (en) 2001-08-22 2003-07-03 Susan Weinbach Pulsatile release compositions and methods for enhanced intestinal drug absorption
WO2003084517A2 (en) 2002-04-09 2003-10-16 Flamel Technologies Oral suspension of amoxicillin capsules
CA2480826C (en) 2002-04-09 2012-02-07 Flamel Technologies Oral pharmaceutical formulation in the form of microcapsule aqueous suspension allowing modified release of active ingredient(s)
FR2843880B1 (en) * 2002-09-02 2006-06-02 Flamel Tech Sa oral pharmaceutical formulation in the form of aqueous suspension of microcapsules allowing the modified release of amoxicillin
DE10260921A1 (en) * 2002-12-20 2004-07-01 Röhm GmbH & Co. KG A method for coating substrates for pharmaceutical applications with a mixture of two film-forming coating compositions
US20070098746A1 (en) * 2005-11-02 2007-05-03 Nichols William M Multi-layered coating technology for taste masking
GB2569119A (en) * 2017-12-05 2019-06-12 Rainbow Valley Nutrients Ltd An aqueous beverage containing microencapsulated food supplement

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JPS6232166B2 (en) * 1983-06-15 1987-07-13 Shionogi & Co
US4849227A (en) * 1986-03-21 1989-07-18 Eurasiam Laboratories, Inc. Pharmaceutical compositions

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