|Número de publicación||US2928770 A|
|Tipo de publicación||Concesión|
|Fecha de publicación||15 Mar 1960|
|Fecha de presentación||28 Nov 1958|
|Fecha de prioridad||28 Nov 1958|
|Número de publicación||US 2928770 A, US 2928770A, US-A-2928770, US2928770 A, US2928770A|
|Inventores||Bardani Frank M|
|Cesionario original||Bardani Frank M|
|Exportar cita||BiBTeX, EndNote, RefMan|
|Citas de patentes (8), Citada por (80), Clasificaciones (9)|
|Enlaces externos: USPTO, Cesión de USPTO, Espacenet|
March 15, 1960 F. M. BARDANl SUSTAINED ACTION PILL Filed Nov. 28, 1958 INVENTOR. FRANK Mv BARDANI WW,ALHM
ATTOF/VEVJ' United States Patent l SUSTAINED ACTION PILL Frank M. Bardani, Plainview, N.Y. Application November 28, 1958, Serial No. 777,131
8 Claims. (Cl. 167-82) This invention relates to pills which sustain medication of the alimentary canal over extended periods of time.
Medication for the purposes of combating diseases, acting on the nervous system or affecting the body in any manner may be accomplished orally or by injection. The oral method is preferred in most instances because it enables self-medication of the patient.
Oral medication may take the form of powders, tablets, capsules, pills and the like. Because of the strong taste of many medicaments and the necessity for releasing them within selected portions of the alimentary canal; i.e., the stomach and intestines, pills are favored for medication in many circumstances. Generally pills have been formed by protecting a medicament with a desired coating to facilitate ingestion and passage into the alimentary canal. The coating used was chosen to effect medication of a desired portion of the alimentary canal. When medication of the stomach was desired, the coating was formulated to resist fluids encountered in the mouth and during passage into the stomach. The gastric fluids there encountered disintegrated the coating and rapid dissolution of the medicament followed.
When it was necessary to release medicament in the intestines, so-called enteric coatings unafiected by stomach fluids were used to ensure passage of such medicament through the stomach to the intestines. Such enteric coatings when immersed in intestinal fluids were attacked and disintegrated or destroyed and the medicament quickly released. I
Sudden release or dumping of large quantities of medicament into the alimentary canal is most undesirable. First, the body cannot absorb large quantities of medicament in a short interval and much will be wasted. Second, and of greater concern, release of too great a quantity of medicament can place the patient in a condition of shock, and cause injurious side effects.
Attempts to provide sustained medication in the gastrointestinal tract have included the use of great numbers or individual granules or pillets coated to release medicament at varying times. Difiiculties have been encountered because of the necessity of timing the granules to release over a long period. If an excessive num er of granules released medicament simultaneously rather than sequentially, overdo-sage resulted rather than a sustained therapeutic effect.
Pills have also been used first to release medicament in the stomach and then, after being passed to the intestines, to provide medication therein. The time a pill remains in the stomach varies greatly and may be from under one-half hour to two or more hours. If a pill is designed to release medicament into the stomach a few minutes after ingestion with the assumption that it will be passed along in an hour to the intestines to release further-medicament, and the pill is thereupon passed within one-half hour to the intestines, the patient may be subjected to a double dose with injurious results. On the other hand, if the pill is retained in the stomach 2,928,770 Patented Mar. 1 5, 1960 for two hours and then passed to the intestines, the time interval between release in the stomach and in. the intestines may be so great as to provide an interval without medication.
In an attempt to remedy this situation, pills have been designed to release medicament in the stomach about one-half hour after ingestion. If such pills are passed into the intestines before release of the stomach dose, a double dosage of medicament is released directly to the intestines with possible bad efiects on the patient. 7
The present invention provides pills which release medicament in the alimentary canal over a wide range of desired periods to sustain medication for long intervals. Such release enables the body to absorb and use far greater percentages of the medicament than if single larger doses were administered, thereby greatly increasing the etliciency of medication. Moreover, sustained medication of the alimentary canal eliminates injurious side effects resulting from the dumping of large quantities of medicament into the system. The impact of the drug is not made on the body during a relatively short interval, as in the past, but is distributed over the period of its release, thereby facilitating use of the drug by the system.
Sustained medication pills in accordance with the principles of the present invention are formed of layers of medicament separated by control coatings. Each coating includes a porous membrane, initially having a substance closing its pores, to control the flow of alimentary fluids therethrough to the medicament. The time each coatin withstands the fluids before becoming porous and the rate of flow of fluids through the coating is determined by its composition and the manner in which it is formed on the medicament layers. Moreover, the time over which medication must be sustained determines the number of layers of medicament and the number of control coatings or membranes interposed between such layers.
Upon subjection of the sustained action pill to alimentary fluids, the material closing the pores is gradually removed and fluids flowing through the resultant permeable membrane leach medicament therethrough. Before complete dissolution of one medicament layer, the next coating is wetted by the fluids to initiate opening of its pores. During the release of medicament, the control coating or membrane remains intact until at least the medicament thereunder is dissolved and passed into the alimentary canal.
One form of sustained action pill according to the invention provides medication in both the stomach and intestines. The coating used in the stomach is of a different composition from that used in the intestines, due 'to the acidity of the stomach and alkalinity of the intestines. This pill medicates the stomach while it remains therein. Passage of the pill to the intestines results in dissolution of the stomach coating or coatings by the intestinal fluids which then initiate leaching of the remaining layers of medicament through the intestinal control coatings into the intestines. The first medicament released may stimulate the stomach to empty into the intestines, and such pill may then act as as a laxative in the intestines. The pill bars exposure of the two different drugs to each other which precludes 7 a number of the inventive pills into a capsule, larger pill or tablet. A patient may then ingest a selected number of sustained action pills in convenient form, the small pills or pillets medicating the gastro-intestinal tract over an extended period.
These and further objects and advantages of the present invention will be more readily understood when the following description is read in connection with the accompanying drawings, in which:
Figure l is an elevation, partially broken away, of a pill formed in accordance with the present invention;
Figure 2 is a view in perspective, partially broken away,
of a tablet containing a plurality of the pills of Figure 1; Figure 3 is an elevation of a larger pill, partially broken away, containing a plurality of the pills of Figure' 1; and ,.:.";Figure'4'is an elevation of a capsule, partially broken away, co'ntaining'a plurality of sustained action pills. Referring to an illustrative embodiment of the invention with referenceto Figure l, a pill -is formed of aplurality of layers of medicament separated by control coatings. An outer layer of medicament 11 for medica- [tion of the alimentary tract surrounds the pill 10. A sugar coating or thin polished wax layer may be placed over the layer 11, if desired, in accordance with conventional practice in the pill manufacturing art.
The term medicament used herein refers to any substance that it may be desirable to release for medication in the gastro-intestinal tract for any purpose. For example, pills formed in accordance with the invention may include antibiotics such as the following: penicillin, Tetracycline, Terramycin, Aureomycin and Chloromycetin; sedatives and hypnotics, as follows: pentabarbital sodium, phenobarbital, secobarbital sodium, codeine, Bromisovalum, carbromal and sodium phenobarbital; hypotensives and vasodilators, as follows; pentaerythritol, erythrityl tetranitrate and nitroglycerin; amines as follows: dl amphetamine sulfate and dextroamphetamine sulfate; hormones as follows; Dienestrol, Diethyl ,stilbestrol, Methyltestosterone and Progesterone; cortisone; vitamins; and tranquilizers as follows; reserpine, chlorpromazine hydrochloride and thiopropazate hydrochloride. 4 Immediately beneath the layer 11 is a coating or control membrane 12 to control the flow of alimentary fluids to a medicament layer 13. The coating 12 consists of a thin composite membrane including pores initially closed by a suitable substance. Alimentary fluids act on the coating to remove after a period of time sufficient amounts of the closure substance from the pores to render the coating permeable. The resulting permeable membrane controls the flow of alimentary fluids to the medicament layer 13. Such fluids dissolve the medicament and leach it out of the pill 10 through the permeable membrane.
The coating 12 must be tough enough to withstand agitation and abrasion in the alimentary canal without rupturing which would permit sudden release of the medicament layer 13. Instead of sudden release by the pill 10 of all of its active ingredients into the alimentary tract within a minute or two after exposure to alimentary fluids in the manner of ordinary pills, which use protective coatings that disintegrate or rupture before or during release of the medicament, the control coating 12 remains intact after its pores have been opened to control release of medicament from the single layer 13.
Before the layer 13 is wholly leached through the permeable membrane, formed from the coating 12, into the gastro-intestinal tract, the alimentary fluids wet a further coating 14 and initiate removal of its pore sealing substance to render it permeable. Fluids passing through the coatings 12 and 13 then leach medicament out of a further layer 15. Inthis manner medication of the gastro-intestinal tract by the pill 16 may be suatt il ed over any desired period limited only by the length of time the body retains the pill.
Extensive use has been made of membranes that provide controlled release of medicament .in the alimentary canal for about one hour. For example, the membrane withstands fluids for about 45 minutes before becoming permeable and then provides release of medicament for about 15 minutes. Accordingly, if six layers of medicaments are separated by one hour control coatings, such pill will provide effective medication of the alimentary canal for about 6 hours. As pointed out hereinafter, by suitably varying'the composition and thickness of the coatingsand the manner of forming such coatings, release of medicament may be controlled by each coating for greater or lesser periods.
Assuming the use of control coatings or membranes in the pill of Figure 1 that each provide medication for one hour, subsequent to dissolution of the outer layer 11 .of the. pill 10 the five coatings will provide release ofthe five medicament layers during a 5 hour period.
Formation of the permeable membrane after the alimentary fluids wet thecoating appears to follow a swelling action of the film or membrane material together with a softening, weakening and at least partial dissolution of the pore closure substance. Such swelling seems to break the softened closure substance out of the membrane pores. Body temperatures apparently assist this action. The coating 12, after exposure to alimentary fluids, has the physical characteristics of a very fine mesh screen which passes alimentary fluids in con-trolled fashion to the medicament. Moreover, the coating 12 re mains intact and functions to control the passage of alimentary fluids at'leastuntil its corresponding medicament layer is released to the alimentary tract. Sudden release of medicament and overdosage is thereby avoided.
Tests have shown that medication is much more efficient and effective when applied over an extended period. The body absorbs a far greater percentage of medicament released in this manner than if the same amount of medicament found in the several layers of the pill were dumped suddenly into the alimentary canal. Moreover, dumping or sudden release of medicament can shock the system and res ult in serious side effects.
If medication of the stomach and intestines is required, the pill 10 of Figure 1 may be formed of medicament and coatings for use in the acid fluids of the stomach and the alkaline fluids of the intestines. The medicament layer 11 will be released immediately to the stomach or, if omitted, as is often the case, gastric juices wetting the coating 12 will open its pores and the resultant permeable membrane will control fluid flow to the medicament layer 13. For example, the coating 12 may comprise a porous film of cellulose acetate phthalate (obtainable from Eastman Kodak Co. in powder form and mixed andcoated as set forth hereinafter) together with beeswaxblocking its pores.
To form an exemplary coating 12, a solution may be prepared from cellulose acetate phthalate and beeswax in a vehicle of acetone in such proportions that a thin coating on the medicament will, after immersion in stomach fluids, form a permeable membrane controlling the'flow' of fluids therethrough. The medicament 13 beneath the permeable membrane is subsequently leached through the membraneinto the stomach while the membrane remains intact.
For example, a film comprising from to by weight of cellulose acetate phthalate and from 5% to 20% by weight of beeswax has been found to provide a satisfactory membrane 12. Such coating may be pre pared by dissolving those components in a solvent such as acetone. The solution may also contain, in place of beeswax, carnuba wax, for example from 10 to 30%. The cellulose acetate phthalate-wax solution is then coated on the medicament layer 13 as described in detail e einafter to form a coat ng controlling the release or medicament. The coating 12- is very thin having the approximate thickness of thin onionskin paper.
An exemplary cellulose acetate phthalate solution com prises 300 grams of cellulose acetate phthalate and 30 grams of beeswax dissolved in 1500 cc. of acetone, the resulting solution being disposed on the medicament layer 11 by conventional coating methods to form the control coating 12. The solids concentration of the coating solution may be varied to determine, to some extent, the thickness of the coating 12. Moreover, the number of times the solution is coated on the pills also determines the coating thickness. In turn, the coating thickness is one factor determining the timing of release of medicament by the stomach fluids. The thicker the coating, the longer it will withstand the stomach fluids before becoming permeable and releasing medicament in a controlled manner to the stomach. Such release also depends on the composition of the coating, the solubility of the medicament and the manner of applying and heat treating the coating.
In use, the pill is ingested into the stomach and the outer medicament layer 11 dissolves rapidly in four or five minutes. The outer layer 11 may be omitted if the pill must reach deep within the stomach before release of medicament. Exposure of the coating 12 to gastric juice causes swelling of the cellulose acetate phthalate film and the softened wax is accordingly broken out of its pores. Stomach fluids pass through the permeable membrane, dissolve the medicament 13 and leach it out of the pill 10 for medication of the stomach. V
In controlling release of the medicament layer 13, the coating 12 impedes the flow of stomach fluids and maintains medicament release for a longer interval than if the layer 13 were exposed directly to stomach fluids. For example, medicament may be released from the pill for a minute period following a minute period of exposure to stomach fluids. In addition, the coating 12 is tough enough to withstand agitation and abrasion in the stomach.
It has been found that, other factors being equal, if the percentage of beeswax in the coating solution is increased, the period that the control coatings withstand exposure to stomach fluids before becoming permeable is decreased while a decrease of the amount of wax in the coating solution results in the opposite effect.
Preferably, the control coating 12 and any further coatings that may be used to release medicament in the stomach are formed of materials that will dissolve in the alkaline intestinal tract when the pill proceeds to the intestines from the acid stomach. Upon entry into the intestines, a second type of control coating or membrane 14 is exposed to the fluids therein, such coating also forming a permeable membrane to control the flow of intestinal fluids therethrough to provide medication in the intestines. H
A n exemplary coating 14 is formed of ethyl cellulose and shellac in such proportions that a thin coating becomes permeable by intestinal fluids. A coating comprising about 70% to 95% by weight of ethyl cellulose and about 5% to 30% by weight of shellac, for example, provides satisfactory results. These percentages are varied in accordance with the time the membrane must withstand the intestinal fluids, the coating thickness, the solubility of the medicamentand the heat treatment of the pills as described hereinafter. In some instances the percentages may fall outside of those specified which are not to be taken as critical. Such control coatings may be prepared by dissolving these components in a vehicle such as alcohol. The resulting ethyl cellulose solution may then be coated by conventional methods on the pill 10 over a layer of medicament 15 intended for release in the intestines, the membrane being very thin as described in connection with the coating 12. I As a specific example of an ethyl cellulose solution,
300 grams of ethyl cellulose and 30 grams of shellac may be dissolved in 3000 cc. of alcohol and the resulting solution coated on a layer of medicament 15 such as potassium penicillin or tetracycline to form the control coating 14, as described in detail hereinafter. I
. The coating 14 will be exposed to the stomach fluids after the layer 13 has been dissolved, if the pill 10 has not yet passed to the intestines. However, the ethyl cellulose and shellac coating 14 is unaffected by such fluids so that the medicament layer 15 therebeneath will be passed into the intestines without being affected in the stomach.
After being wetted by intestinal fluids, removal of the pore closing shellac of the control coating 14 is initiated and intestinal fluids then flow through the resulting permeable membrane to leach the medicament layer 15 into the intestines in a controlled manner.
The proportion of shellac in the coating 16 is one factor that determines the rate at which medicament will be released from the layer 15. The thickness of the coating 16 and heat treatment of the pill also are factors in such release. Thus, other factors being equal, a greater percentage of shellac decreases the periodlthat the coating will withstand the intestinal fluids before becoming permeable while a thicker control coating increases that period.
The coating 14 must also have characteristics enabling it to withstand considerable agitation and abrasion as it travels through the intestinal tract. Ethyl cellulose is admirably suited to perform this function since it affords a tough resilient skin on the pill 10 in the intestines.
Prior to complete dissolution of the medicament layer 15, intestinal fluids wet the next control coating 16, simi lar to the coating 14, and opening of its pores for penetration by the intestinal fluids to the medicament 17 therebelow is initiated. The time which the control coating 16 is designed to withstand the intestinal fluids before becoming permeable depends on the absorption characteristics of the medicament. If the drug in the pill 10 is absorbed quickly and then has a therapeutic effect for one hour, for example nitroglycerin, the coating 16 may be designed to initiate release of a medicament layer 17 within one hour after the intestinal fluids wet the control coating. With such drugs a fairly large number of layers of active material, for example ten layers, separated by control coatings may be used to sustain medication over about a 10 hour period with proper heat treatment of the pills as described hereinafter.
On the other hand, if a drug absorbed slowly by the intestines maintains its therapeutic effect for several hours, for example potassium penicillin, the control coating 16 may be designed to withstand intestinal fluids for several hours before becoming permeable to intestinal fluids. Thus, such a-coating would use less shellac, be
thicker, and heat treated in a manner to insure such function. With drugs having longer lasting therapeutic effects, it is apparent that a lesser number of layers need be provided since the release of medicament from one layer will provide medication for several hours. For example, it has been found that a pill incorporating two layers of potassium penicillin separated by a control coating designed to withstand intestinal fluids about seven hours provides medication in excess of sixteen hours.
Returning to the pill 10 shown in Figure 1, medication of the intestines provided by the medicament layer 17 is then sustained due to the release of further quantities of medicament 19 and 21 through further control coatings 18 and 20 in timed sequence. If each coating provides therapeutic effects for about one hour, the pill 10 illustrated will be effective for at least 6 hours. Any greater or lesser number of medicament layers and permeable coatings may be used so that the inventive pill may provide medication and therapeutic effects for any desired period. In that regard, the length of time pills remain in the intestines ranges from a period of about 4 hours to a period in excess of 16' hours.
The coatings 14, 16, 18 and 20 become permeable membranes after exposure to intestinal fluids but remain intact throughout the period of release of the medicament layers therebeneath to control medication of the intestines. In contras known enteric coatings rupture or disintegrate after exposure to intestinal fluids and, accordingly, medicament in relatively large quantities is dumped into the intestinal tract at one time.
A further exemplary coating that may be utilized to sustain medicament release in the alimentary tract includes ethyl cellulose and polyethylene glycol. For example, 100 grams of ethyl cellulose and 3 grams of polyethylene glycol (Carbowax No. 6000 for example) may be dissolved in 1000 cc. of alcohol and the resulting solution coated in a conventional manner on a plurality of layers of chloroprornazine, for example, in a pill to provide sustained medication in the intestinal tractas described above. Such coatings when heat treated as specified hereinafter and exposed to intestinal fluids initially inhibit for a period and then control the flow of intestinal fluids to the medicament layers therebeneath and in such manner sustained medication and therapeutic efiects for desired periods.
Since pills remain in the intestines for much longer periods than in the stomach, release of drugs and medication may continue over longer periods inthe intestines than in the stomach so that ordinarily, a greater number of medicament layers, separated by intestinal fluid controlling coatings, are used when medication over extended periods is desired.
Tests of 180 patients have shown that the average time a pill remains in the stomach is approximately 47 minutes. A single permeable membrane provided by the invention has been found to withstand stomach fluids for any fraction of that period and then to become permeable and release medicament so that it is not necessary ordinarily to employ more than one coating to release a single medicament to the stomach. However, in the event two or more medicaments must be released sequentially in the stomach, two or more coatings each providing release for about 10 minutes at 20 minute intervals, for example, may be coated over layers of medicament to provide such sequential release pills.
x The invention can be illustrated by the following examples:
EXAMPLE I Step 1.Mix 2.5 gm. of dextroamphetamine sulfate with 100 gm. of powdered sugar (dextrose). Moisten this mixture with =10 cc. of water and thoroughly dry at a temperature at 80 F. To this mixture add 2.5 gm. of magnesium stearate (for lubrication to prevent sticking during compression) and compress into 1000 spherical cores or pillets each weighing 105 mg. with a diameter of %2".
Step 2.Prepare a solution A, which will provide a coating resistant to stomach fluids and permeable after exposure by intestinal fluids, by mixing 5 gm. of ethyl cellulose, 1 gm. of shellac and 94 cc. of methyl alcohol. Prepare a solution B, which provides a coating permeable after exposure by stomach fluids, by mixing 5 gm. of cellulose acetate phthalate, 1 gm. beeswax and 94 cc.
Step 3.-Rotate the pillets formed by step i in a coating pan while adding 5 cc. of solution A. During such coating maintain the temperature at the pill surfaces between 90 and 100 F. After allowing the pills to dry for 15 minutes at room temperature, add another 5 cc. of solution A while rotating the pills in the coating pan at the same temperature. Each coating or membrane thus formed will withstand intestinal fluids for about 45 minutes and release a layer of dextroamphetamine sulfate over a period of about 15. minutes, depending on the final heat treatment, as stated in step 7.
Step 4.Dissolve 2.5 gm. of dextroamphetamine sulfate and 22.5 gm. of powdered sugar (dextrose) in 200 cc. of water and cc. of methyl alcohol, mix well and apply to the pills in a coating pan to provide a medicament layer about 4 thick. Allow the pills to dry for a period of about thirty minutes. Each pill will now weigh mg.
Step 5.Repeat steps 3 and 4 a total of three times. Each pill will now weigh mg.
Step 6.-While rotating the pills in a coating pan add 5 cc. of solution B while maintaining the temperature at the pill surfaces between 90 and 100 F., allow to dry andvthen add another 5 cc. of solution B. The coat-, ing or membrane thus formed will withstand stomach fluids for about 45 minutes and then release through it's opened pores the dextroamphetamine sulfate for about '15 minutes depending on the'flfinal heat. treatment. Dissolve 2.5 gm. of dextroamphetaminesulfate and 22.5 gm. of powdered sugar (dextrose) in 200 cc. of water and 100 cc. of methyl alcohol, mix well and apply about a ,4 layer to the pills in a coating pan. Each pill will now weigh 205 mg.
Step 7.-Place the pills in an oven maintained at 97 to 98 for heat treatment for a period of 4 hours.
S'rep 8.-Coat the pills with 1 pint U.S.P. syrup containing 100 mg. red color until a weight of 299.5 mg. is reached. Then polish the pills with a solution of .25 gm. of beeswax, .25 gm. of carnuba wax in 10 cc. of acetone. Each pill will now Weigh 300 mg.
The pills formed in accordance with Example I will provide continuous therapeutic effects for about 6 to 7 hours due to release of medicament in the stomach over about a 2 hour period and in the intestines over about a 4 to 5 hour period. In other words, although there are only 4 layers of medicament (including the center pillet) released in the intestines, the sequence of release in the intestines is such that it will beabout 4 hours (6 hours if the stomach period is included) befor substantially all of the material isreleased. Of course, absorption and therapeutic effects continue for some time after the release of the drug is completed.
If a slower release of medicament is desired, the pills may be heat treated for 6 or 8 hours and medication will be sustained in the. alimentary tract 8 to 9 or 9 to 10 hours, respectively. Thus, a factor in the time that the control coatings withstand alimentary fiuids is the period during which the pills are heat treated.
The heat treatment dries the pills and causes the pore closure substance to enter and close the pores in the permeable membrane. The longer the heat treatment, the greater the drying and entry of shellac, for example,
into the pores of the ethyl cellulose, and the longer the control membrane will Withstand alimentary fluids before being rendered permeable. I
The duration of heat treatment must also be related to the solubility of the medicaments used. For example, a sustained action pill with 10 layers of very soluble or hydroscopic medicaments such as ascorbic acid (vitamin C) separated by 9 control coatings, becoming permeable sequentially after exposure to intestinal fluids are formed as described in Example I, will medicate the intestines as shown in Table 1.
aieaep'ro amphetamine sulfate, the following table applies to medication in the alimentary canal:
When pills as described in connectionvwith. Example I incorporate medicaments relatively insoluble in water, such as phenobarbitol, the. following table. applies:
Table 3 Time Pills Heat Medication Oven Temperature Treated Period,
in Oven, Hours Hours 6 9 to 10 4 8'to 9 2 6 to 7 From the foregoing tables, it will be apparent'that-the greater the solubility of the medicament,- the longer the pills must be heat treated to provide the same release period, other factors being equal.
A further method of producing sufiicient pills to manufacture 500,000 mg. dextroamphetamine sulfate tablets is set forth in the following example:
EXAMPLE II Step 1.To form pillets (center cores) place 100 lb. of'coarse granulated sugar in a closed revolving coating pan of' about 40" diameter and rotate. Moistenthe sugar with one quart methyl alcohol containing 5% water, rotating the pan until all the solution is evenly distributed throughout the granulated sugar, and then dust with a dusting powder containing 50% sugar and 50% corn starch. Repeat this procedure three times drying the material between each moistening. Continue moistening with a solution made of one gallon of water (lukewarm) in which 5 lbs. of powdered sugar has been dissolved and then dust and dry after each moistening until. desired size pillets are obtained. A preferable size is approximately 13 to 16 mesh. Dry the-resulting pillets with a high temperature heating unit. Toremove all excess large pillets screen them through a size screen that will eliminate those pillets in excess of about ,4 diameter. Coat the pillets with 5 coatings of U.S.P. syrup (sugar and water syrup) and dry to give them a smooth surface in preparation for a layer of medicament.
Step 2.Prepare a solution A-1 by mixing one gallon of water, one gallon of methyl or isoprophynol alcohol and 8 ounces edible soluble gelatin. Dissolve the gelatin into the water by placing it in a bath and heating. After the gelatin solution has been cooled to about 100 F. the alcohol is added and the solution mixed and strained to remove any solidified gelatin.
Step 3.Prepare several quarts of solution B-1 by mixing ethyl cellulose, shellac and methyl alcohol as follows: Provide an ethyl cellulose solution inthe proportions of 25 gr. of ethyl cellulose in 100 cc. methyl alcohol, provide pharmaceutical glaze shellac (5 lb. shellac per gallon of methyl alcohol). To obtain 100 cc. of solution B-l mix '25 cc. of the ethyl cellulose solution, cc. of the shellac glaze and 50 cc. of'methyl alcohol:
Step 4.--To prepare the active ingredient-for coating;
after entry into the intestines.
10 pulverize 7.5 kilograms of dextroamphetamine sulfate to avery fine mesh. powder and. mix in about 1% of talent magnesium stearate for lubrication purposes.
Step 5..-Place 32.5 kg. of the pillets formed in step 1 inan enclosed coating pan of about 40 diameter and moisten with two pintsa solutionA-l whilethe pilletsare being revolved until the solution is thoroughly coated on the pills. Open the pan and blow hot airinto it for approximately 10 seconds to dry the interior pan wall. Then add 2.5 kg. of the pulverized dextroamphetamine sulfate and revolve in the closed. pan until all. of the active ingredient adheres to the pills. Dry the pills with thehot air blower.
Step 6 .Rotate thedry pillets in the coating pan, spray on two pints of warm solution B-1 and dry the coating well. Then spray on two more pints of solution B'-1 while the pills are rotating in the coating pan. Dust with a small amount of talc if necessary between coatings to prevent sticking.
Step 7.Repeat steps 5 and 6.
Step 8.-Repeat step 5 and dry well.
Step 9.-Weigh the pills and divide into three equal portions. Place one portion aside and rotate the two re: maining' portions in the coating pan and repeat the coating procedure of step 6 on these two portions 3 times.
Step 10.--Remove half of the pills from the coating pan and repeat 3 times coating step 6 on the pills remaining in the pan.
Step 11.-Place all three portions of the pills together in the coating-pan and rotate for about 2 hours with the hot airblower turned on. This rounds out the pills and mixes the three portions thoroughly.
Step 12.-Allow the pills to cool 12 hours.
Step 13.Place the pills in an oven and heat treatfor 10 hours at a temperature of from 97 to 98 F.
Step. 14.Assay the pills to determine the quantity of them in milligrams necessary to incorporate in each tablet to release the selected quantity of drug. In the present example the assay results will show that about 130 mg. of pills are required to release 15 mg. dextroamphetamine sulfate.
Step 15.To form tableting filler material mix 100 lbs. powdered sugar with 1% magnesium stearate (for lubrication).and granulate with a'3% ethyl cellulose solution formed by mixing 3 grams of ethyl cellulose with 100 cc. of chloroform.
Step 16.-Mix the pills with the tablet filler material in such amounts that the maximum weight of the pills compressed into the tablets by a tableting machine is about 50% of the weight of the tablets. Use 260 mg. of the pills-filler mixture in a tableting machine to form each of about 500,000 15 mg. dextroamphetamine tablets incorporating the inventive sustained action pills.
The three portions of pills of Example II initiate release of medicament at three different times. Thus, the first portion releases its outer layer immediately followed by its second and third layers in the next two hours. Since the outer layer of the second portions of pills is covered with a thicker control membrane, release therefrom is initiated about 3 hours after it enters the intestines, and release from the third portion is initiated about 6 hours Since each of the three portions provides release of medicament over a three hour period, their sequential action affords release over a nine hour period and medication for at least that long.
Any desired number of groups of the inventive sus: tained action pills may be incorporated in tablets or capsules (see Figure 4) to provide release of medicament and medication over extendedperiods. The groupsfor classesof pillsmay be designed to release sequentially or, if desired, the release from two groups may overlap to insure continuity ofmedication.
The following table indicates the manner of releaseofdextroamphetamine sulfate from a sample tablet produced in accordance with ExampleII.
Total material released over period of 9 hours, 14.93 mg.
. To contrast the release of medicament over long periods with the release of dextroamphetamine sulfate in the gastro-intestinal tract from a conventional pill protected by an enteric coating of 50% shellac and 50% ethyl cellulose, the following table should be examined:
Further exemplary tablets incorporating the inventive pills may be formed as follows:
EXAMPLE III Step 1.-Place 107 lbs. of pillets (center cores) formed in accordance with step 1 of Example II in a 40 diameter coating pan.
Step 2.Moisten the pills in the coating pan with one pint of solution A-l (see step 2 of Example 2). Rotate pan until all of the solution A-l is well distributed and the pan dry. Dust the pills with 6 lbs. 9 ounces of a powder containing 10% nitroglycerin and 80% beta-lactose. Continue to rotate the coating pan until all the nitroglycerin is absorbed by the pillets and then turn on the warm air and dry well. Step 3.Spray the pillets with 2 pints of solution B-l (see step 3 of Example II), dry and dust with about 1 lb. of talcum powder. Then coat with 2 more pints of solution B-l, dry and dust with talc.
Step 4.--Repeat steps 2 and 3 nine times. Dry the pills well and coat with 8 layers of shellac, one pint for each coat, dusting between each layer. The total weight of the pills will now be about 197 lbs.
Step 5 .-Heat treat the pills for 12 hours at a temperature of 97 to 98 F.
Step 6.To provide tablet filler material, mix 100 lbs. powdered sugar, 1 lb. talc or magnesium stearate for lubrication, and granulate with a solution of 3 gr. ethyl cellulose and 100 cc. of chloroform. Add nitroglycerin powder to the filler material to provide instant medication in the stomach.
Step 7.-Dissolve 5 gr. of red coloring in 1 pint of water and 3 pints of methyl alcohol. Coat 4 layers of red coloring solution on the pills, one pint per coat.
Step 8.Assay the pills and filler material to determine the quantity of pills and the weight of filler material necessary to provide 6.5 mg. nitroglycerin. In the prescnt'example the assay results will show that about 224 mg. of pills and 224 mg.of filler material will provide proper amount of drug.
Step 9.-Supply the mixed pills and filler material to a tableting machine set for 448 mg. tablets. The matcrial specified in this example will besufiicient to manufacture about one million tablets incorporating the inventive sustained action pills.
The following table shows the amount of material released from 6.5 mg. nitroglycerin tablets produced in accordance with Example III.
Table 6 Drug Cumulative Exposure in Hours Released Drug in Mg. Released in Mg.
1 1. 04 1. 04 Intestinal Fluid:
Material released in 11 hours, 6.3 mg.
It is apparent from Table 6 that the inventive sustained action pills provide medication in the alimentary canal over an extended period and the nitroglycerin released following the initial release of medicament from the tablet filler is about the same during each hourly period. Although the alimentary canal absorbs nitroglycerin within a few minutes after release, its therapeutic value in the body lasts over one hour so that constant medication is provided by the inventive pill. If the therapeutic efiect lasted for longer periods, it would not be necessary to'provide as many layers of material as are found in this pill.
Heat treating the pills at temperatures of 97 to 98 F. has proven satisfactory since it softens the membrane material (ethyl cellulose, cellulose acetate phthalate, for example) and the pore closure substance (shellac, beeswax, polyethylene glycol, for example) to close gradually the pores in the control membrane. The smaller pores resist penetration by fluids for longer periods. Higher heat treating temperatures may be used for shorter periods to effect the same results as heat treating at 97 F., bearing in mind, however, that excessive temperatures will destroy certain medicaments. Moreover, such temperatures must not be high enough to aifect adversely the pore closure substance and render it unsuitable to perform its function of closing the membrane pores and withstanding alimentary fluids. The pills may be heat treated at lower temperatures for longer periods to effect the same results as heat treating at 97 F. so long as the temperatures are high enough to soften the membrane and pore closure substance.
Referring next to Figure 2, a tablet 22 containing a number of the pills 10 is illustrated. The tablet 22 is basically pressed from a powder consisting of starch and sugar in the ratio of starch to 10% sugar, for example. The toughness of the pills 10, due to the ce lulose filter preferably on its exterior in this instance, permits a firm tablet 22 to be pressed without cracking the pills 10. Thus, one tablet may contain a plurality of the pills 10 for releasing medicament in the stomach and subsequently in the intestines. Alternatively, the tablet 22 may contain a plurality of pills adapted to release medicament in the stomach and a further plurality of pills for releasing medicament in the intestines. Thus, the layers of medicament in the first-mentioned pills would be separated by control coatings formed from cellulose acetate phthalate and the layers of medicament in the last-mentioned pills would be separated by control coatings formed from ethyl cellulose.
For example, the tablet 22 may both stimulate the stomach causing it to empty into the intestines and subsequently act as a laxative in the intestines. This is 13 sometimes preferable to employing two difierent drugs in a single pill since it protects against any possible ill effects from the reaction of the drugs with each other.
Turning to Figure 3, a pill 23 is pressed from a starch and sugar powder similar to that employed in forming the tablet 22, and contains a plurality of the pills 10. It may be formed and utilized in the same manner as set fiorth in connection with the tablet 22.
Referring next to Figure 4, a capsule 24 is formed of two halves 25 and 26 in a conventional capsulating machine, the half 26 being transparent as shown. A desired number of the pills are carried within the capsule 24 to assist in oral administration of medicament. The material forming the capsule may dissolve afterexposure to stomach fluids. At that time the sustained action pills 10 contained therein will initiate release of medicament over any desired extendedperiod as discussed in detail above. The sustained action pills 10 found in the capsule 24 may be of several different types or classes, one type releasing drugs over a period of three hours, the second type initiating release of medicament after three hours for an additional three hours, etc.
It will be understood that the above-described embodiments of the invention are illustrative only and modifications thereof will occur to those skilled in the art. Therefore, the invention is not to be limited to the specific embodiments disclosed herein but is to be defined by the appended clairns.
1. In a'sustained action pill to release medicament over an extended period for medication of the alimentary tract, a plurality of medicament layers, heat treated control membranes having pores containing a pore closure substance separating adjacent medicament layers, alimentary fluids rendering each of the membranes perineable after acting thereon for a period by removing at least partially the pore closure substance from the pores of the membranes, the temperature and duration of the membrane heat treatment softening the membrane and pore closure substance to decrease the size of the membrane pores and lengthen the period the control membranes resist penetration by the alimentary fluids, the alimentary fluids penetrating the permeable membrane to leach its corresponding medicament layer therethrough and thereafter wet the next membrane to render it permeable after a period of exposure thereto, each of the membranes remaining permeable and intact to control fluid flow at least until substantially all of the medicament in the layer therebeneath has been leached therethrough.
2. A pill as defined in claim 1, wherein the membrane is formed of ethyl cellulose and the pore closure substance is shellac, and the alimentary fluids rendering the membranes permeable consist of intestinal fluids.
3. A pill as defined in claim 1, wherein the membrane is formed of cellulose acetate phthalate and the pore closure substance is beeswax and the alimentary fluids rendering the membranes permeable consist of intestinal fluids.
4. A pill as defined in claim 1, wherein the membrane is formed of ethyl cellulose and the pore closure substance is polyethylene glycol, and the alimentary fluids rendering the membranes permeable consist of stomach fluids.
5. A tablet incorporatingpills as defined in claim 1,
id in which a plurality of different groups of pills are provided, each group consisting of pills releasing medicament over a different extended period after exposure to alimentary fluids, thereby providing medicament release and therapeutic effects over an extended period of time.
6. A tablet incorporating pills as defined in claim 1, in which some of the pills release medicament over a first extended period and other of the pills release medicament over a second different extended period not coextensive with the first period, whereby medicament is released ovcr a period greater than either one of the first and second periods.
7. In a sustained action pill to release medicament over an extended period for medication of the intestines, a plurality of medicament layers, heat treated control membranes comprising to ethyl cellulose and 30 to 5% shellac separating adjacent medicament layers, intestinal fluids rendering each of the membranes permeable after acting thereon for a period by removing at least partially the shellac from the ethyl cellulose pores, the temperature and duration of the membrane heat treatment softening the ethyl cellulose and shellac to decrease the size of the ethyl cellulose pores and lengthen the period the control membranes resist penetration by the intestinal fluids, the intestinal fluids penetrating the permeable membrane to leach its corresponding medicament layer therethrough and thereafter wet the next membrane to render it permeable after a period of exposure thereto, each of the membranes remaining permeable and intact to control fluid flow at least until substantially all of the medicament in the layer therebeneath has been leached therethrough.
8. In a method of producing sustained action pills releasing medicament over extended periods, the steps of coating alternately on pillets a plurality of medicament layers and control membranes of ethyl cellulose and shellac, and heat treating the pills for a predetermined time and at a temperature sufficient to soften the ethyl cellulose and shellac to decrease the size of the ethyl cellulose pores to enable each of the control membranes to withstand intestinal fluids for a selected time interval before beingrendered permeable by such fluids.
References Cited in the file of this patent UNITED STATES PATENTS OTHER REFERENCES JAPA, January 1934, p. 75. Silver et al.: Manuf. of Compressed Tablets, F. J.
Stokes Machine Co., Philadelphia, Pa., 1944, pp. 22 and 23.
Drug and Cos. Ind., vol. 63, No. 4, October 1948, p. 431.
Drug and Cosmetic Ind., September 1948, p. 286.
UNITED STATES PATENT O-FFCICE CERTIFICATE OF CORRECTION Patent No, 2 928 770 March 15,, 19cc Frank M, Bardani It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should readas corrected below.
Column 2 line 62 strike out "as"; column 9 line 63 for "it" read them column 10 line 6,, for "in" read am of column l3 line 57 for intestinal read stomach line 62 for "stomach" read intestinal Signed and sealed this. 23rd day of August 1960..
KARL H. AXLINE ROBERT C. WATSON Attesting Officer Commissioner of Patents
|Patente citada||Fecha de presentación||Fecha de publicación||Solicitante||Título|
|US1881197 *||6 Dic 1929||4 Oct 1932||Kirk William J||Medical tablet|
|US2099402 *||17 Ene 1934||16 Nov 1937||Pratt Food Company||Pill or tablet|
|US2196768 *||11 Mar 1938||9 Abr 1940||Eastman Kodak Co||Enteric coating|
|US2410417 *||4 Mar 1944||5 Nov 1946||Lever Brothers Ltd||Vitamin and mineral dietary supplement and method of making|
|US2540253 *||8 Feb 1949||6 Feb 1951||Merck & Co Inc||Granulation process|
|AU109438B *||Título no disponible|
|GB378714A *||Título no disponible|
|GB461317A *||Título no disponible|
|Patente citante||Fecha de presentación||Fecha de publicación||Solicitante||Título|
|US2991226 *||3 Feb 1958||4 Jul 1961||Frosst & Co Charles E||Long-acting wax-like talc pillage of penicillin|
|US3080294 *||20 Oct 1960||5 Mar 1963||Key Pharma||Sustained release type of pharmaceutical vehicles|
|US3097144 *||14 Oct 1960||9 Jul 1963||Upjohn Co||Heat-cured, polymeric, medicinal dosage film coatings containing a polyvinylpyrrolidone copolymer, polyethenoid acid, and polyethylene glycol|
|US3109775 *||31 Ene 1961||5 Nov 1963||Key Pharma||Theophylline-noscapine sustained release composition for treatment of asthma|
|US3131123 *||12 Ene 1960||28 Abr 1964||Lab Francais De Therapeutique||Enteric tablets and manufacture thereof|
|US3139383 *||26 Jun 1961||30 Jun 1964||Norton Co||Encapsulated time release pellets and method for encapsulating the same|
|US3198700 *||29 May 1961||3 Ago 1965||Blessings Inc||Sedative tablet and method for producing the same|
|US3220925 *||15 Nov 1962||30 Nov 1965||Upjohn Co||Tetracycline-novobiocin compositions and method of use|
|US3247066 *||12 Sep 1962||19 Abr 1966||Parke Davis & Co||Controlled release dosage form containing water-swellable beadlet|
|US3371015 *||27 Jun 1963||27 Feb 1968||Haessle Ab||Pharmaceutical core compositions with thin rapidly disintegrating coatings|
|US3383283 *||24 Ene 1964||14 May 1968||Merck & Co Inc||Medicinal pellets coated with overlapping porous fatty acid leaflet layers|
|US3395213 *||5 Dic 1963||30 Jul 1968||Boehringer & Soehne Gmbh||Sugar- and polyethylene glycol-coated dragees, nonsticking together, or to dragee-making kettles|
|US3437728 *||15 Jun 1964||8 Abr 1969||Diwag Chemische Fabriken Gmbh||Protracted release pharmaceutical compositions|
|US3485914 *||5 Jul 1966||23 Dic 1969||Chem & Pharm Patent Hold Ltd||Process for the production of a pharmaceutical antibiotic preparation having delayed therapeutic action and the composition prepared according to such process|
|US3492397 *||7 Abr 1967||27 Ene 1970||Warner Lambert Pharmaceutical||Sustained release dosage in the pellet form and process thereof|
|US3499959 *||5 Jul 1966||10 Mar 1970||Chem & Pharm Patent Hold Ltd||Therapeutic tetracycline preparation having delayed therapeutic action and processes for the production of said preparation|
|US3538214 *||22 Abr 1969||3 Nov 1970||Merck & Co Inc||Controlled release medicinal tablets|
|US3625214 *||18 May 1970||7 Dic 1971||Alza Corp||Drug-delivery device|
|US3710795 *||29 Sep 1970||16 Ene 1973||Alza Corp||Drug-delivery device with stretched, rate-controlling membrane|
|US3835221 *||4 Mar 1971||10 Sep 1974||Hoechst Ag||Orally administrable drug dosage form having delayed action|
|US3926188 *||14 Nov 1974||16 Dic 1975||Alza Corp||Laminated drug dispenser|
|US3939259 *||24 May 1974||17 Feb 1976||Anthony Pescetti||Coating composition and therapeutic preparation incorporating same|
|US4138475 *||14 Sep 1977||6 Feb 1979||Imperial Chemical Industries Limited||Sustained release pharmaceutical composition|
|US4173626 *||11 Dic 1978||6 Nov 1979||Merck & Co., Inc.||Sustained release indomethacin|
|US4217898 *||23 Oct 1978||19 Ago 1980||Alza Corporation||System with microporous reservoir having surface for diffusional delivery of agent|
|US4261971 *||17 Dic 1979||14 Abr 1981||Aktiebolaget Hassle||Pharmaceutically preparation comprising a cardiac glycoside in combination with a polymer|
|US4263273 *||17 Dic 1979||21 Abr 1981||Aktiebolaget Astra||Pharmaceutical preparation comprising a cardiac glycoside with a polymer coating|
|US4289795 *||21 Feb 1979||15 Sep 1981||Aktiebolaget Hassle||Method for preparing preparations having controlled release of an active component|
|US4341759 *||27 Oct 1980||27 Jul 1982||Aktiebolaget Hassle||Granule having controlled release properties|
|US4361546 *||15 Jun 1981||30 Nov 1982||Boehringer Ingelheim Gmbh||Retard form of pharmaceuticals with insoluble porous diffusion coatings|
|US4367217 *||31 Dic 1980||4 Ene 1983||Boehringer Ingelheim Gmbh||Dipyricamole sustained release forms comprising lacquer-coated particles and the preparation thereof|
|US4415547 *||14 Jun 1982||15 Nov 1983||Sterling Drug Inc.||Sustained-release pharmaceutical tablet and process for preparation thereof|
|US4432966 *||31 Ago 1982||21 Feb 1984||Roussel-Uclaf||Compressed tablets for disintegration in the colon comprising an active ingredient containing nucleus coated with a first layer containing microcrystalline cellulose which is coated with an enteric organic polymer coating|
|US4459279 *||18 Ago 1982||10 Jul 1984||Boehringer Ingelheim Gmbh||Retard form of pharmaceuticals with insoluble porous diffusion coatings|
|US4508702 *||3 Feb 1984||2 Abr 1985||Key Pharmaceuticals, Inc.||Sustained release aspirin|
|US4555399 *||8 Mar 1984||26 Nov 1985||Key Pharmaceuticals, Inc.||Aspirin tablet|
|US4587118 *||12 Dic 1984||6 May 1986||Key Pharmaceuticals, Inc.||Dry sustained release theophylline oral formulation|
|US4634587 *||16 Ago 1984||6 Ene 1987||Key Pharmaceuticals, Inc.||Sustained release quinidine dosage form|
|US4642230 *||21 May 1985||10 Feb 1987||Castex Products Limited||Release device|
|US4668517 *||4 Abr 1985||26 May 1987||Norwich Eaton Pharmaceuticals, Inc.||Furazolidone dosage form|
|US4713248 *||8 Feb 1985||15 Dic 1987||A/S Alfred Benzon||Diffusion coated multiple-units dosage form|
|US4716041 *||8 Feb 1985||29 Dic 1987||A/S Alfred Benzon||Diffusion coated multiple-units dosage form|
|US4752470 *||24 Nov 1986||21 Jun 1988||Mehta Atul M||Controlled release indomethacin|
|US4789548 *||24 Abr 1986||6 Dic 1988||Tisdale John W||Medication and method for treating heartworms in dogs|
|US4795644 *||3 Ago 1987||3 Ene 1989||Merck & Co., Inc.||Device for pH independent release of drugs through the Donnan-like influence of charged insoluble resins|
|US4800084 *||13 Ago 1987||24 Ene 1989||Horst Zerbe||Pharmaceutical product in the form of a pellet with continuous, delayed medicament substance emission|
|US4810500 *||1 Jun 1988||7 Mar 1989||Tisdale John W||Medication and method for treating heartworms in dogs|
|US4851231 *||16 Mar 1987||25 Jul 1989||Alza Corporation||System for delivering drug in selected environment of use|
|US4851232 *||8 Jun 1987||25 Jul 1989||Alza Corporation||Drug delivery system with means for obtaining desirable in vivo release rate pattern|
|US4863741 *||30 Ene 1989||5 Sep 1989||Abbott Laboratories||Tablet composition for drug combinations|
|US4863744 *||16 Mar 1987||5 Sep 1989||Alza Corporation||Intestine drug delivery|
|US4867984 *||17 Feb 1989||19 Sep 1989||Nagin K. Patel||Drug in bead form and process for preparing same|
|US4874614 *||30 Ene 1989||17 Oct 1989||Abbott Laboratories||Pharmaceutical tableting method|
|US4940588 *||17 Mar 1988||10 Jul 1990||Elan Corporation||Controlled release powder and process for its preparation|
|US4952402 *||17 Mar 1988||28 Ago 1990||Elan Corporation, P.L.C.||Controlled release powder and process for its preparation|
|US4960765 *||26 Jun 1989||2 Oct 1990||Farmaceutisk Laboratorium Ferring A/S||Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration|
|US4963365 *||4 Nov 1988||16 Oct 1990||Tanabe Seiyaku Co., Ltd.||Controlled release dosage form|
|US4980173 *||26 Jun 1989||25 Dic 1990||Farmaceutisk Laboratorium Ferring A/S||Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration|
|US4994273 *||20 Jul 1989||19 Feb 1991||Merck & Co., Inc.||Solubility modulated drug delivery device|
|US5013727 *||26 Jun 1989||7 May 1991||Farmaceutisk Laboratorium Ferring A/S||Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration|
|US5041431 *||26 Jun 1989||20 Ago 1991||Farmaceutisk Laboratorium Ferring A/S|
|US5320853 *||22 Dic 1992||14 Jun 1994||Merrell Dow Pharmaceuticals Inc.||Controlled release formulation for pharmaceutical compounds|
|US7838037||23 Nov 2010||Tagra Biotechnologies Ltd.||Method of microencapsulation|
|US20050175699 *||29 Abr 2003||11 Ago 2005||Cuine-Backert Marie E.||Multilamellar system for the administration of active agents by means of ingestion|
|US20060051425 *||22 Ago 2005||9 Mar 2006||Tagra Biotechnologies Ltd.||Method of microencapsulation|
|US20060099263 *||22 Dic 2005||11 May 2006||Edgren David E||Antidepressant dosage form|
|US20080055036 *||29 Ago 2006||6 Mar 2008||International Business Machines Corporation||Electrical component tuned by conductive layer deletion|
|CN101309746B||22 Ago 2006||30 Mar 2011||塔格拉生物科技有限公司||Method for production of single- and multi-layer microcapsules|
|DE1492140B1 *||21 May 1965||31 May 1972||Ile De France||Dragierverfahren|
|EP0163000A2 *||16 Ene 1985||4 Dic 1985||3 M Medica GmbH||Pharmaceutical product in pellet form with a continuous sustained release|
|EP1267844B2 †||21 Mar 2001||13 Abr 2016||Omega Pharma NV||Sustained release vitamin composition|
|EP2913103A1 *||22 Ago 2006||2 Sep 2015||Tagra Biotechnologies Ltd||Method for production of single- and multi-layer microcapsules|
|WO1983000284A1 *||8 Jul 1982||3 Feb 1983||Key Pharma||Sustained release theophylline|
|WO1984000004A1 *||14 Jun 1983||5 Ene 1984||Key Pharma||Sustained release aspirin|
|WO1984000295A1 *||8 Jul 1983||2 Feb 1984||Key Pharma||Sustained release quinidine dosage form|
|WO1985003436A1 *||8 Feb 1985||15 Ago 1985||A/S Alfred Benzon||Diffusion coated multiple-units dosage form|
|WO2007023495A2 *||22 Ago 2006||1 Mar 2007||Tagra Biotechnologies Ltd.||Method for production of single- and multi-layer microcapsules|
|WO2007023495A3 *||22 Ago 2006||5 Jul 2007||Tagra Biotechnologies Ltd||Method for production of single- and multi-layer microcapsules|
|WO2011161666A2 *||14 Abr 2011||29 Dic 2011||White Innovation Ltd.||Enclosed liquid capsules|
|WO2011161666A3 *||14 Abr 2011||29 Mar 2012||White Innovation Ltd.||Enclosed liquid capsules|
|Clasificación de EE.UU.||424/469, 424/473|
|Clasificación internacional||A61K9/22, A61K9/20, A61K9/50|
|Clasificación cooperativa||A61K9/5073, A61K9/2081|
|Clasificación europea||A61K9/20K2B, A61K9/50K|