SUSTAINED RELEASE METHOD AND PRODUCT

Abstract: A capsule product and method for gradually releasing a medicament for absorption to a body of a warm blooded animal through the gastrointestinal system. The capsule has a fill material which includes a masticatory substance and a medicament that is dispersed throughout the gum. The medicament is of a type that is effectively and desirably released for absorption by the body through the gastrointestinal tract over an extended period of time. The masticatory substance forms a supporting cohesive matrix for the medicament. The gelatin shell, usually formed from gelatin, water, and a plasticizer, is formed around the fill material into a capsule of a size and shape to be readily swallowable. Upon swallowing, the gelatin shell is rapidly dissolved in the gastrointestinal juices, while the fill material is substantially insoluble in the gastrointestinal juices. The matrix having the medicament dispersed throughout is subjected to substantially continuous random motion while contained within the gastrointestinal juices, while at body temperatures, and while under the influence of peristaltic movement for substantially varying the exposed surface area of the fill. As the surface area of the fill material is being changed, the medicament is gradually released from the exposed surface area for an extended period of time for ultimate absorption of the drug by the body.

Description: SUSTAINED RELEASE METHOD AND PRODUCT BACKGROUND OF THE INVENTION This invention relates to an improved sustained release product and method used for administering drugs to warm blooded animals and it particularly relates to a gelatin capsule product and method for gradually releasing a drug, contained in the fill material of the capsule, to warm blooded animals; the invention more specifically relates to an improved sustained release soft elastic drug form and method of administration. Generally speaking, orally administered drug dosage forms include elixirs or drugs administered as liquids, compressed tablets, compressed coated tablets, hard shell gelatin capsules, and soft shell gelatin capsules, all of which contain unit dosage amounts of a selected drug. The dosage regimen for drugs that are orally administered quite commonly requires a predetermined schedule of two, three or four times a day, of the unit dosage forms of the drug. It can be generally said that, with many drugs, the administration of the drug or medicament to the patient in one or two doses per day, while ensuring substantially constant blood levels with adeqliate drug bioavailability, is highly desirable. This is the reason for the desirability of having so-called sustained release drug dosage forms, that is, dosage forms which enable the drug to be released to the body of a warm blooded animal over an extended and generally pre¬ determined period of time. Although a dosage regimen involving one or two oral doses of the drug per day is considered to be highly desirable, not all drugs are logical candidates for a sustained release dosage form. Generally speaking, drugs having a relatively short half life, for example, less than about 8-10 hours, are good candidates for sustained release drug dosage forms. The purpose of having a sustained release dosage form for a drug is to generally flatten the plasma concentration curve, that is, reduce the concentration level of the drug in the plasma immediately or shortly after administration so as to attain a fairly constant plasma level for the drug. On the other hand, there is no rational basis for having sustained release preparations for drugs having a long biological half life, such as twelve hours or more. Similarly, highly potent drugs are not generally reasonable candidates for sustained release drug forms since it is desirable to have the option to withhold the drug at will during the dosage regimen so that control is not lost when the patient is under continuous medication. Sustained release dosage forms have generally been used with hard gelatin capsules having enteric coated microeapsules therein or compressed into tablets and with coated tablets, but have generally not been used with soft gelatin capsules which are usually filled with a liquid or a flowable substance, thereby making a sustained release dosage form, as a practical matter, almost impossible. Canadian Patent No. 888,683 relates to a sustained release soft elastic gelatin (SEG) capsule dosage form in which the capsule filling, upon coming in contact with water or with the juices of the gastrointestinal tract, forms a microporous, spongy substance, including the medicament, which gives off the active substance, continuously, through diffusion for absorption into the ambient medium. Although the sustained release drug form disclosed in this Canadian patent does relate to a possible sustained release system used in connection with gelatin capsules, there is a need and interest in the development of sustained release formulations that are en¬ capsulated within gelatin capsules, particularly soft elastic gelatin capsules of the type normally containing a liquid or flowable substance. Although it is not difficult to develop theoretical equations that would describe the desired release characteristics of sustained action tablets and capsules, it is another matter to formulate and manufacture products that will predictably deliver a drug under conditions which are variable due to patient physiology and therapy and yet reflect the desired plasma level profiles designed into the dosage form. SUMMARY OF THE INVENTION It is therefore an important object of the present invention to provide a highly unique sustained release drug delivery system wherein the drug dosage form is swallowed and the drug is encapsulated within a soft or hard shell gelatin capsule. n∞ It is also an object of the present invention to provide a highly unique sustained release drug delivery system particularly suitable for utilization of soft elastic gelatin capsule dosage forms. It is a further object of the present invention to provide an improved sustained release drug delivery system wherein the drug is dispersed within a gum or elastomer matrix system which defines a fiU material that is surrounded by a soft or hard shell gelatin capsule for oral administration and swallowing. It is another object of the present invention to provide a highly unique sustained release drug delivery system particularly useful for the drug theophyUine, in soft elastic gelatin capsule or hard shell gelatin capsule form. It is still another important object of the present invention to provide a highly unique method for administering drugs, particularly adapted for sustained release administration over an extended period of time, utilizing a highly unique delivery system in which a gelatin capsule dosage form contains a fill material of a gum pr .elastomer defining a matrix for a drug dispersed therein. It is also a further object of the present invention to provide a highly unique method for administering the drug theophyUine over an extended period of time to a warm blooded animal by dispersing the drug theophyUine in a gum or elastomer matrix which is encapsulated within a soft elastic gelatin capsule, then oraEy administered and swaUowed. it is stiU a further object of the present invention to provide a highly unique sustained release drug delivery system which involves encapsulation of a fiU material of a drug in a gum or elastomer matrix of the type which is capable of being constantly deformed by peristaltic movement in the gastrointestinal system in order to continuously provide a new surface area for the fiU material in order that a drug on the exposed surface area may be released by the surrounding medium and then absorbed by the body through the gastrointestinal system. Further purposes and objects of the present invention wiU appear as the specification proceeds. O PI The foregoing objects are accomplished by providing a fiU material of a masticatory gum or elastomer having a medicament dispersed substantiaUy uniformly throughout a matrix, the medicament being of a type that is desirably and effectively released for absorption by the body of a warm blooded animal through the gastrointestinal tract over an extended period of time, the gum or elastomer forming a supporting matrix for the medicament, the gum or elastomer being substantiaUy insoluble in the gastrointestinal juices, a sheU of gelatin and water, with or without a plastieizer, a plastieizer, being formed around the fiU material to define a fiUed capsule, the capsule being sized and shaped to be read y swaUowable, the gelatin sheU being substantiaUy dissolved by the gastrointestinal juices, the fiU material with a medicament dispersed therein being subjected to substantiaUy constant random motion whUe in the gastrointestinal juices, while at body temperatures, and whUe under the influence of peristaltic movements in the gastrointestinal tract for continuously varying the exposed surface area of the fiU material, so as to graduaUy release the medicament located in the exposed surface to the gastrointestinal juices for ultimate absorption by the body over an extended period of time. BRIEF DESCRIPTION OF THE DRAWINGS Referring to the accompanying drawings, there is provided a graphic iUustration of the mechanism by which a drug in a fiU material, encapsulated within the gelatin capsule results in the desired sustained release effect for the drug, and also there is provided graphs showing the drug release curves resulting from specific examples of the invention, wherein: FIGURE 1 is a cross sectional iUustration of a soft elastic gelatin capsule dosage form enclosing a fiU material wherein the capsule dosage form is made in accordance with the present invention; FIGURE 2 is an iUustration of the fiU material of the capsule of FIGURE 1 after dissolution of the gelatin sheU; FIGURE 3 is an iUustration of the fiU material after being softened by body temperature and, whUe under the influence of OMPI peristaltic movement and while being subjected to convolutions; FIGURE 4 is an. iUustration of new surface area exposure of the fiU material of FIGURE 3 foUowing the initial convolutions iUustrated in FIGURE 3; FIGURE 5 shows the state of the fiU mass foUowing continuing convolutions thereof as the drug is being graduaUy released and the expended matrix is in condition for excretion from the gastrointestinal system; FIGURE 6 iUustrates the drug release curve for Example I; and FIGURE 7 iUustrates the drug release curve for Example H. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT GeneraUy speaking, the present invention relates to a sustained release drug deUvery system for oral administration, wherein the deUvery system comprises an effective unit dosage amount of a drug capable of being absorbed into the blood of a warm blooded animal from the gastrointestinal tract. Preferably, the unit drug form is -encapsulated as a fiU material within a gelatin capsule, preferably a soft elastic gelatin (SEG) capsule as opposed to a two piece telescoping hard gelatin capsule. The capsule fiU material generaUy comprises a masticatory substance, preferably a gum or elastomer, with a preselected drug or medicament dispersed sub¬ stantiaUy uniformly throughout the masticatory substance which defines a matrix for the drug. Since not aU medicaments are candidates for the sustained release form, the drug or medicament that is utUized in our invention is a type that is desirably and effectively graduaUy releasable for absorption by the body over an extended period of time. The masticatory substance itself defines a cohesive support matrix for the medicament. The gelatin sheU of the capsule is rapidly dissolvable in the gastrointestinal juices while the capsule fiU material, specificaUy the masticatory substance, is substantiaUy insoluble in the gastric juices. The matrix has a formulation that is capable of being fiUed into the gelatin capsule. After swaUowing, while in the presence of the gastrointestinal juices at body tem¬ peratures and while under the influence of the peristaltic movement of the gastrointestinal tract, the matrix is subjected to continuous random motion for substantiaUy continuously varying the exposed surface area of the matrix. The medicament or drug is graduaUy released over an extended period of time from the exposed surface area as the surface area is being varied. In this way, the drug or medicament is graduaUy and ultimately absorbed by the body through the gastrointestinal tract whUe attaining suitable plasma concentration levels for the particular drug. Thus, the drug is released from the matrix for an extended period of time whUe in the gastointestinal tract. Our unique drug form or deUvery " system and method, providing a sustained release effect for absorption of drugs or medicaments, are useful for a wide range of drugs or drug categories including, but not Umited to antihistamines, sedatives, tranquilizers, cardiovascular drugs, respiratory drugs (antiasthmaties, antitussives), sympathomimetic drugs, diuretic drugs, analgesics and antipyretics, antimotion sickness and antinauseants, and electrolytes and hematinics. Specific examples of such antihistamines are: chlorpheniramine maleate (such as Deconamine SR capsules by Berlex and Chlor-trϊmeton by Schering), brompheniramine maleate (such as Bromfed capsules by Muro and Dimetane tablets by A.H. Robins) and dexchlorpheniramine maleate (such as Polaraϊmine Repetabs by Schering). Suitable sedatives include doxylamine succinate (such as Unisom Nighttime Sleep-aid by Leeming), and promethazine hydro- chloride (such as Remsed tablets by Endo). Suitable tranquiUzers for use in our sustained release drug form include diazepam (such as Valrelease capsules by Roche), Uthium carbonate (such as EskaUth CR tablets by Smith, Kline δc French), and perphenazine (such as TrUafon Repetabs tablets by Schering). Cardiovascular drugs which may be uti zed in our sustained release drug form inelude quinidine sulfate (such as in Quinidex Extentabs by A.H. Robins), nitroglyeerin (such as Nitrostat SR capsules by Parke-Davis), propranolol hydro- chloride (such as Inderal by Ayerst), and nifedipine (such as in Procardia by Pfizer). Suitable antiasthmaties or antitussives include theophyUine (such as Theo-Dur by Key Pharmaceuticals), guaifenesin (such as Congess SR <Sc JR capsules by Fleming & Co.), dextro ethorphan hydrobromide (such as Cotylenol tablets or capsules by McNeil Consumer Products), and codeine phosphate (such as Empirin with codeine tablets by Burroughs WeUcome Co.). Suitable sympathomimetie drugs useful in our sustained release drug form include ephedrϊne, (such as Quibron Plus by Mead Johnson Pharmaceuticals), Pseudoephedrine hydrochloride (such as Bromfed capsules by Muro Pharmaceuticals), and phenylpropanolamine hydro¬ chloride (such as Histabid Duracap timed action capsules by Glaxo Inc.). Diuretic drugs that are useful in our sustained release drug form include acetazolamide (such as Diamox Sequels sustained release capsules by Lederle), and hydrochlorothiazide (such as Hydro DiurU tablets by Merck, Sharp & Dohme). Analgesics and antipyretics useful in our sustained release drug form include aspirin and indomethacin (such as Indocin SR capsules by Merck Sharp & Dohme). Suitable antimotion sickness and antinauseants include meclizine hydrochloride (such as Bonine tablets by Pfizer), dimenhydrinate (such as Dramamine tablets by Searle), hydroxyzine hydrochloride (such as Atarax tablets by Roerig), and prochlorperazine maleate (such as Compazine tablets by Smith, KUne & French). Electrolytes and hematinics useful in our sustained release drug form include potassium chloride (such as Micro-K Extencaps by Robins and Slow-K tablets by Ciba), and ferrous fumarate (such as Ferro-Sequels by Lederle). In certain of the above-identified drugs, it is desirable to utilize enteric coatings to insure that the drug wiU remain intact in the stomach. Therefore, enteric coatings may be used with various drugs. The enteric coated drug microcapsules are dispersed through¬ out the matrix as is the drug itself. However, because of the enteric coating, the drug would nor aUy not be released until the matrix leaves the stomach and passes into the intestine. The primary intention of an enteric coated drug is to delay release of the drug or inactivating the drug whUe in the stomach, for example, some drugs may cause nausea or bleeding by irritation of the gastric mucosa. Examples of such drugs are aspirin and steroids. Useful enteric coatings in manufacturing our coated drug forms include hydroxy- propylmethylceUulose phthalate, ceUulose acetate phthalate, OMPI polyvinyl acetate phthalate, methacryUe acid-methacryUc acid ester copolymers, ceUulose acetate suecinate, styrene-maleic acid polymer, amylόse acetate phthalate, sheUac, phenyl saUcylate, and formaUzed gelatin. The procedures for applying enteric polymers to drugs are weU known. Suitable procedures for enteric coating of drugs include pan coating, air suspension coating, dip coating, compression coating, electrostatic coating, coacervation-phase separation process coating, and multiorifice-centrifugal process coating. Since the particular methods used for forming the enteric coating are not considered a part of the present invention, reference is made to the Uterature, including, for example, The Theory and Practice of Industrial Pharmacy, by Lachman, Liebeman, and Kanig, pages 376-386. AU of the above drugs, whether entericaUy coated or not, are suitable candidates for our sustained release drug form or delivery system as aE of the drugs have a half life of less than about 8-10 hours. Also, aU of the drugs are capable of being absorbed into the blood of the gastrointestinal tract of warm blooded animals. The amount of the drug used in our drug form or deUvery system and method may vary over a wide range although, generaUy, any therapeutiσaUy effective unit dosage amount of a selected drug is used. As previously discussed, an important component of the fill material is an insoluble, cohesive masticatory substance, a gum or elastomer, which defines the matrix system for the medicament or drug which is entrapped in the matrix system. Thus, the fiU material comprises, as its essential components, the desired drug and the masticatory substance. Other materials, such as paraffin, mineral oU, neutral oils, and the Uke may be added to the fiU material in order to attain the desired consistency of the fiU material for fiUing purposes, that is, for fiUing of the f iU material into a gelatin capsule, preferably a soft elastic gelatin capsule, although two piece hard sheU gelatin capsules may also be used. Not only is the flowabUity of the fiU material important for fiUing purposes for soft gelatin capsules, but it is also important that the fiU material provide the desired drug release profUe foUowing administration and swaUowing of the encapsulated drug. The masticatory substance useful as the gum matrix is generaUy a gum of the type listed in the Code of Federal Regulations, Title 21, Section 172.615. Suitable insoluble masticatory substances utilized in our method and product include various natural and synthetic masticatory substances or elastomers which may be used alone or in a variety of combinations. Such natural masticatory substances (coagulated or concentrated lattices) of vegetable origin are as foUows: Chicle, Chiquibul, Crown gum, Gutta hang kang, Massaranduba balata (and the solvent-free resin extract of Massaranduba balata), Massaranduba chocolate, Nispero, Rosidinha (rosadinha), Venezuelan chicle, Jelutong, Leche caspi (sorva), Pendare, PeriUo, Leche de vaca, Niger gutta, Tunu (tuno), Chite, and Natural rubber (smoked sheet and latex Hevea brasiUensis solids). Suitable synthetic masticatory substances include: Butadiene-styrene rubber, isobutylene-isoprene copolymer (butyl rubber), siUcone elastomers, paraffin, petroleum wax, petroleum wax synthetic, polyethylene (mol. wt. 2,000-21,000), polyisobutylene (mol. wt. 37,000), polyvinyl acetate (mol. wt. 2,000), and polyvinyl alcohol (not Usted in Fed. Reg.) As indicated previously, various inert paraffins or oils may be utilized, if needed, in connection with the gum in order to obtain t e desired consistency. The desired consistency is particularly important when fiUing the fiU material into an SEG capsule. In preparing the fiU material, in order to attain the desired flow characteristics, it is important for the masticatory substance to be molten, whUe being mixed with the drug so that the drug is dispersed substantiaUy uniformly throughout the fiU matrix. The dispersion of the medicament within the masticatory substance is accomplished in a variety of ways. AU the ingredients of the fiU material, including the drug and the masticatory substance as weU as other materials, such as the oils or paraffin, may be mixed together, with heating, if necessary, until the desired consistency for fiUing and the desired dispersion of the drug throughout the fiU material is attained. Alternatively, the masticatory substance may be heated to molten temperatures and then the medicament may be added; the molten masticatory substance and the medicament are then mixed in iRH OMPI fa WIPO order to obtain the desired consistency for fiUing and untU the desired consistency is attained. An important aspect of the method for manufacture is appropriate mixing in order to provide a substan¬ tiaUy uniform dispersion of the medicament in the molton masticatory substance. One preferred masticatory gum particularly useful as a gum matrix is a synthetic masticatory substance which is present in the fiU in an amount of about U%-28% by weight, a plasticizing material or softener present in a range of about 3596-57% by weight, a water insoluble adjuvant, such as calcium carbonate, which is present in an amount of about 40-50% by weight, and an antioxϊdant, such as butylated hydroxytoluene, which is present in very minor amounts, normaUy not more than 0.1% by weight. TypicaUy, the gum base that is utilized as the masticatory substance has a softening end point of about 67-76° C, an ash content of 46% plus or minus 2%, and a moisture content of 1% maximum. In a preferred aspect of the present invention, the fiU material is fiUed into a soft elastic gelatin sheU which encloses the fiU material, including the drug, which does not attack the walls of the seamless, one piece, soft elastic gelatin capsule. The gelatin capsule sheU is formulated in accordance with conventional techniques for making filled, seamless, soft elastic gelatin capsules containing therapeutieaUy effective unit dosage amounts of an active drug ingredient. In one conventional sheU formulation, there is included about 30-53 parts by weight of gelatin, about 15-48 parts by weight of a plastieizer, such as glycerin or sorbitol, and about 16-40 parts by weight of water. AdditionaUy, the gelatin sheU may contain preservatives, such as mixed parabens, ordinarUy methyl or propyl parabens in about a 4:1 ratio. The parabens may be incorporated in the sheU formulation in minor proportions as compared to the total weight of the sheU formulation. Conventional gelatin capsules utiUze gelatin having a Bloom value of about 160-200 although this value may be varied over a wider range. In a conventional manner, the gelatin composition is mixed and melted under vacuum conditions. The capsules may be simultaneously formed and filled using conventional methods and apparatus such as disclosed, for example, in U.S. Patent Nos. 1,970,396; 2,288,327; and 2,318,718. The gelatin capsules are formed into the desired shape and size so that they can be readily swaUowed, usuaUy with the aid of water. Upon incorporation of the fiU material, including the masticatory gum and the medicament, into the gelatin sheU, since the capsule is soluble in water and in the gastrointestinal juices, upon swaUowing, the gelatin sheU rapidly dissolves in the stomach leaving the substantiaUy insoluble fiU material. Referring to FIGURE 1, there is shown a cross sectional view of a typical capsule 10 made in accordance with our invention. The capsule 10 includes the gelatin sheU 12 and the fiU material 14 comprising the masticatory gum matrix that supports the medicament. Referring to FIGURE 2, the fiU material is shown upon dissolution of the gelatin sheU in the stomach. Referring to FIGURE 3, the fiU material 14 is shown during early convolutions or movement imparted to the fiU material as a result of the softening of the fiU material by the body temperature, while in the gastric juices, and whUe under the influence of peristaltic motion within the stomach. Referring to FIGURE 4, it is clearly seen that there is new surface area exposure of the fiU material 14 due to the convolutions imparted thereto by the influence of peristaltic movement. As the fiU material 14 passes through the gastrointestinal tract including the stomach and smaU intestine towards the large intestine or colon, there are further convolutions imparted to the fiU material 14 until the insoluble fiU material is aU that remains and substantiaUy aU the drug has been released. The insoluble fiU material passes through the entire gastrointestinal tract to the lower intestine or colon until substantiaUy aU the drug is released from the matrix, and is ultimately excreted from the system. Since the fiU material is insoluble and non-toxic and because of the convolutions that are imparted to the fiU material 14 over an extended period of time through peristaltic motion imparted thereto, during time in the gastrointestinal tract, such as 24 to 36 hours, the desired sustained release effect for the selected drug is attained. Data show that the masticatory gum matrix system remains a cohesive, semi-soUd mass whUe under the action of normal gastro- intestinal motiUty. For example, in in vivo testing, the cohesive masticatory gum matrix gum system controls the continuous release of an initial dosage, for example, three hundred milligrams of the drug theophyUine, initiaUy contained in a soft elastic gelatin capsule during passage through the gastrointestinal tract over a period of about 24 hours. In test, the bioavaUabiUty of the drug was determined by monitoring the human saUva theophyUine concentration by high performance Uquid ehromatography. In in vitro studies there was no more than 20% of theophyUine released in 900 miUUiters of water at 37° C in 7 hours as determined by the U.S.P. Paddle Method at 50 r.p.π There was no less than 40 percent theophyUine dissolved in 50 ml of water at 37° C at 7 hours as measured by a rotating bottle method. The system's degree of sustained release action is apparent from testing which wiU be described in detail. GeneraUy speaking, the continuous sustained release effect of the drug or other chemical from the cohesive, semi- soUd masticatory gum matrix gum is not affected by pH changes of going from the stomach to the intestine. The foUowing examples set forth test results illustrating the advantages of the present invention. The foUowing test results show the sustained release effects of the present invention utiUzing a capsule composition comprising a soft elastic gelatin capsule containing a fiU of 300 miUigrams of theophyUine (anhydrous). The formulation of the fiU material was: TheophyUine (anhydrous), USP 300.000 (+ or - 10%) Neutral OU 240.000 + or - 10%) Masticatory Substance 225.000 + or - 10% Mineral OU, USP 50.000 + or - 10% Paraffin, NF 50.000 + or - 10% The sheU formulation was as foUows: Gelatin USP (type 195) 217.859 (+ or - 10%) Glycerin, USP 132.318 (+ or - 10%) Purified water, USP 26.907 (+ or - 10%) Methyparaben, NF .864 (+ or - 10%) Propylparaben 0.216 (+ or - 10%) OMPI The theoretical capsule fiU weight was 865 milHgrams plus or minus 10%, the theoretical capsule fiU volume was 12.44 minims plus or minus 10%, the die size (R.P. Scherer Corporation) was W/16 oval B, the die dimensions were a height of 0.46 inches plus or minus 10%, and a diameter of 0.70 inches plus or minus 10%, and the capsule was opaque white in color. Example I The purpose of the test was to determine the rate and extent of theophyUine absorption from the sustained release dosage formu¬ 0 lation of the present invention as compared to an immediately released theophyUine product foUowing administration of a single dose.- The capsules utiUzed were the 300 miUigram sustained release theophyUine capsule as described above having a preferred fiU material of the present invention. Test results were compared * -* against EloxophyUin^ an elixir manufactured by Berlex Laboratories. Twenty normal and healthy non-smoking males were utilized for the experiment. The subjects met the foUowing criteria of eUgibility for participation in the experiment: (a) 19-35 years of age; (b) no more than plus or minus 15% from ideal weight for their height, as defined by Metropolitan Life Insurance Company Statistical BuUetin 40:1, 1959, and a weight of greater than or equal to 125 lbs.; (c) no history of serious hepatic, renal, gastrointestinal or cardiovascular disease, alcohol or drug abuse, as evidenced by a medical history, physical examination and vital signs within 30 days prior to the start of the study; and (d) blood chemistry hematology and urinalysis were performed to eUminate potential subjects who did not have test values within normal ranges. After an overnight fast, each subject was fitted with either a Cathelon IV (18G, 1-3/4 in.) I.V. catheter or a butterfly infusion set, each equipped with a Jelco intermittent injection cap as a heparin lock. A baseline blood sample was drawn within 15 minutes of each subject's scheduled dose time. A standard blood withdrawal procedure was employed. Each subject was then given a 300 mg dose of theophyUine as either the sustained release capsule of the present invention or ElixophyUin^ at his scheduled dose time. Xanthine-free meals were served to the subjects during the course of the day. Plasma samples were drawn at the foUowing time intervals after dosing: 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24-hours. After the 12 hour blood draw was complete, the catheters were removed. The 24 hour samples were obtained using routine venipuncture techniques. FIG. 6 is a graphic summary of the average plasma concentration of theophyUine foUowing a single oral dose of 300 mg of the sustained release capsule of the present invention and ° ElixophyUin® elixir, 80 mg/15 ml (Lot No. W10835, Exp. U/84). Table I summarizes the area under the curve ("AUC") of FIG. 6 data for both the sustained release capsule and the theophyUine elixir. A comparison of individual bioavaUabiUty values for each subject is also included. Twelve of eighteen subjects had AUC values for the capsule that feU within 70% of their AUC values for the eUxir. The overaU relative bioavaUabiUty, F%, determined over a 24 hour period was 94.5%. Table E compares the values for peak times, t , and peak blood levels, ' c m m ax-_,' obtained for the cap e sule and the elixir in each 0 individual. The average c m for the sustained release product was 6.31 g/ml. and the average was 4.39 hours. For the elixir, an average e I_Ilc o LX v of 8.25 g/ml was achieved and the average t l_ϊlα Q- X_ was 1.47 hours. TABLE I • Comparison of AUC's for Human Subjects Receiving a Single Dose, 300 mg, of Elixir of TheophyUine (Berlex Labβ. Inc.) and Sustained Release Capsules of TheophyUine (R.P. Scherer) Subject 10 Average Sample Sustained Release 91.52 81.95 97.63 98.15 69.96 78.62 68.03 61.07 54.74 76.96 1 EUxir 94.37 79.23 58.58 82.13 95.89 90.56 67.69 91.52 91.28 83.47 BioavaUabiUty (F%) 98 103 167 109 73 87 101 67 60 96.00 I Subject 12 13 14 15 16 17 18 19 20 Average Average of 18 Subjects Sample Sustained Release 60.00 66.71 51.93 66.51 71.79 80.07 69.61 108.86 94.47 74.44 75.70 EUxir 58.37 100.72 78.04 80.36 98.72 90.88 89.46 70.57 75.61 82.53 83.00 BioavaUabiUty (F%) 103 66 67 83 73 88 78 156 125 93.00 94.50 AUC determined over 24 hour period F% = ' AUCu g/ml x hr. (Sustained Release) x 100 AUCμg/mi x hr. (Elixir) TABLE U Comparison of the t and c for TheophyUine In Human Subjects Receiving a Single Oral Dose, 300 mg, of SustalneoKelease (*8-R. n ) capsules (R.P. Scherer) and Elixir (Berlex Labβ. Inc.) Subject 10 Average EUxir 3.0 3.0 1.0 1.0 1.0 1.0 3.0 0.5 0.5 .56 max (hours) S.R. 3.0 5.0 5.0 7.0 6.0 6.0 2.0 4.0 5.0 4.78 EUxir 7.47 9.04 7.25 7.96 7.09 _".18 7.18 10.88 10.00 8.44 max (■g/ml) S.R. 8.40 7.78 7.33 7.71 5.68 5.3 7.44 5.32 4.90 β.ββ σ_ I Subject 12 13 14 15 16 17 16 19 20 Average Average (18 Subjects) EUxir 3.0 1.0 2.0 1.0 1.0 1.0 0.5 1.0 2.0 1.39 1.47 t max (hours) S.R. 5.0 4.0 4.0 2.0 4.0 6.0 4.0 3.0 4.0 4.00 4.39 EUxir 5.92 8.93 7.69 8.17 9.96 8.84 7.50 8.55 7.00 8.06 8.25 max EXAMPLE U The human subjects of Example I were utUized for the study detaUed in this Example. Again, the purpose of the study was to compare the theophyUine levels of a sustained release capsule containing the fiU material made in accordance with the present invention, an intermediate release reference product, and a sustained release reference product foUowing a multiple dosing regimen designed to achieve steady state plasma levels of theophyUine. The samples examined were the 300 mg sustained release capsule, of the present invention, discussed above, containing a fiU of theophyUine, EUxophyUin ^elixir, 80 mg/15 ml, manufactured by Berlex Laboratories as the intermediate release reference product, and sustained release tablets containing theophyUine as manufactured by Key Pharmaceuticals, Inc., as a reference material. The single dose study of Example I served as the pre-test dose evaluation for the multiple dose, steady state study. The subjects were instructed to avoid the use of any other medication, including non-prescription drugs, on a regular basis, from one week prior to the beginning of the study and throughout its 22-day duration. They were also instructed to exclude aU xanthine-containing foods and beverages from 48 hours prior to the initiation of the study until after the study was completed. Fasting overnight was required between days 4 and 5, 12 and 13, and 20 and 21. The subjects were divided into 3 groups which participated in three separate five-day treatment periods, one for each sample tested. The 22-day multiple dose study included a 4-day washout between each of the separate treatment periods. The sustained release capsule having the fiU material of the present invention and the sustained release reference tablet were administered according to identical dosage schedules. A dose of 300 mg of the capsule or 300 mg of the tablet were administered in the morning and evening on the first through the fourth days and in the morning of the fifth day of the treatment period. A dose of 200 mg of the intermediate . release reference elixir was administered in the morning only on the fifth day. A dose was also self administered by each patient at midnight of each day. For the sustained release capsule and tablet, plasma samples were taken in the morning and evening of the fourth day of the treatment period and, on the fifth day, at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16 and 24 hours foUowing the final dose of the treatment period. For the intermediate release eUxir, plasma samples were taken, for each treatment period, in the morning and afternoon of the fourth day, and, on the fifth day, at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16 and 24 hours foUowing the final dose of the treatment period. The average plasma concentrations of theophyUine in the 18 human subjects after 5 days of multiple dosing of the three samples are shown graphicaEy in FIG. 7. A dose of 200 mg as the eUxir (Berlex Lot No. W10836, Exp. U/84) was administered every 8 hours and 300 mg as the sustained release capsules (Scherer Lot No. EU994), containing the fill material of the present invention, and 300 mg of the sustained release tablets (Key Lot N.o. 220031, Exp. 2/84) was administered every 12 hours to achieve the steady state theophyUine * levels. Subjects receiving the eUxir exhibited highest levels within 2 hours and the lowest levels after 6 hours. Plasma levels for the sustained release capsules and the sustained release tablets were simUar from 1 hour through 10 hours. The sustained release capsule produced higher levels through that time period and sUghtly lower at zero hours and 12 hours. Tables IE, IV and V present a comparison of the areas under the curves ("AUC") of FIG. 2 and relative bioavaUabiUties, F%, between samples for each individual over a 12 hour time period for the sustained release capsules and sustained release tablets and an 8 hour time period for the eUxir. The AUC for the eUxir reported was multipUed by 1.5 to normaUze the data for the smaUer dose. This is probably an over-estimate because it does not take into account the residual theophyUine from previous dosing. The average F% for the sustained release capsules was greater than for the sustained release tablets. Both exhibited AUC's less than the eUxir. Sixteen of the 18 subjects had AUC values for the sustained release capsules that feU within 79% of their AUC values for the elixir. Thirteen of the 18 -^OTEA OMPI subjects had AUC values for the sustained release tablet that feU within 76% of their AUC values for the eUxir. The overaU bioavailability, F%, for the sustained release capsules was 88.58%, compared with 84.18% for the sustained release tablets. (Average 5 data presented in Table V.) Tables Via, VIb and Vic present a comparison of peak blood levels of theophyUine, c lϊlcLX , peak times, t maχ , and average minimum blood levels of theophyUine, c m i n , values for the subjects by group. The combined average for each parameter is presented in Table Via. The sustained release capsules 10 had an average c QctX of U.46 μg/ml and an average t m£tX of 4.42 hours, while the sustained release tablets had an average c of 9.91μg/ml and an average t „ of 3.56 hours. The elixir had an ° ° max average c m_s Q .„x of 13.75 μg/ l and an average t • m lTic Q L V X of 1.06 hours. The average c . value for the sustained release capsules was 6.62 μg/ml 1 compared to 7.67 μg/ml for the sustained release tablets and 7.75 μg/ml for the elixir. As can be seen from the data in Tables Via, VIb and Vic, a significant difference was observed between the AUC values for the • elixir and both the sustained release capsules and sustained release ' 0 tablets. There was no significant . difference between the AUC values for the sustained release capsules and the sustained release tablets. The c m i n values for the elixir and the sustained release tablets were not significantly different from one another but both were significantly different from that of the sustained release capsules. The t values for the sustained release capsules and the sustained release tablets were not significantly different from one another but were significantly different from the t for the eUxir. There was also a sig & nificant difference between the c max values of aU 3 samples with the elixir having the highest value and 0 the value of the sustained release capsules being higher than that of the sustained release tablets. No significant variation was seen between subject groups. For the data reported in Examples I and E, the foUowing procedure was used to obtain the data: The fresh plasma samples taken from the subjects were centrifuged and were then separated, labeled and frozen. The plasma samples for each subject were grouped as individual sample sets after each 24-hour sampUng period. Prior to analysis, each set of samples was aUowed to thaw at room temperature. The samples were then prepared for analysis by adding, to 0.5 ml of the plasma, 0.1 ml of a standard solution which consisted of 1 ml of aqueous solution containing 0.5 mg of β -hydroxy ethyl theophyUine (H-9006, Sigma Chem. Co.) added to 9 ml of 20% caffiene in acetonitrEe. The sample-standard solution was then vortexed for 30 seconds in a Vortex Genie, aUowed to stand for 30 minutes, and then centrifuged for 20 minutes at 10,000 r.p.m. in an Eppendorf Model No. 5412 centrifuge. The resulting plasma filtrate was removed for analysis and the precepitate was discarded. A 0.1 ml sample of the plasma filtrate was then injected into a Beckman High Performance Liquid Chromatograph, Model U0A, equipped with a Hewlett-Packard 3390A integrator-recorder. AU theophyUine concentrations were determined in dupUcate using the theophyUine peak curves from the integrator-recorder and a standard curve for theophyUine. Examples I ..and E demonstrate that the sustained release capsules having the fiE material of the present invention provide therapeutic equivalence to the sustained release tablets without the danger of reaching toxic theophyUine levels when utiUzing a 12 hour dosage interval. bTJREX OMPI TABLE HI Comparison of AUC's for Subjects at the End of Five Days of Multiple Dosing of TheophyUine Products. Each Subject Received 300 mg Every 12 Hours of Sustained Release Capβules (S.R.I) (R.P. Scherer), 300 mg Every 12 Hours of Sustained Release Tablets (S.R. U) (Key Pharmaceuticals, Inc.) and 200 mg Every 8 Hours of the EUxir (Berlex Laboratories, Inc.) on Alternate Weeks During the Triple Crossover Phase of the Study. Subject 21 Average Sample AUC 1 (S.R.I) (Scherer) U2.50 107.91 U4.48 U1.Θ2 U3.45 100.02 U0.00 AUC (S.R.II) (Key) 80.05 U8J8 136.69 99.03 U5.07 99.85 108.20 AUC (EUxir) (Berlex) 124.08 121.86 U8.85 104.94 133.22 145.08 124.67 BioavaUabilltyt F% AUC-S.R.1 , nft 90.66 88.55 96.32 106.37 85.13 68.94 89.33 AtlC-BUx. * 100 F% AUC-S.R.1I AUC-ElIx. x lOO 64.51 96.98 U5.92 94.37 86.38 68.82 87.83 TABLE IV ' Compar felon of AUC^s for Subjects at the End of Five Days of Multiple Dosing of TheophyUine Products. Each Subject Received 300 mg Every 12 Hours of Sustained Release Capsules (S.R.I) (R.P. Scherer), 300 mg Every 12 Hours of Sustained Release Tablets (S.R.U) (Key Pharmaceuticals, Inc.) and 200 mg Every 8 Hours of the Elixir (Berlex Laboratories, Inc.) on Alternate Weeks During the Triple Crossover Phase of the Study. Subject 10 12 13 14 Average Sample Aϋc '1 (S.R.I) (Scherer) U4.64 102.28 U0.50 62.95 140.70 132.25 U0.55 AUC (S.R.U) (Key) 115.17 88,29 80.87 75.08 121.17 84.87 94.41 t t AUC (BUxir) (Berlex) U7.73 U6.21 100.77 79.09 142.30 148.78 U7.48 F% l AUC-S.R.I _ lnn Auc-tellx. * 100 97.38 88.01 109.63 79.59 98.88 88.89 93.06 v% AUC-S.RΛ ... AUC-BUx. x ,0 ° 98.67 75.07 80.25 94.93 85.15 57.04 82.00 F TABLE V • v Comparblon of AUC's for Subjects at the End of Five Days of Multiple Dosing of TheophyUine Products. Bach Subject Received 300 mg Every 12 Hours of Sustained Release Capsules (S.R.I) (R.Pi Scherer), 300 mg. Every 12 Hours of Sustained Release Tablets (S.R.π) (Key Pharmaceuticals, Inc.) and 200 mg Every 8 Hours of the Elixir (Berlex Laboratories, Inc.) on Alternate Weeks During the Triple Crossover Phase (Phase D) of the 8tudy. Subject 15 16. 17 18 19 20 Average Average of 18 Subjects Sample AUC (S.R.1) 1 (Scherer) 70.74 143.27 U8.84 U1.99 101.89 104.89 108.60 109.72 AUC (S.R.H) d (Key) 83.18 146.83 127.35 U8.52 94.65 82.U 108.78 103.79 co AUC (BUxir) (Berlex) 123.60 150.66 132.32 128J0 U9.98 128.53 130.53 124.23 F% AUC S.RJ .„„ AUC-ELIx.* 100 57.23 95.09 89.81 87.42 84.92 81.61 82.68 88.58 F% AUC-S.RJI ,„„ AuC-Elix. x I0β 67.30 97.46 96.24 92. 152 78.89 63.88 81.05 84.18 F% TABLE VI A Comparison of <V , -„,_ > . en Average C , »s for Subjects Receiving TheophyUine Products. Bach Subject Recefv σOι?_rDo_es of 300 mg ότ Sustained Release Capsules (S.R.I) (R.P. Scherer), 300 mg of Sustained Release Tablets (S.R.U) (Key Pharmaceuticals) Every 12 Hours for 5 days, and 200 mg of BUxir (Berlex Labβ) Every 8 Hours for- 5 Days on Alternate Weeks During the Triple Crossover Phase (Phase U) of the Study. Subject 21 Average Combined Ave. N=6 N=18 Sample S.R.I (Scherer) 12.38 10.39 10.72 13.03 U.32 10.78 U.43 U.46 max (hours) S.R.II (Key) 6.0 1.0 1.0 5.0 2.0 6.0 3.5 3.56 BUxir (Berlex) 0.5 2.0 1.0 1.0 2.0 1.25 1.06 S.R.I (Scherer) 5.35 7.81 6.34 6.91 6.96 6.87 6.62 TABLE VI (Continued) 10 12 13 14 Average N=β S.R.I (Scherer) U.39 U.81 10.25 7.67 14.07 14.25 H.57 C max S.R.U tøm_) (Key) 8.20 13.38 13.00 10.94 9.02 8.42 10.4.9 EUxir (Berlex) 13.60 13.88 12.07 9.12 15.98 15.53 13.36 S.R.I (Scherer) 6.0 5.0 8.0 5.0 3.0 3.0 5.00 C S.R.U max (Key) 4.0 6.0 8.0 3.0 0.0 2.0 3.83 (hours) EUxir (Berlex) 1.0 1.0 0.5 2.0 0.5 1.0 1.00 S.RJ 5.93 5.30 6.93 3.52 8.78 7J9 6.28 (Scherer) °mln S.R.U (_tg/ml) (Key) 6.08 9.23 9.75 8.34 7.32 7.29 8.00 BUxir (Berlex) 6.65 J5 5.84 3.92 9.86 9.28 7.12 TABLE. VI (Continued) 15 16 17 18 19 20 Average S.R.I (Scherer) β.50 15.21 U.60 U.96 12.28 10.65 U.37 max S.R.U (Key) tig/ml) 10.98 840 7.62 7.20 11.62 8.05 8.93 BUxir (Berlex) 14.17 15.20 13.65 12.99 14.45 15.57 14134 S.R4 (Scherer) 6.0 0.5 3.0 4.0 4.0 2.0 3.25 S.R.U I max (hours) (Key) 2.0 3.0 6.0 1.0 4.0 4.0 3.33 t CD I Elixir (Berlex) 0.5 1.0 2.0 1.0 ' 0.5 0.5 0.92 S.R.I (Scherer) 4.67 7.85 8.02 7.77 6.43 5.50 6.71 C 'mln S.R.II (Key) (•g ml) 8.37 7.42 4.62 5.36 8.67 7.18 6.94 BUxir (Berlex) 7.55 9.27 10.25 6.85 7.99 8.42 8.38 "The average C . reported for the sustained release capsules and sustained release tablets represent While in the foregoing there has been provided a detailed description of preferred embodiments of the present invention, it is to be understood that all equivalents obvious to those having skill in the art are to be included within the scope of the invention as claimed.

Claims: CLAIMS; 1. A filled, gelatin capsule comprising in combination, a shell formed from gelatin, a fill material contained within said shell, said shell being sized and shaped to be readily swallowable, said fill material comprising a masticatory substance and a medicament dispersed throughout said substance, said medicament being of a type that is desirably and effectively gradually released for absorption by the body over an extended period of time, said substance defining a cohesive matrix for said medicament, said gelatin sheU being rapidly dissolved in said gastrointestinal juices, said masticatory substance matrix being substantially insoluble in the presence of gastrointestinal juices, said matrix being of a type that is capable of being subjected to substantially continuous random motion while in said juices while at body temperature and while under the influence of peristaltic movement in the gastro- intestinal tract for substantially varying the exposed surface area of said fill, and said medicament being gradually released over an extended period as said exposed surface area is varied for ultimate absorption of said medicament by the body. 2. The capsule of Claim 1 wherein said gelatin sheE is a one- piece, soft elastic gelatin capsule formed from gelatin, water and a plastieizer. 3. The capsule of Claim 1 wherein said medicament is selected from the group consisting of antihistamines, sedatives, tranquilizers, cardiovascular drugs, respiratory drugs, sympathomimetic drugs, diuretic drugs, analgesics and antipyretics, antimotion sickness and antinauseants, and electrolytes and hematinics. 4. The capsule of Claim 1 wherein said medicament is theophyUine. 5. The capsule of Claim 3 wherein said medicament is enclosed by an enteric coating. OMPI 6. The capsule of Claim 1 wherein said fiU material includes gum which comprises an insoluble, cohesive, masticatory substance. 7. The capsule of Claim 6 wherein said fiU material further includes paraffin, ineral oil, or neutral oil. 8. The capsule of Claim 6 wherein the insoluble cohesive masticatory substance is a natural masticatory substance selected from the group consisting of Chicle, Chiquibul, Crown gum, Gutta hang kang, Massaranduba balata (and the solvent-free resin extract of Massaranduba balata), Massaranduba chocolate, Nispero, Rosidinha (rosadinha), Venezuelan chicle, Jelutong, Leche caspi (sorva), Pendare, PeriUo, Leche de vaca, Niger gutta, Tunu (tuno), Chite, and Natural Rubber smoked sheet and latex Hevea brasiliensis soUds). 9. The capsule of Claim 6 wherein the masticatory substance a synthetic masticatory substance selected from the group which consists of Butadiene-styrene rubber, isobutylene-isoprene copolymer (butyl rubber), silicone elastomers, paraffin, petroleum wax, petroleum wax synthetic, polyethylene (mol. wt. 2,000-21,000), polyisobutylene (mol. wt. 37,000), polyvinyl acetate (mol. wt. 2,000), and polyvinyl alcohol. 10. The capsule of Claim 1 wherein said fiU material comprises masticatory substance present in an amount of U 6-2896 by weight, a plasticizing material present in an amount of about 3596-57% by weight, a water insoluble adjuvant present in an amount of about 40- 50% by weight, and a minor amount of an antioxidant, said masticatory substance having a softening end point of about 67-76° C, an ash content of 46%, plus or minus 2%, and a maximum moisture content of about 1%. . E. A method for graduaEy releasing a medicament for absorption by the body through the gastrointestinal system, said method comprising the steps of preparing a fiU material of a masticatory substance and a medicament and said medicament being dispersed throughout said masticatory substance, said medicament being of the type that is desirably and effectively released for absorption from the gastrointestinal tract over an extended period of time, forming a supporting cohesive matrix for said medicament from said masticatory substance, said masticatory substance being substantiaUy insoluble in gastrointestinal juices, forming a sheE of gelatin around said fiU material to form a fiUed capsule, said capsule being sized and shaped to be readily swaUowable, oraUy administering said capsule, dissolving said gelatin sheE after swaEowing with said juices, subjecting said fiE material with said medicament therein to substantiaEy constant random motion whEe in said juices whEe at body temperatures and whEe under the influence of peristaltic movements in the gastrointestinal tract for continuously varying the surface area of said fiE material, and graduaEy releasing said medicament from said exposed surface area over an extended period of time for absorption by the body. 12. The method of Claim E wherein said gelatin sheE is a one- piece, soft elastic gelatin capsule formed from gelatin, water and a plastieizer. 13. The method of Claim E wherein said medicament is selected from the group consisting of antihistamines, sedatives, tranquEizers, cardiovascular drugs, respiratory drugs, sympathomimetic drugs, diuretic drugs, analgesics and antipyretics, antimotion sickness and antinauseants, and electrolytes and hematϊnics. 14. The method of Claim E wherein said medicament is theophyUine. 15. The method of Claim 13 including the step of enteric coating said medicament. 16. The method of claim E wherein said masticatory substance includes an insoluble, cohesive, gum. 17. The method of Claim 16 wherein said fiE material further includes paraffin, mineral oil, or neutal oil. 18. The method of Claim E wherein said masticatory substance is a natural masticatory substance selected from the group of Chicle, Chiquibul, Crown gum, Gutta hang kang, Massaranduba balata (and the solvent-free resin extract of Massaranduba balata), Massaranduba chocolate, Nispero, Rosidinha (rosadinha), Venezuelan chicle, Jelutong, Leche caspi (sorva), Pendare, PeriEo, Leche d.e vaca, Niger gutta, Tunu (tuno), Chite, and Natural rubber (smoked sheet and latex Hevea brasEiensis solids). 19. The method of Claim E wherein said masticatory gum substance is a synthetic masticatory substance selected from the group consisting of butadiene-styrene rubber, isobutylene-isoprene copolymer (butyl rubber), silicone elastomers, paraffin, petroleum wax, petroleum wax synthetic, polyethylene (mol. wt. 2,000-21,000), polyisobutylene (mol. wt. 37,000), polyvinyl acetate (mol. wt. 2,000), and polyvinyl alcohol. 20. The method of Claim E wherein said gum comprises a synthetic masticatory substance present in an amount of E%-28% by weight, a plasticizing material or softener present in a range of about 35%-57% by weight, about 40%-50% by weight of a water insoluble adjuvant, and a minor amount of an antioxidant, said masticatory substance having a softening end point of about 67-76° C, an ash content of 46% plus or minus about 2%, and a maximum moisture content of about 1%.

Inventors: EBERT WILLIAM R, HOM FOO S, EBERT, WILLIAM, R., HOM, FOO, S.
Applicants: SCHERER CORP R P, R. P. SCHERER CORPORATION
Application year: 1984
Main classification: A61K9
IPC codes: A61K9