CA1096307A - Pharmaceutical preparations - Google Patents
Pharmaceutical preparationsInfo
- Publication number
- CA1096307A CA1096307A CA220,535A CA220535A CA1096307A CA 1096307 A CA1096307 A CA 1096307A CA 220535 A CA220535 A CA 220535A CA 1096307 A CA1096307 A CA 1096307A
- Authority
- CA
- Canada
- Prior art keywords
- digoxin
- preparation
- solution
- amount
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Abstract of the Disclosure Provided by the invention is a pharmaceutical pre-paration comprising a solution of digoxin in a soluble capsule shell together with a method of preparing such a preparation which comprises marginally welding two sheets of the material comprising the capsule shell together around a unit dose of the solution of digoxin comprising the content of the capsule. In one aspect the digoxin is present in the preparation in an amount of 80% of that conventionally presented as a tablet formulation. Also provided is a method for the treatment of cardiac insufficiency in a mammal including man which comprises the administration to the mammal of a pharmaceutical preparation as above described containing an effective cardiac insufficiency treatment amount of digoxin.
Description
3~i7 rhe pre~ent inY~ntiOn relates to a new and improYed ll!e ChOd OJ inCr~.1 .;~in~r, the bio~vailability of di~;oxin in arnmals includin~ man. The present; in~ention enables sub-stalltially h-igher concentrations of digoxin in the blood to be acnieve~ tharl ar~ obtaiilea ~nrougn tne use oC taD -le-cs COA~tain.L~g tne sarne amo~lt of digoxinv The pres0nt invention al30 relates to pharmaceutical preparations comprisin$ a solution of digoxi1l in a eap~ule which will rapidly release the digroxin for uptake in. for example and preferably, the upper gastrointestinal tract of a m&~ma1 su^h as a h-e~man~
Ths glyc^side d-~roxin5 che~isally named 3~-tri-(~
ciigitoxosyl)oxy-12~14 ~dihydroxy-5~-card-20(22)-en~lide, nas fo~ld extensive use in ihe treaiment OI numan paiients with cardiac insufficiency. As used herein the ter~ carcliac ~nsufficiency shoulcd be ~Iderstood to includc congestive heart failure, atrial fibrillation, atrial flutter, ~upra-~entricular tachycardia and pre~ature extrasystoles.
In tho past, patientq (i.e. adult humans) have sener-~ ally been administered digoxin orally in the fo~n of tab-lets which have conventionally bee~ formulæted to contain CoO625 ;ng~ 0~125 mg~ 0~25 mO~ C~ 375 ;nOF~ or 0.5 mg of digoxin. Of these the tablets containing respectively 0.0~25 mO~ 0.125 mg and 0.25 mg Or digo~in have been *ne niost conuuonly us~d s~ tile 0.25 mg tai~le.- finding the most gener-al acceptance. As u~ed herein, th~ -term pa*ient ~hould be t~derstood to mean a hw~an patien*.
~i~
C~2~ l ~5 In cases where rapid digitalization to treat car-diac insufficiency is desired in one day or less, the pati-ent is normally given 0.5 mg to 1.5 mg of digoxin initially followed by 0.25 mg to 0.5 mg of digoxin every six to eight hours, as required, to complete digitalization. In elderly patients, and where there is less urgency, a smaller initial dose of 0.25 mg to 1.0 mg of digoxin may be given. In gen-eral, the average total digitalizing dose of digoxin for the patient is 2 mg to 3 mg. Thereafter maintenance doses of about 0.125 mg to 0.5 mg of digoxin are administered daily.
All these doses relate to the use of digoxin tablets as described above.
Digoxin is known to be a drug for which the thera-peutic blood levels are quite close to, and indeed sometimes overlap with, the blood levels causing toxic symptoms such as anorexia, nausea, vomiting, and various cardiac arrhyth-mias, etc. Although these toxic symptoms are not normally encountered in titrated patients having digoxin uptake or absorption within normal limits, patients which exhibit abnormal digoxin uptake may be at considerable risk.
Patients with abnormal uptake due to conditions such as greatly increased gastrointestinal mobility often require larger than normal doses of digoxin to evoke appro-priate digitalization. Clearly, in such patients receiving larger than normal doses, the greater the variation and the quantity of digoxin available for uptake the greater is the risk that the therapeutic to toxic threshold will be crossed.
All oral digoxin preparations investigated to date and known to us have been less than completely absorbed and hence have the potential for variable absorption. The 1~63~7 present invention enables a reduction in the risk of variable uptake because it enables a significant reduction in the in-completeness of absorption.
The present invention relates to a new and improved method and pharmaceutical preparation for increasing the bioavailability of digoxin in marnmals including man.
According to one aspect of this invention, digoxin is ad-ministered to a patient in an amount which is approximately 80% of the dosage administered as conventional digoxin tab-lets to achieve substantially the same blood level of digo-xin in the patient. The aforementioned increase in bio-availability is accomplished by the utilization of a solu-tion of digoxin in a soluble capsule shell, for example, soluble in the upper gastrointestinal tract of the patient.
The capsule thus preferably comprises a soft gelatin shell which will substantially completely dissolve within the upper gastrointestinal tract in a short period of time to release a solution containing digoxin in an effective car-diac insufficiency treatment amount, The dissolution rate of the capsule shell in the upper gastrointestinal tract is desirably 100% in not more than one hour, preferably 100%
in not more than 30 minutes and optionally 100% in not more than 15 minutes.
It should be clearly understood that wherever reference is made herein to the adrninistration of conven-tional digoxin tablets or of capsules of the present inven-tion the said administration is by the oral route with the tablets or capsules being swallowed by the patient while still in an essentially intact condition. Further, the capsules of the present invention as herein described should ~63~7 be understood to permit of administration in this manner.
As used herein the following terms should be under-stood to have the definitions respectively indicated there-for: (i) the upper gastrointestinal tract means the stomach and the duodenum, (ii) a solution of digoxin means a phar-maceutically and medicinally acceptable solution of digoxin;
(iii) a solution means a pharmaceutically and medicinally acceptablesolution, and (iv) pharmaceutically and medicinally acceptable means acceptable to the gastrointestinal tract of the patient. Further, as the term is used herein, a solution of digoxin should be understood to include those mixtures in which at least a portion of the digoxin is in solution, and pharmaceutical preparations comprising a solution of digoxin in a soluble capsule shell should accordingly be understood to include those preparations wherein at least a portion of the digoxin held within the capsule shell is in solution.
The capsule shell when preferably made of gelatin may include plasticizers such as glycerin or sorbitol water, preservative(s), colouring agent(s), and opacifying agent(s). Reference may be had to the standard work "Remington's Practice of Pharmacy", Martin and Cook (eds.), 14th Edition, published by The Mack Publishing Company, Easton, Pennsylvania, page 1675 under the heading "Elastic Capsules" to page 1677, for a description of gelatin cap-sules rapidly dissolvable in the gastrointestinal tract and the manufacture of such capsules. Reference may also be had to U.S. Patents 1,970,396, 2,899,361 and 2,928,128 for a description of soft gelatin capsules and their manufacture.
In addition reference may be had to the standard work "The Theory and Practice of Industrial Pharmacy" by Lackman, Lieberman and Kanig, published by Lea and Febiger, ~19Si3~
Philadelphia, Pennsylvania (1970) at pages 359 to 384 for a discussion of soft gelatin capsule technology.
Thus conventionallly a gelatin mass is first pre-pared comprising gelatin, water, and the other ingredients of the capsule shell (as detailed hereinabove) by milling together the ingredients in a suitable mixer. The mixture is then transferred to a melter where it is kept under a more or less complete vacuum and heated until a smooth, fluid mass is obtained. The filled capsules of the present invention may be prepared from this plastic mass by in general forming the mass into two plastic sheets and margi-nally welding two such sheets together around a unit dose of the solution of digoxin which will form the content of the resulting capsule. Advantageously, to enable uniformity of quality of the capsule shells, the gelatin mass is completely and constantly agitated until the step of forming into sheets.
Apparatus suitable for the continuous production of soft elastic capsules is well known in the art. In one form such apparatus comprises a pair of smooth-faced drums on each of which a gelatin ribbon or film is cast, a pair of cooperating die rolls containing complementary die cavities in which the ribbon is shaped to form the capsules, and a feeder head disposed in the bight of the die rolls for introducing the liquid content (in the present invention, the solution of digoxin) into the capsule as it is formed.
The ribbons are stripped from the drums and simultaneously fed over the rotating rolls into juxtaposition whereupon the liquid content is ejected, at precisely the correct time, from the feeder head into the ribbons to stretch them into 63~ J
opposed die cavities to shape ancl fill the capsule. As the die rolls rotate, ridges surrounding each of the cooperating opposed cavities serve progressively to seal the ribbon to-gether about the entire periphery of the distended portion of the ribbon which comprises the capsule and sever the formed capsule from the ribbon. In this process the content of each capsule is measured individually by the single stroke of a pump.
Immediately after a capsule of conventional con-struction as described above has been formed, the shell thereof still contains the water content of the gelatin mass from which the shell has been made. For this reason the capsules are characteristically relatively weak when first made. To make the capsules stronger they are therefore, in general, dehydrated by exposure to dry warm air, to acetone, or to some other agent capable of extracting water from the capsule shell.
The shell thickness of conventional soft gelatin capsules ranges typically from 0.018 inch to 0.030 inch and may average about 0.025 inch. The capsules are generally circular in transverse cross-section. The capsules provided by the present invention are preferably elongated such as ellipsoidal, oval, or cylindrical with rounded ends.
The digoxin is placed in solution prior to the encapsulation step. A suitable solution may be prepared by conventionally mixing digoxin with a solvent such as ethanol, glycerin, propylene glycol, isopropanol, and poly-ethylene glycols such as polyethylene glycol 400, or a mix-ture of two or more of these solvents. Heating may option-ally be employed to speed solution of the digoxin. It will 3~
be appreciated that a suitable mixture of solvents will vary with the desired concentration and composition of the solvent system. As used herein the term solvent should be understood to mean a solvent which is pharmaceutically and medicinally acceptable to the gastrointestinal tract of a mammal, which will dissolve digoxin to form a soltuion, and which is not substantially destructiveof the capsule shell.
A cosolvent which may be used together with the above-men-tioned solvents is polyvinyl-pyrrolidone.
Polyethylene glycols having an average molecular weight of 190 to 6000 and containing 2 to 136 ethylene glycol monomer units (-CH2CH2O-) may advantageously be used as a cosolvent, and polyethylene glycols having an average molecular weight of 190 to lO00 and containing about 2 to 25 ethylene glycol monomer units as above may advantageously be used as a solvent or cosolvent. Other solvents or co-solvents which are suitable include 1,2-propylene glycol, hexamethylene glycol, 1,3-butylene glycol, dimethylsul-foxide, polyethylene glycol ethers of tetrahydrofurfuryl alcohol, and di-(1,2-propylene glycol). In addition water may be used as a cosolvent in an amount not more than 60~/~
(by weight) of the solvent mixture, preferably up to 5% (by weight) of the solvent mixture.
Preferred capsules of the present invention are those which each contain a digoxin solution in an amount which contains digoxin in the range 0.05 mg to 0.4 mg, more preferably 0.05 mg to 0.2 mg. Specifically preferred cap-sules of the present invention contain digoxin in an amount per capsule selected from 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg and 0.4 mg, of these, capsules each containing 0.05 mg, 0,1 mg or 0.2 mg are more preferred and a capsule containing ~ D' ~L~9~3~
0,2 mg of digoxin the most preferred. For general con-venience capsules containing a lesser amount of digoxin are preferably physically smaller than those capsules containing a greater amount of digoxin.
The concentration of the digoxin solution within the capsules of the present invention may be in the range 0.1 to 2.0 mg digoxin/ml., but is preferablyin the range 0,25 to 0.95 mg digoxin/ml., more preferably 0.35 to 0.6 mg digoxin/ml., and optimally 0.4 to 0.5 mg digoxin/ml. As the term is used herein, concentration should be understood to mean mg of digoxin/ml of solution. Thecapsuleshells may be chosen from those that are commercially available, the size (capacity) thereof and the concentration of the digoxin solution filled therein being balanced the one against the other such that eachcapsule contains the desired unit dose of digoxin.
As used herein the term an effective cardiac in-sufficiency treatment amount of digoxin should be understood to mean one or more capsules of the present invention as described herein, each capsule preferably containing digoxin in the range 0.05 mg to 0.4 mg as detailed hereinabove. The capsules of the present invention, by virtue of their providing as herein described an increased bioavailability of digoxin as compared with digoxin tablets, enable the dosing schedule detailed below to be utilized in the treat-ment of cardiac insufficiency. Each individual dose and the cumulative dosage of digoxin thereby administered is but 80% of that required with the equivalent schedule as set out hereinabove utilizing digoxin tablets.
~9~i3~'~
Thus where rapid digitalization is desired in one day or less the patient may be given 0.4 mg to 1.2 mg of digoxin initially followed by 0.2 mg to 0.4 mg o digoxin every six to eight hours, as required, to complete digitali-zation. In elderly patients, ancl where there is less urgency a smaller initial dose of 0.2 mg to 0.8 mg of digoxin is suitable. Thereafter maintenance doses of 0.1 mg to 0.4 mg of digoxin per day may be given, depending of course upon the patient and the discretion of the physician.
Thus according to the invention there is provided an orally ingestible pharmaceutical preparation comprising a solution of digoxin in a soft gelatin capsule shell which is soluble in the upper gastrointestinal tract of a mammal, the amount of digoxin in the capsule being an amount which is less than the digoxin content of a conventional tablet to provide upon oral administration of the capsule to man sub-stantially the same therapeutic effect as is provided by oral administration to man of the conventional tablet.
Suitably the digoxin is present in an amount which is 80% of that of a conventional tablet formulation.
In another aspect of the invention there is provided a method of preparing the pharmaceutical prepara-tion of the invention which comprises providing a solution of digoxin and encapsulating unit dose of the solution in a soft gelatin capsule for oral administration.
In a particular embodiment of this latter aspect of the invention there is provided a method of preparing a pharmaceutical preparation as defined above which comprises marginally welding two sheets of the soft gelatin material comprising the capsule shell together around a unit dose of the solution of digoxin comprising the content of the capsule.
.
~L~9~i3~
The invention provides in another aspect a method for the treatment of cardiac insufficiency in a mammal including man which comprises the administration to the mammal of a pharmaceutical preparation according to the invention above containing an effective cardiac insufficiency treatment amount of digoxin.
In a further aspect of the invention there is provided a method for increasing the bioavailability of digoxin in a mammal including man suffering from cardiac insufficiency which comprises administering to the mammal a pharmaceutical preparation of the invention containing an effective cardiac insufficiency treatment amount of digoxin.
The following Examples are provided by way of illustration of the present invention and should not be construed as in any way providing a limitation thereof.
Example (I) The following comparative example illustrates the unexpected properties of a capsule containing digoxin in solution in comparison with tablets containing digoxin in dry form at the same dose or in a greater dose than in the capsule. All capsules and tablets used in this example were subjected to quality control testing to ensure con-tent uniformity. -The procedure used for obtaining the results was as follows.
Eight normal human subjects were given each of the four following digoxin preparations with rest periods in between to permit digoxin clearance.
(A) 0.2 mg digoxin in solution in soft gelatin capsule shell - dissolution rate 100% at 63~
1 hour (6th Interim revision, U.S.P~ XVIII
(November 15, 1973)) (B) 0.2 mg digoxin in tablet - dissolution rate 97% at 1 hour (C) 0.25 mg digoxin in tablet - dissolution rate 97% at 1 hour (D) 0.25 mg digoxin in tablet (standard Lanoxin (Trade Mark) brand digoxin) - dissolution rate 78% at 1 hour Dosage was 4 doses at 8-hour intervals each of 2 tablets or capsules, then 1 tablet or capsule twice a day on days 3-9. Serum digoxin levels after the first dose and in the steady state (days 8-10), and 24-hour urine digoxin excretion on day 1 were measured by radioimmunoassay.
The results (mean and standard errors) are as below.
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~!9963n~.' Preparation (A) was be-tter absorbed than (B), as indicated by 1 hr (pc.05) serum levels, 24 hr urine levels (p<.01), areas under curve (p<.001), and steady state serum levels(p<.02). Despite the smaller digoxin dosage, absorp-tion of (A) was similar to that of (C) and (D). There were also no significant differences between (C) and (D). (B)-to-(C) and (B)-to-(D) differences were significant, consis-tent with different digoxin content. Coefficient of variation of steady state serum values did not differ significantly among the four preparations. ECG (electro-cardiogram) changes (8 hr monitoring) were similar with all four preparations.
It was concluded that (1) digoxin tablets having a dissolution rate of 97% at 1 hr are no better absorbed by normal human subjects than currently available tablets (preparation (D)), and (2) a switch from tablet to solution filled capsules would require a reduction in digoxin dosage.
The soft gelatin capsules (preparation (A)) con-tained 0.2 mg digoxin in a fill volume of 6.65 minims, a fill weight of 448 mg. The digoxin was dissolved in a solvent comprising ethanol (absolute), water, propylene glycol, and polyethylene glycol 400. With the above fill weight the concentration of the digoxin was calculated to be about 0.45 mg/ml by dividing the weight of digoxin by the fill volume in ml, assuming the solution to have a density of 1.0 g/ml. The percentage amounts of the various ingredients of the solvent were as set forth in Example (II).
Example (II) A suitable solvent system for use in preparing capsules each containing 0.2 mg of digoxin includes the following ingredients (percentages by weight):
~ i .
~ 31~3C~ 1~
Polyethylene glycol 400 - 90%
Ethanol (absolute) - 6%
Propylene glycol - 3O/o Water - 1%
A solution of digoxin in the aforementioned sol-vent system was packaged in a conventional soft gelatin capsule shell using conventional soft gelatin capsule pack-aging machinery to provide soft gelatin capsules, each containing 0.2 mg of digoxin. The solution ingredients are conventionally stirred together and may be heated if desired to speed solution of the digoxin.
For a solution having a concentration of 0.35 mg of digoxin/ml, a capsule containing 0.2 mg of digoxin would require about 0.57 ml of solvent. This is conventionally determined by dividing the weight of the digoxin to be in-corporated in the capsule by the concentration of the solu-tion, assuming the weight of digoxin in the solution to be negligible. For the capsules of Example (I), the amount of solvent of Example (II) used would weigh about 447.8 mg and may be determined by subtracting the weight of digoxin from the fill weight. The concentration would be calculated as detailed in Example (I).
Example (III) A soft gelatin capsule shell was filled with a solution containing 0.1 mg of digoxin in polyethylene glycol 400, 100% by weight. For a solution having a concentration of 0.25 mg/ml, a capsule containing 0.1 mg of digoxin was calculated to require about 0.4 ml of polyethylene glycol 400.
Examples (IV) to (X?
By methods analogous to that described in Example (II), the following solutions of digoxin were prepared and packaged in soft gelatin capsule shells to provide capsules each containing digoxin in the respective amounts shown.
Solution Example Weight of No. Solvent Digoxin concn. digoxin per (% by weight)(m~/ml) capsule (mq) (IV) Polyethylene0.50 0.05 glycol 400 (90/O) Glycerin ( 10%) (V) Propylene 0.40 0.05 glycol ( 100%) (VI) Propylene 0.50 0.2 glycol (100%) (VII) Ethanol (absolute) 0.45 0.1 (50O/o) Proplene glycol (50/O) (VIII) Ethanol (absolute) 0.50 0.2 (5%) Glycerin (5%) Propylene glycol (90%) (IX) Ethanol (absolute) 0.43 0.1 ( 1 0/0 ) Propylene glycol (89%) Water (1%) ~.~
1~6~
(X) Propylene glycol 0'35 0.
( g 90/o ) Water (1%) Example (XI) Seven normal human subjects were each given (i) two of the capsules (preparation (A)) of Example (I), and (ii) an equivalent (as regards digoxin content) dose of a digoxin solution corresponding to the contents of the said capsules, with a rest period between the administration of (i) and (ii) to permit digoxin clearance.
The mean results obtained are as shown below: all data refer to digoxin.
Capsules Solution Peak serum concn. (ng/ml) : 3.63 2.53 Area under curve (serum), 0-6 hrs (ng/ml x min) : 471 314 Area under curve eliminating subject: 409 303 with double peak (ng/ml x min) Mean 6 hr serum concn. (ng~ml) : 0.42 0.39 24 hr Urine excretion (~g) : 102 85 Examples (XII) to (XVI) By methods analogous to that described in Example (II), soft gelatin capsules were prepared each containing digoxin in the respective amounts shown.
Weight of digoxin Example Fill vol. Fill weight per capsule No. (minims) (mq) (mq) (XII) 0.90 59 0 05 (XIII) 1.80 118 0.10 (XIV) 3,60 235 0.20 (XV) 5.40 353 0.30 (XVI) 7.20 470 0.40 3~
The digoxin solution filled into the capsule shells had the samecomposition in each instance, as below (all percentages by weight).
Solvent:
Polyethylene glycol 400 : 89.5%
Ethanol (absolute) 6%
Propylene glycol : 3.5%
Water : 1%
Concentration of digoxin : 0.94 mg/ml Examples (XVII) to (XXXII) By methods analogous to that described in Example (II) solutions of digoxin in the following solvent systems were prepared and packaged in soft gelatin capsule shells to provide capsules each containing 0.05 mg of digoxin, the concentration of digoxin (mg/ml) in the solution and the size (capacity) of the capsule shells being chosen appropriately in each case. All references are to percentages by weight: the ethanol was in each case absolute.
Example No. Solvent (XVII) Glycerin ( 100%) (XVIII) Ethanol (40/O), water (60%) (XIX) Ethanol (50/O)~ water (50O/o) (XX) Ethanol ( 80%), water ( 200/o) (XXI) Propylene glycol (lOOo/o) (XXII) Propylene glycol (75%), water (25%) (XXIII) Propylene glycol (50/O), water (50/O) (XXIV) Propylene glycol (40/O)~ water (600/o) (XXV) Polyethylene glycol 200 ( 100%) : 30 (XXVI) Polyethylene glycol 400 ( 100%) ~63~ 1f' (XXVII) Isopropanol ( 100%) (XXVIII) Propylene glycol (40/0), ethanol (5%), water (55%) (XXIX) Propylene glycol ( 50/0), ethanol (5%), water (45%) (XXX) Propylene glycol (30/0), ethanol (10%) water ( 600/o) (XXXI) Propylene glycol (40/0), ethanol (l~/o) water (50/0) (XXXII) Propylene glycol (50/0), ethanol ( 10%) water (40/0).
Ths glyc^side d-~roxin5 che~isally named 3~-tri-(~
ciigitoxosyl)oxy-12~14 ~dihydroxy-5~-card-20(22)-en~lide, nas fo~ld extensive use in ihe treaiment OI numan paiients with cardiac insufficiency. As used herein the ter~ carcliac ~nsufficiency shoulcd be ~Iderstood to includc congestive heart failure, atrial fibrillation, atrial flutter, ~upra-~entricular tachycardia and pre~ature extrasystoles.
In tho past, patientq (i.e. adult humans) have sener-~ ally been administered digoxin orally in the fo~n of tab-lets which have conventionally bee~ formulæted to contain CoO625 ;ng~ 0~125 mg~ 0~25 mO~ C~ 375 ;nOF~ or 0.5 mg of digoxin. Of these the tablets containing respectively 0.0~25 mO~ 0.125 mg and 0.25 mg Or digo~in have been *ne niost conuuonly us~d s~ tile 0.25 mg tai~le.- finding the most gener-al acceptance. As u~ed herein, th~ -term pa*ient ~hould be t~derstood to mean a hw~an patien*.
~i~
C~2~ l ~5 In cases where rapid digitalization to treat car-diac insufficiency is desired in one day or less, the pati-ent is normally given 0.5 mg to 1.5 mg of digoxin initially followed by 0.25 mg to 0.5 mg of digoxin every six to eight hours, as required, to complete digitalization. In elderly patients, and where there is less urgency, a smaller initial dose of 0.25 mg to 1.0 mg of digoxin may be given. In gen-eral, the average total digitalizing dose of digoxin for the patient is 2 mg to 3 mg. Thereafter maintenance doses of about 0.125 mg to 0.5 mg of digoxin are administered daily.
All these doses relate to the use of digoxin tablets as described above.
Digoxin is known to be a drug for which the thera-peutic blood levels are quite close to, and indeed sometimes overlap with, the blood levels causing toxic symptoms such as anorexia, nausea, vomiting, and various cardiac arrhyth-mias, etc. Although these toxic symptoms are not normally encountered in titrated patients having digoxin uptake or absorption within normal limits, patients which exhibit abnormal digoxin uptake may be at considerable risk.
Patients with abnormal uptake due to conditions such as greatly increased gastrointestinal mobility often require larger than normal doses of digoxin to evoke appro-priate digitalization. Clearly, in such patients receiving larger than normal doses, the greater the variation and the quantity of digoxin available for uptake the greater is the risk that the therapeutic to toxic threshold will be crossed.
All oral digoxin preparations investigated to date and known to us have been less than completely absorbed and hence have the potential for variable absorption. The 1~63~7 present invention enables a reduction in the risk of variable uptake because it enables a significant reduction in the in-completeness of absorption.
The present invention relates to a new and improved method and pharmaceutical preparation for increasing the bioavailability of digoxin in marnmals including man.
According to one aspect of this invention, digoxin is ad-ministered to a patient in an amount which is approximately 80% of the dosage administered as conventional digoxin tab-lets to achieve substantially the same blood level of digo-xin in the patient. The aforementioned increase in bio-availability is accomplished by the utilization of a solu-tion of digoxin in a soluble capsule shell, for example, soluble in the upper gastrointestinal tract of the patient.
The capsule thus preferably comprises a soft gelatin shell which will substantially completely dissolve within the upper gastrointestinal tract in a short period of time to release a solution containing digoxin in an effective car-diac insufficiency treatment amount, The dissolution rate of the capsule shell in the upper gastrointestinal tract is desirably 100% in not more than one hour, preferably 100%
in not more than 30 minutes and optionally 100% in not more than 15 minutes.
It should be clearly understood that wherever reference is made herein to the adrninistration of conven-tional digoxin tablets or of capsules of the present inven-tion the said administration is by the oral route with the tablets or capsules being swallowed by the patient while still in an essentially intact condition. Further, the capsules of the present invention as herein described should ~63~7 be understood to permit of administration in this manner.
As used herein the following terms should be under-stood to have the definitions respectively indicated there-for: (i) the upper gastrointestinal tract means the stomach and the duodenum, (ii) a solution of digoxin means a phar-maceutically and medicinally acceptable solution of digoxin;
(iii) a solution means a pharmaceutically and medicinally acceptablesolution, and (iv) pharmaceutically and medicinally acceptable means acceptable to the gastrointestinal tract of the patient. Further, as the term is used herein, a solution of digoxin should be understood to include those mixtures in which at least a portion of the digoxin is in solution, and pharmaceutical preparations comprising a solution of digoxin in a soluble capsule shell should accordingly be understood to include those preparations wherein at least a portion of the digoxin held within the capsule shell is in solution.
The capsule shell when preferably made of gelatin may include plasticizers such as glycerin or sorbitol water, preservative(s), colouring agent(s), and opacifying agent(s). Reference may be had to the standard work "Remington's Practice of Pharmacy", Martin and Cook (eds.), 14th Edition, published by The Mack Publishing Company, Easton, Pennsylvania, page 1675 under the heading "Elastic Capsules" to page 1677, for a description of gelatin cap-sules rapidly dissolvable in the gastrointestinal tract and the manufacture of such capsules. Reference may also be had to U.S. Patents 1,970,396, 2,899,361 and 2,928,128 for a description of soft gelatin capsules and their manufacture.
In addition reference may be had to the standard work "The Theory and Practice of Industrial Pharmacy" by Lackman, Lieberman and Kanig, published by Lea and Febiger, ~19Si3~
Philadelphia, Pennsylvania (1970) at pages 359 to 384 for a discussion of soft gelatin capsule technology.
Thus conventionallly a gelatin mass is first pre-pared comprising gelatin, water, and the other ingredients of the capsule shell (as detailed hereinabove) by milling together the ingredients in a suitable mixer. The mixture is then transferred to a melter where it is kept under a more or less complete vacuum and heated until a smooth, fluid mass is obtained. The filled capsules of the present invention may be prepared from this plastic mass by in general forming the mass into two plastic sheets and margi-nally welding two such sheets together around a unit dose of the solution of digoxin which will form the content of the resulting capsule. Advantageously, to enable uniformity of quality of the capsule shells, the gelatin mass is completely and constantly agitated until the step of forming into sheets.
Apparatus suitable for the continuous production of soft elastic capsules is well known in the art. In one form such apparatus comprises a pair of smooth-faced drums on each of which a gelatin ribbon or film is cast, a pair of cooperating die rolls containing complementary die cavities in which the ribbon is shaped to form the capsules, and a feeder head disposed in the bight of the die rolls for introducing the liquid content (in the present invention, the solution of digoxin) into the capsule as it is formed.
The ribbons are stripped from the drums and simultaneously fed over the rotating rolls into juxtaposition whereupon the liquid content is ejected, at precisely the correct time, from the feeder head into the ribbons to stretch them into 63~ J
opposed die cavities to shape ancl fill the capsule. As the die rolls rotate, ridges surrounding each of the cooperating opposed cavities serve progressively to seal the ribbon to-gether about the entire periphery of the distended portion of the ribbon which comprises the capsule and sever the formed capsule from the ribbon. In this process the content of each capsule is measured individually by the single stroke of a pump.
Immediately after a capsule of conventional con-struction as described above has been formed, the shell thereof still contains the water content of the gelatin mass from which the shell has been made. For this reason the capsules are characteristically relatively weak when first made. To make the capsules stronger they are therefore, in general, dehydrated by exposure to dry warm air, to acetone, or to some other agent capable of extracting water from the capsule shell.
The shell thickness of conventional soft gelatin capsules ranges typically from 0.018 inch to 0.030 inch and may average about 0.025 inch. The capsules are generally circular in transverse cross-section. The capsules provided by the present invention are preferably elongated such as ellipsoidal, oval, or cylindrical with rounded ends.
The digoxin is placed in solution prior to the encapsulation step. A suitable solution may be prepared by conventionally mixing digoxin with a solvent such as ethanol, glycerin, propylene glycol, isopropanol, and poly-ethylene glycols such as polyethylene glycol 400, or a mix-ture of two or more of these solvents. Heating may option-ally be employed to speed solution of the digoxin. It will 3~
be appreciated that a suitable mixture of solvents will vary with the desired concentration and composition of the solvent system. As used herein the term solvent should be understood to mean a solvent which is pharmaceutically and medicinally acceptable to the gastrointestinal tract of a mammal, which will dissolve digoxin to form a soltuion, and which is not substantially destructiveof the capsule shell.
A cosolvent which may be used together with the above-men-tioned solvents is polyvinyl-pyrrolidone.
Polyethylene glycols having an average molecular weight of 190 to 6000 and containing 2 to 136 ethylene glycol monomer units (-CH2CH2O-) may advantageously be used as a cosolvent, and polyethylene glycols having an average molecular weight of 190 to lO00 and containing about 2 to 25 ethylene glycol monomer units as above may advantageously be used as a solvent or cosolvent. Other solvents or co-solvents which are suitable include 1,2-propylene glycol, hexamethylene glycol, 1,3-butylene glycol, dimethylsul-foxide, polyethylene glycol ethers of tetrahydrofurfuryl alcohol, and di-(1,2-propylene glycol). In addition water may be used as a cosolvent in an amount not more than 60~/~
(by weight) of the solvent mixture, preferably up to 5% (by weight) of the solvent mixture.
Preferred capsules of the present invention are those which each contain a digoxin solution in an amount which contains digoxin in the range 0.05 mg to 0.4 mg, more preferably 0.05 mg to 0.2 mg. Specifically preferred cap-sules of the present invention contain digoxin in an amount per capsule selected from 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg and 0.4 mg, of these, capsules each containing 0.05 mg, 0,1 mg or 0.2 mg are more preferred and a capsule containing ~ D' ~L~9~3~
0,2 mg of digoxin the most preferred. For general con-venience capsules containing a lesser amount of digoxin are preferably physically smaller than those capsules containing a greater amount of digoxin.
The concentration of the digoxin solution within the capsules of the present invention may be in the range 0.1 to 2.0 mg digoxin/ml., but is preferablyin the range 0,25 to 0.95 mg digoxin/ml., more preferably 0.35 to 0.6 mg digoxin/ml., and optimally 0.4 to 0.5 mg digoxin/ml. As the term is used herein, concentration should be understood to mean mg of digoxin/ml of solution. Thecapsuleshells may be chosen from those that are commercially available, the size (capacity) thereof and the concentration of the digoxin solution filled therein being balanced the one against the other such that eachcapsule contains the desired unit dose of digoxin.
As used herein the term an effective cardiac in-sufficiency treatment amount of digoxin should be understood to mean one or more capsules of the present invention as described herein, each capsule preferably containing digoxin in the range 0.05 mg to 0.4 mg as detailed hereinabove. The capsules of the present invention, by virtue of their providing as herein described an increased bioavailability of digoxin as compared with digoxin tablets, enable the dosing schedule detailed below to be utilized in the treat-ment of cardiac insufficiency. Each individual dose and the cumulative dosage of digoxin thereby administered is but 80% of that required with the equivalent schedule as set out hereinabove utilizing digoxin tablets.
~9~i3~'~
Thus where rapid digitalization is desired in one day or less the patient may be given 0.4 mg to 1.2 mg of digoxin initially followed by 0.2 mg to 0.4 mg o digoxin every six to eight hours, as required, to complete digitali-zation. In elderly patients, ancl where there is less urgency a smaller initial dose of 0.2 mg to 0.8 mg of digoxin is suitable. Thereafter maintenance doses of 0.1 mg to 0.4 mg of digoxin per day may be given, depending of course upon the patient and the discretion of the physician.
Thus according to the invention there is provided an orally ingestible pharmaceutical preparation comprising a solution of digoxin in a soft gelatin capsule shell which is soluble in the upper gastrointestinal tract of a mammal, the amount of digoxin in the capsule being an amount which is less than the digoxin content of a conventional tablet to provide upon oral administration of the capsule to man sub-stantially the same therapeutic effect as is provided by oral administration to man of the conventional tablet.
Suitably the digoxin is present in an amount which is 80% of that of a conventional tablet formulation.
In another aspect of the invention there is provided a method of preparing the pharmaceutical prepara-tion of the invention which comprises providing a solution of digoxin and encapsulating unit dose of the solution in a soft gelatin capsule for oral administration.
In a particular embodiment of this latter aspect of the invention there is provided a method of preparing a pharmaceutical preparation as defined above which comprises marginally welding two sheets of the soft gelatin material comprising the capsule shell together around a unit dose of the solution of digoxin comprising the content of the capsule.
.
~L~9~i3~
The invention provides in another aspect a method for the treatment of cardiac insufficiency in a mammal including man which comprises the administration to the mammal of a pharmaceutical preparation according to the invention above containing an effective cardiac insufficiency treatment amount of digoxin.
In a further aspect of the invention there is provided a method for increasing the bioavailability of digoxin in a mammal including man suffering from cardiac insufficiency which comprises administering to the mammal a pharmaceutical preparation of the invention containing an effective cardiac insufficiency treatment amount of digoxin.
The following Examples are provided by way of illustration of the present invention and should not be construed as in any way providing a limitation thereof.
Example (I) The following comparative example illustrates the unexpected properties of a capsule containing digoxin in solution in comparison with tablets containing digoxin in dry form at the same dose or in a greater dose than in the capsule. All capsules and tablets used in this example were subjected to quality control testing to ensure con-tent uniformity. -The procedure used for obtaining the results was as follows.
Eight normal human subjects were given each of the four following digoxin preparations with rest periods in between to permit digoxin clearance.
(A) 0.2 mg digoxin in solution in soft gelatin capsule shell - dissolution rate 100% at 63~
1 hour (6th Interim revision, U.S.P~ XVIII
(November 15, 1973)) (B) 0.2 mg digoxin in tablet - dissolution rate 97% at 1 hour (C) 0.25 mg digoxin in tablet - dissolution rate 97% at 1 hour (D) 0.25 mg digoxin in tablet (standard Lanoxin (Trade Mark) brand digoxin) - dissolution rate 78% at 1 hour Dosage was 4 doses at 8-hour intervals each of 2 tablets or capsules, then 1 tablet or capsule twice a day on days 3-9. Serum digoxin levels after the first dose and in the steady state (days 8-10), and 24-hour urine digoxin excretion on day 1 were measured by radioimmunoassay.
The results (mean and standard errors) are as below.
3~7 ~ E
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ci ~
~n ~ o o o ~ ~q _ . . . ~ 3 >1 O O O O O
E +l +l +l +l n~ ~ 0 ~1 ~ r~ ~
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u~ ~1 0 ~1 ~1 h +
ci a) o _ 3 _ ~
~ ~ r~
h a~~1 ~1 ~1 ~ ~q .
~i ~+l +l +l +l o ~,~ ~ ~ 0 0 h I` O d' ~D C
:~ ~ ~ ~ ~ ~
~q h _~
h--a~ c ~q ~rl h --E $
a) X
h ~--l ~ E h 0~ ~ O
Ci ~D ~ ~ + I
h C ~ ~1 ~ ~1 0 0 a)--+l +l +l +l ~1 ~1 0 ~D
C h u~ ~ d' I` ~1 d' ~`1 ~ ~ ~Q
..
a) ~ I ~ ^
h O O
~1 E
h ,a--u~ ~ o c~ m n~ ~ ~ ~ t~
~ O O O O ~
C d~ 1 0 0 ~ O
h-- ~) o ~D ~1 ~ ~ d' V~ ~ ~ ~ ~ ~'i O O
~i +l +l n~
1` ~n ~ ~ ~ .
O ~ ~1 .. ..
n1 h ~ ,~c m c~
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;
~!9963n~.' Preparation (A) was be-tter absorbed than (B), as indicated by 1 hr (pc.05) serum levels, 24 hr urine levels (p<.01), areas under curve (p<.001), and steady state serum levels(p<.02). Despite the smaller digoxin dosage, absorp-tion of (A) was similar to that of (C) and (D). There were also no significant differences between (C) and (D). (B)-to-(C) and (B)-to-(D) differences were significant, consis-tent with different digoxin content. Coefficient of variation of steady state serum values did not differ significantly among the four preparations. ECG (electro-cardiogram) changes (8 hr monitoring) were similar with all four preparations.
It was concluded that (1) digoxin tablets having a dissolution rate of 97% at 1 hr are no better absorbed by normal human subjects than currently available tablets (preparation (D)), and (2) a switch from tablet to solution filled capsules would require a reduction in digoxin dosage.
The soft gelatin capsules (preparation (A)) con-tained 0.2 mg digoxin in a fill volume of 6.65 minims, a fill weight of 448 mg. The digoxin was dissolved in a solvent comprising ethanol (absolute), water, propylene glycol, and polyethylene glycol 400. With the above fill weight the concentration of the digoxin was calculated to be about 0.45 mg/ml by dividing the weight of digoxin by the fill volume in ml, assuming the solution to have a density of 1.0 g/ml. The percentage amounts of the various ingredients of the solvent were as set forth in Example (II).
Example (II) A suitable solvent system for use in preparing capsules each containing 0.2 mg of digoxin includes the following ingredients (percentages by weight):
~ i .
~ 31~3C~ 1~
Polyethylene glycol 400 - 90%
Ethanol (absolute) - 6%
Propylene glycol - 3O/o Water - 1%
A solution of digoxin in the aforementioned sol-vent system was packaged in a conventional soft gelatin capsule shell using conventional soft gelatin capsule pack-aging machinery to provide soft gelatin capsules, each containing 0.2 mg of digoxin. The solution ingredients are conventionally stirred together and may be heated if desired to speed solution of the digoxin.
For a solution having a concentration of 0.35 mg of digoxin/ml, a capsule containing 0.2 mg of digoxin would require about 0.57 ml of solvent. This is conventionally determined by dividing the weight of the digoxin to be in-corporated in the capsule by the concentration of the solu-tion, assuming the weight of digoxin in the solution to be negligible. For the capsules of Example (I), the amount of solvent of Example (II) used would weigh about 447.8 mg and may be determined by subtracting the weight of digoxin from the fill weight. The concentration would be calculated as detailed in Example (I).
Example (III) A soft gelatin capsule shell was filled with a solution containing 0.1 mg of digoxin in polyethylene glycol 400, 100% by weight. For a solution having a concentration of 0.25 mg/ml, a capsule containing 0.1 mg of digoxin was calculated to require about 0.4 ml of polyethylene glycol 400.
Examples (IV) to (X?
By methods analogous to that described in Example (II), the following solutions of digoxin were prepared and packaged in soft gelatin capsule shells to provide capsules each containing digoxin in the respective amounts shown.
Solution Example Weight of No. Solvent Digoxin concn. digoxin per (% by weight)(m~/ml) capsule (mq) (IV) Polyethylene0.50 0.05 glycol 400 (90/O) Glycerin ( 10%) (V) Propylene 0.40 0.05 glycol ( 100%) (VI) Propylene 0.50 0.2 glycol (100%) (VII) Ethanol (absolute) 0.45 0.1 (50O/o) Proplene glycol (50/O) (VIII) Ethanol (absolute) 0.50 0.2 (5%) Glycerin (5%) Propylene glycol (90%) (IX) Ethanol (absolute) 0.43 0.1 ( 1 0/0 ) Propylene glycol (89%) Water (1%) ~.~
1~6~
(X) Propylene glycol 0'35 0.
( g 90/o ) Water (1%) Example (XI) Seven normal human subjects were each given (i) two of the capsules (preparation (A)) of Example (I), and (ii) an equivalent (as regards digoxin content) dose of a digoxin solution corresponding to the contents of the said capsules, with a rest period between the administration of (i) and (ii) to permit digoxin clearance.
The mean results obtained are as shown below: all data refer to digoxin.
Capsules Solution Peak serum concn. (ng/ml) : 3.63 2.53 Area under curve (serum), 0-6 hrs (ng/ml x min) : 471 314 Area under curve eliminating subject: 409 303 with double peak (ng/ml x min) Mean 6 hr serum concn. (ng~ml) : 0.42 0.39 24 hr Urine excretion (~g) : 102 85 Examples (XII) to (XVI) By methods analogous to that described in Example (II), soft gelatin capsules were prepared each containing digoxin in the respective amounts shown.
Weight of digoxin Example Fill vol. Fill weight per capsule No. (minims) (mq) (mq) (XII) 0.90 59 0 05 (XIII) 1.80 118 0.10 (XIV) 3,60 235 0.20 (XV) 5.40 353 0.30 (XVI) 7.20 470 0.40 3~
The digoxin solution filled into the capsule shells had the samecomposition in each instance, as below (all percentages by weight).
Solvent:
Polyethylene glycol 400 : 89.5%
Ethanol (absolute) 6%
Propylene glycol : 3.5%
Water : 1%
Concentration of digoxin : 0.94 mg/ml Examples (XVII) to (XXXII) By methods analogous to that described in Example (II) solutions of digoxin in the following solvent systems were prepared and packaged in soft gelatin capsule shells to provide capsules each containing 0.05 mg of digoxin, the concentration of digoxin (mg/ml) in the solution and the size (capacity) of the capsule shells being chosen appropriately in each case. All references are to percentages by weight: the ethanol was in each case absolute.
Example No. Solvent (XVII) Glycerin ( 100%) (XVIII) Ethanol (40/O), water (60%) (XIX) Ethanol (50/O)~ water (50O/o) (XX) Ethanol ( 80%), water ( 200/o) (XXI) Propylene glycol (lOOo/o) (XXII) Propylene glycol (75%), water (25%) (XXIII) Propylene glycol (50/O), water (50/O) (XXIV) Propylene glycol (40/O)~ water (600/o) (XXV) Polyethylene glycol 200 ( 100%) : 30 (XXVI) Polyethylene glycol 400 ( 100%) ~63~ 1f' (XXVII) Isopropanol ( 100%) (XXVIII) Propylene glycol (40/0), ethanol (5%), water (55%) (XXIX) Propylene glycol ( 50/0), ethanol (5%), water (45%) (XXX) Propylene glycol (30/0), ethanol (10%) water ( 600/o) (XXXI) Propylene glycol (40/0), ethanol (l~/o) water (50/0) (XXXII) Propylene glycol (50/0), ethanol ( 10%) water (40/0).
Claims (34)
1. An orally ingestible pharmaceutical preparation comprising a solution of digoxin in a soft gelatin capsule shell which is soluble in the upper gastrointestinal tract of a mammal, the amount of digoxin in the capsule being an amount which is less than the digoxin content of a conven-tional tablet to provide upon oral administration of the capsule to man substantially the same therapeutic effect as is provided by oral administration to man of the conventional tablet.
2. A preparation as claimed in claim 1, comprising an amount of digoxin which is 80% of that of the conventional tablet formulation.
3. A preparation as claimed in claim 1 or 2, wherein the capsule shell has a dissolution rate in the upper gastrointestinal tract of 100% in not more than one hour.
4. A preparation as claimed in claim 1 or 2, wherein the concentration of digoxin in the solution is 0.1 to 2.0 mg digoxin/ml.
5. A preparation as claimed in claim 1, wherein the digoxin is present in an amount in the range of 0.05 mg to 0.4 mg.
6. A preparation as claimed in claim 1, wherein the digoxin is present in an amount selected from 0.05 mg, 0.1 mg and 0.2 mg.
7. A preparation as claimed in claim 1, 5 or 6, wherein the solution of digoxin comprises digoxin and at least one solvent selected from glycerin, propylene glycol and a polyethylene glycol having an average molecular weight of 190 to 1000.
8. A preparation as claimed in claim 1, 2 or 5, wherein the solution of digoxin comprises digoxin and a solvent mixture comprising not more than 60%, by weight, of water.
9. A preparation as claimed in claim 1, 2 or 6 wherein the capsule shell includes at least one ingredient selected from a plasticizer, a preservative, a colouring agent and an opacifying agent.
10. A preparation as claimed in claim 1, 2,or 6 wherein the digoxin is present in an amount selected from 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg and 0.4 mg.
11. A preparation as claimed in claim 6,wherein the solution of digoxin comprises digoxin and at least one solvent selected from glycerin, propylene glycol and a polyethylene glycol having an average molecular weight of 190 to 1000.
12. A preparation as claimed in claim 6, wherein the solution of digoxin comprises digoxin and a solvent mixture comprising not more than 60%, by weight, of water.
13. A preparation as claimed in claim 1, 2 or 5, wherein the solution of digoxin comprises digoxin and at least one solvent selected from ethanol and isopropanol.
14. A preparation as claimed in claim 1, 2 or 5 wherein the solution of digoxin comprises digoxin and at least two solvents selected from glycerin, propylene glycol, ethanol and water, the water being present in an amount of not more than 60%, by weight, of the solvent mixture.
15. A preparation as claimed in claim 1, 2 or 5 wherein the solution of digoxin comprises digoxin and a solvent mixture comprising up to 5%, by weight, of water.
16. A preparation as claimed in claim 1,2 or 5 wherein the solution of digoxin comprises digoxin and at least two solvents selected from glycerin, ethanol, propylene glycol and a polyethylene glycol having an average molecular weight of 190 to 6000.
17. A preparation as claimed in claim 1,2 or 5 wherein the solution of digoxin comprises digoxin, ethanol, propylen glycol and a polyethylene glycol having an average molecular weight of 190 to 6000.
18. A preparation as claimed in claim 1, 2 or 5 wherein the solution of digoxin comprises digoxin and at least two solvents selected from glycerin, ethanol, propylene glycol and a polyethylene glycol having an average molecular weight of 190 to 1000.
19. A preparation as claimed in claim 1, 2 or 5 wherein the solution of digoxin comprises digoxin, ethanol, propylene glycol and a polyethylene glycol having an average molecular weight of 190 to 1000.
20. A preparation as claimed in claim 1,2 or 5 wherein the solution of digoxin comprises digoxin and at least one solvent selected from ethanol, isopropanol, propylene glycol and polyethylene glycol 400.
21. A preparation as claimed in claim 1 or 2,wherein the digoxin is present in an amount selected from 0.1 mg, 0.2 mg and 0.4 mg and wherein the solution thereof comprises digoxin and a solvent mixture comprising a polyethylene gly-col having an average molecular weight of 190 to 6000, ethanol, propylene glycol, and water, the water being present in an amount of not more than 60%, by weight, of the solvent mixture.
22. A preparation as claimed in claim 1 or 2,wherein the digoxin is present in an amount selected from 0.1 mg and 0.2 mg and wherein the solution thereof comprises digoxin and a solvent mixture comprising a polyethylene glycol having an average molecular weight of 190 to 1000, ethanol, propylene glycol and water, the water being present in an amount of up to 5%, by weight, of the solvent mixture.
23. A preparation as claimed in claim 1 or 2,wherein the concentration of the solution of digoxin is in the range 0.25 to 0.95 mg digoxin/ml.
24. A preparation as claimed in claim 1 or 2,wherein the concentration of the solution of digoxin is in the range 0.4 to 0.5 mg digoxin/ml.
25. A preparation as claimed in claim 2, wherein the digoxin is present in an amount of 0.05 mg, 0.1 mg or 0.2 mg and said solution comprises digoxin, polyethylene glycol having an average molecular weight of 190 to 1000, propylene glycol and water, the water being present in an amount of up to 5%,by weight, of the solvent mixture.
26. A preparation as claimed in claim 25,wherein said polyethylene glycol is polyethylene glycol 400.
27. A preparation as claimed in claim 26, comprising, in weight %, about 90% of said polyethylene glycol, about 6%
of ethanol, about 3% of propylene glycol and about 1% of water.
of ethanol, about 3% of propylene glycol and about 1% of water.
28. A preparation as claimed in claim 27, wherein the digoxin is present in an amount of 0.05 mg.
29. A preparation as claimed in claim 27, wherein the digoxin is present in an amount of 0.1 mg.
30. A preparation as claimed in claim 27, wherein the digoxin is present in an amount of 0.2 mg.
31. A method of preparing a pharmaceutical preparation of claim 1, 2 or 5 comprising providing a solution of digoxin and encapsulating unit dose of said solution in a soft gelatin capsule for oral administration.
32. A method of preparing a pharmaceutical preparation as defined in claim 1, which comprises marginally welding two sheets of soft gelatin comprising the capsule shell together around a unit dose of the solution of digoxin comprising the content of the capsule.
33. A method as claimed in claim 32,wherein the capsule shell is subsequently dehydrated by exposure to an agent capable of extracting water therefrom.
34. A method as claimed in claim 33,wherein the agent is dry warm air or acetone.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US44496174A | 1974-02-22 | 1974-02-22 | |
| US444961 | 1974-02-22 | ||
| US45300074A | 1974-03-19 | 1974-03-19 | |
| US453000 | 1974-03-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1096307A true CA1096307A (en) | 1981-02-24 |
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ID=27034126
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA220,535A Expired CA1096307A (en) | 1974-02-22 | 1975-02-21 | Pharmaceutical preparations |
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| JP (1) | JPS50126822A (en) |
| AU (2) | AU501549B2 (en) |
| CA (1) | CA1096307A (en) |
| DE (1) | DE2507635A1 (en) |
| ES (1) | ES434971A1 (en) |
| FI (1) | FI750489A (en) |
| FR (1) | FR2261752B1 (en) |
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| IE (1) | IE41620B1 (en) |
| IL (1) | IL46682A (en) |
| IT (1) | IT1233251B (en) |
| LU (1) | LU71894A1 (en) |
| NL (1) | NL7502121A (en) |
| SE (1) | SE426549B (en) |
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|---|---|---|---|---|
| GB1508770A (en) * | 1974-04-01 | 1978-04-26 | Scherer Ltd R | Pharmaceutical compositions |
| US4002718A (en) * | 1974-10-16 | 1977-01-11 | Arnar-Stone Laboratories, Inc. | Gelatin-encapsulated digoxin solutions and method of preparing the same |
| FR2380030A1 (en) * | 1977-02-09 | 1978-09-08 | Christiaens Sa A | Liquid and solid solns. of gitoxin - with high bio:availability for treating cardiac disorders |
| IT1158722B (en) * | 1977-07-08 | 1987-02-25 | Simes | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF SLEEP TURBES |
| JPS5625428U (en) * | 1979-08-03 | 1981-03-09 | ||
| US4366145A (en) * | 1981-06-24 | 1982-12-28 | Sandoz, Inc. | Soft gelatin capsule with a liquid ergot alkaloid center fill solution and method of preparation |
| SE8203953D0 (en) * | 1982-06-24 | 1982-06-24 | Astra Laekemedel Ab | PHARMACEUTICAL MIXTURE |
| US4994260A (en) * | 1982-05-28 | 1991-02-19 | Astra Lakemedel Aktiebolag | Pharmaceutical mixture |
| DE3445237C1 (en) * | 1984-12-12 | 1986-06-05 | R.P. Scherer GmbH, 6930 Eberbach | Soft gelatin capsules and process for their manufacture |
| DE3529694A1 (en) * | 1985-08-20 | 1987-02-26 | Scherer Gmbh R P | GELATINE CAPSULES AND METHOD FOR THEIR PRODUCTION |
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| GB1481411A (en) * | 1973-07-20 | 1977-07-27 | Scherer Ltd R | Pharmaceutical compositions |
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- 1975-02-21 LU LU71894A patent/LU71894A1/xx unknown
- 1975-02-21 FI FI750489A patent/FI750489A/fi not_active Application Discontinuation
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| AU520082B2 (en) | 1982-01-14 |
| JPS50126822A (en) | 1975-10-06 |
| LU71894A1 (en) | 1975-12-09 |
| IL46682A (en) | 1979-07-25 |
| ES434971A1 (en) | 1977-05-16 |
| FR2261752B1 (en) | 1978-07-21 |
| IE41620L (en) | 1975-08-22 |
| FI750489A (en) | 1975-08-23 |
| GB1506016A (en) | 1978-04-05 |
| AU501549B2 (en) | 1979-06-21 |
| DE2507635A1 (en) | 1975-08-28 |
| IT8349395A0 (en) | 1983-11-28 |
| FR2261752A1 (en) | 1975-09-19 |
| IL46682A0 (en) | 1975-04-25 |
| SE7501967L (en) | 1975-08-25 |
| SE426549B (en) | 1983-01-31 |
| IT1233251B (en) | 1992-03-24 |
| NL7502121A (en) | 1975-08-26 |
| DE2507635C2 (en) | 1991-07-25 |
| IE41620B1 (en) | 1980-02-13 |
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