CA2034569C - Oral pharmaceutical forms of pimobendan - Google Patents
Oral pharmaceutical forms of pimobendan Download PDFInfo
- Publication number
- CA2034569C CA2034569C CA002034569A CA2034569A CA2034569C CA 2034569 C CA2034569 C CA 2034569C CA 002034569 A CA002034569 A CA 002034569A CA 2034569 A CA2034569 A CA 2034569A CA 2034569 C CA2034569 C CA 2034569C
- Authority
- CA
- Canada
- Prior art keywords
- pimobendan
- citric acid
- composition
- tablets
- pellets
- 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.)
- Expired - Lifetime
Links
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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
-
- 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
- A61K9/20—Pills, tablets, discs, rods
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
- Plural Heterocyclic Compounds (AREA)
- Cosmetics (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Constant, satisfactory resorption of pimobendan is ensured even when there are major pH fluctuations in the gastrointestinal tract, when it is formulated for oral administration together with citric acid.
Description
56224.701 Pimobendan Compositions This invention relates to orally administrable pharmaceutical compositions comprising pimobendan and methods for their preparation. Pimobendan is 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-3(2H)-pyridazinone and is a substance having cardiotonic, hypotensive and antithrombotic activities.
Pimobendan and other structurally different substances are described in European Patent No. 8391.
However, unlike other substances described in that patent, the resorption of pimobendan when administered orally is prone to considerable inter- and intra-individual fluctuations when incorporated in known or conventional oral pharmaceutical forms. The reason for this is that pimobendan is characterised by a low and very highly pH-dependent solubility in aqueous media.
Depending on the buffer system used, about 100 to 300 mg of pimobendan dissolve per litre at a pH between 1 and 3 (corresponding to a 0.01 to 0.03% solution), but at pH 5 only about 1 mg/1 will dissolve in water (corresponding to a 0.0001% solution or 1 ppm).
In in vivo tests on humans in which pimobendan was packed into hard gelatin capsules, one test subject showed no detectable blood level of pimobendan, a second test subject showed a very low blood level and a third showed higher blood levels. Overall, the blood levels of pimobendan fluctuated very considerably from one individual to another and the levels were generally too low. These unsatisfactory resorption characteristics can be explained primarily by the high pH-dependency of the solubility of pimobendan in aqueous media and by the fluctuating pH conditions in the gastrointestinal tracts of the test subjects. It is known that the pH of the gastric juices, particularly in patients who have been fasting, can fluctuate between 1 and 6, whereas in patients who have not fasted it is more frequently between 3 and 5 than 1 and 2.
It therefore appeared to be clear that the solubility of pimobendan could be increased by the simultaneous administration of an acid. In vitro tests showed, however, that pimobendan in 0.1 N hydrochloric acid (pH 1.1) dissolved in a quantity of only 100 mg/1 (corresponding to a 0.01% solution). In a fumaric acid solution (pH 2.27) only 50 mg/1 dissolve (corresponding to a 0.005% solution), in a 20% (by weight) tartaric acid solution (pH 1.2) 960 mg/1 dissolve (corresponding to a 0.096% solution), and in a 40% (by weight) tartaric acid solution (pH 0.7) only 3.9 g/1 dissolve (corresponding to a 0.39% solution). None of these levels is sufficient, or the quantity of acid required is no longer practicable for dissolving a sufficient quantity of the active substance and thereby ensuring reliable resorption, even if such quantities of these acids are administered orally simultaneously with the active substance.
Surprisingly, we have now succeeded in overcoming the low solubility and high pH-dependency of the solubility of pimobendan thereby ensuring a very satisfactory and more constant resorption, even when there are considerable pH fluctuations in the gastrointestinal tracts. This is achieved by formulating pimobendan together with citric acid in an acid:pimobendan ratio by weight of at least 5:1.
Thus viewed from one aspect the invention provides an orally administrable pimobendan-containing pharmaceutial composition comprising an intimate mixture of citric acid and pimobendan in a weight ratio of at least 5:1, optionally together with one or more pharmaceutical carriers or excipients.
The compositions of the invention may be produced by intimately mixing pimobendan with citric acid in a ratio of up to 1 part by weight of pimobendan per 5 parts by weight of citric acid, and subsequently processing it with conventional excipients to form a powder, pellets or granules for oral administration.
The granules, powder or pellets may also be compressed with suitable excipients to form tablets which may, if desired, be covered with a flavour-masking coating.
Citric acid is a safe and well tolerated excipient which increases the solubility of pimobendan by a factor of 100, compared with artificial gastric juice (pH 1.2).
Thus, 7.6g of pimobendan will dissolve per litre in an aqueous solution containing 20% by weight of citric acid (pH 1.4), whilst in an aqueous solution containing 40%
by weight of citric acid (pH 1.0) as much as 12.1 g of pimobendan will dissolve per litre. These quantities of dissolved pimobendan are sufficient to ensure adequate resorption of the active substance even in patients who, when given conventional pimobendan preparations by oral route, showed either no detectable blood level or a very low and sharply fluctuating blood level of pimobendan.
Citric acid is difficult to process into solid preparations. To avoid the formation of salts of pimobendan with citric acid, which would increase the hygroscopicity of the formulation, it would appear that one should process the active substance and acid in two separate granulates. However, it has been found (see Examples 1b to 1d and 2a below) that when separated in this way the citric acid is unable to develop its full solubilising activity. However, it has been found that by intimately mixing pimobendan with citric acid to form a powder mixture which may subsequently be processed into granules, pellets or tablets, it is possible to obtain preparations with small amounts of citric acid which ensure adequate dissolution and sufficiently high blood levels of pimobendan.
Thus viewed from a further aspect the invention also provides a process for preparing compositions according to the invention in which citric acid and _ ,1 _ pi_mobeadan i.n a wei_dht rat~:io of at lea~;i: 5:1. :rrr~ broudlai lrlt0 all lrlti_mate.l.y mixed for-m by granm.lai iorr.
Tec)rn_ica_Lly, t~lW s can k>e aclri.evr~cl, I or- exnmpl_e~, lay aqueou~~ or non-aqueous granulation, e.d. k>y dranulat: ion with al_ccohol or by t:he use of suitab l c> rlt-anu_Lati ncl methods which make i.t poss.i ble t:o add the dram.rl at.incl fluid in <3ccurately metered amounts, w_i.t=.Ir sirnul.tanec~m;
dry.i_ng. Another p«;,sibi_7..it=y i s the f~i-~parat i on of granules by dry granulation, t=hese dr_antr l.es conta.i.n i.ocl the active st.rbstanr::e~ and c_itr_ is acjd irrt. i ma t-.e 1y m i xecl .
Owing to the hygro:~copi.c properties of tire cit:r_:ic ac:i.ci, care must be taken t.o ensure that: the composit.i.ons disintegrate rapid_l.y in the re 1. ease mecli_trm; in the c:a<~e of tablets, this may be achieved Por example by the addition of di_sintegrants, e.g. Amberl it~* IF2H F3 t3 (methacryl i_c res in with exchangeable protons ) , Crospovidone* (cros~~7_inked polyvinyl_pyrr_-ol. i.done) and microcrystalline cellulose, which simult~aneotrsl.y improve the compression properties oL c:itric acid.
A weight ratica of pimobendan to c:i t:.r:-ic aci.d of between 1:10 and 1:20 is pr-eferred, the upper li.m:it being defined by the abi_li_ty of the preparations to be swallowed.
Viewed from a still. further aspect the invention also provides a method of treatment of the human or_ non-human animal. body to combat cardlotonlc, hypo tensi.vf=a and anti-thrombotic conditions, said method cornpr:ising orally administering to said body a pharrmaceutical composition according to the invention.
The prevention of sharply fluct:uat.ing blood leve~l_s (both inter- and int:ra-i.Ildiv_i_drrall.y) by t_he addition of:
citric acid can perhaps be explained as follows: when the intimate mixture o1 active sub:~tance and citric acid comes into contact with gastric juices, an acidic . microsphere is formed around the particles due to the high rate of dissolution of the citric acid. This microsphere is a Lway:~ acidic, i rrespect i.ve of the pII of *Trademark A ~4 ~~~
the gastrointestinal juices, and ensures that the finely divided active substance reliably dissolves and is therefore freely available for resorption.
Solubility tests have shown, for pH values between 1 and 6, that the active substance dissolves out of this intimate mixture virtually irrespective of the pH. In addition, the active substance also forms supersaturated solutions with the citric acid which remain stable for hours. This ensures a high level of resorption in any case, even in patients with gastrointestinal juices of abnormally high pH. Of the many acids tested for this purpose, citric acid has unexpectedly proved to be outstanding;
not only does it act as an acid, but it also serves as a solubilizing agent and a stabilizer for the solution of active substance obtained. An important prerequisite for the dissolving of the active substance independently of the local physiological pH value is the intimate mixing of the pimobendan with the citric acid. For this, both substances should be present in powder form or as very small crystals, thereby ensuring contact with each other over a large surface area.
In the following description of the invention reference is made to the accompanying drawings, of which:
Figure 1 is a graph showing the pimobendan plasma level with time, after oral administration of pimobendan in the absence of citric acid to dogs;
Figure 2 is a graph showing the pimobendan plasma level with time, after oral administration of pimobendan and citric acid to dogs;
,, A4a~9 Figures 3 and 4 are graphs showing the pimobendan plasma level with time, after oral administration of pimobendan and citric acid to humans; and Figures 5a, 5b and 5c are graphs showing the pimobendan plasma levels with time, after oral administration of pimobendan in the absence of citric acid to humans.
A comparison of the results from tests on dogs after oral administration of a composition according to Example 1a containing 5 mg of pimobendan, with those from a composition according to Example 1b containing 5 mg of pimobendan and 50 mg of citric acid, showed that the pimobendan plasma level was approximately trebled by the form containing the citric acid compared with the form containing no citric acid. Each test was carried out on 5 experimental animals. The mean curves for the plasma levels of pimobendan found are shown in Figures 1 and 2, in which the plasma level values are given in nanograms per millilitre as a function of time.
Human trials using oral pimobendan compositions according to Examples 3b and 3c (capsules) on 11 test subjects gave the mean curves for the plasma levels of pimobendan shown in Figure 3. The maxima occurred at 1 5a to 1. 5 hours after uc:lministrat.i.on. In add.i ti_Orl to the capsule for-mtrlat.iorm> according to F;xmmpl.~s 11:~ m~cl rtc;, the plasma level curves of pi.mobendan for the tW.~let according to Example 2b and the capsule according t:.o Example 4 were each tested on 11 t=est subjects. It: was found that the tab:.l_ei~ containing only 50 mg of ci.tr-.ic acid according to l~x.ample 2b :i s bi.oec uival.ent to t.t-m capsule formulat1011 contalni ng ?.09 and of c.i.tr is nc ic.l according t;o Example 4. The plasma levels of pimobemlao were obtained by h.i_cltr pressure 1 i_quid chromatogra~luiw methods, resu:Lung i.n the mean curves shown i.n Fi.guro ~1 (mean values ~ standard deviati.ons).
By way of a comparison, a tablet formulation according to Examp:l_c~ 3a, i.e. a formulation with no citric acid, was ac.lministered o.ral_ly. '1'hi.:~ re~~ul_tecl in the curves for_ the plasma 1. evel.s of. pimober~dan i.11 thr-ce test subjects as shown in Figures 5a to 5c. I1: Figures 5a to 5c are compared with Figure 4, the superiority of the citric acid containing composition over a composition without. c:i_tric acid becomes very clear.
This is made apparent by the reduced fluctuations in plasma levels of pi.mobendan.
It goes withor:rt. saying, that instead of using pimobendan, one of it:s pas..>ible enanti.omer_s can also lie used with equal suwc:ess.
The following n.on-limiting Examples are provided to illustrate the preparation of some oral pharmaceutical compositions of pimobendan. All percentages given are by weight. In the~~e Examples Amber:lite I:RP 88 = methacryl_ic resin with exchangeable IlF
Collidone 25 - polyvinylpyrrol.idone, aver_ age molecular weight ?9,000 Avicel - microcrystalline cellulose Polyplasdone XL - crosslinked polyvinylpyrroli.done * polyvinylpolypyrrolic~one Comprit.ol t'.88 - qlyceryl. monobehenate *Trademark Tween F30 _. ~c~l.yoxyethylen~e-(2c>)-sorb.i.ton mf»~o-_ ~oleate Explotah* --- sodium carboxymethyl. starch Aer_osil 130 V - lhighly dispersed, X-.ray amorphou~~
ailicon di_oxic3e.
All measurements of rates of dissolution of pi_mobendan were carried out according t.o iJSP XX:11-I , paddle method, 7_50 rpm, in Mcl:lva:ine buffer, pIt ~: . ~-> ~~toc3 in each case mean v~al_ues were ca:lcul ated from 3 individual measurements.
*Trademark _8_ Example 1 Tablets containing 5 mg of pimobendan a) Tablets without citric acid Each tablet comprises (1)Pimobendan 5.0 mg (2)Microcrystalline cellulose 58.0 mg (3)Sec. calcium phosphate 72.0 mg (4)Corn starch 54.0 mg (5)Amberlite IRP 88 10.0 mg (6)Magnesium stearate 1.0 mg Total weight 200.0 mg Some of the corn starch is dissolved in water with heating and the mixture of ingredients (1) to (4) is granulated therewith. (5) and (6) are added to the dried granules. Tablets 8 mm in diameter and weighing 200 mg are compressed from the finished mixture.
Results:
Time (min) % pimobendan dissolved 8.5 10.2 10.7 10.8 10.8 b) Tablets containing 50 mg of citric acid Each tablet comprises (1) Pimobendan 5.0 mg (2) Citric acid 50.0 mg (3) Microcrystalline cellulose 42.0 mg 2Q3~569 _ g _ (4)Collidone 25 0.5 mg (5)Sec. calcium phosphate 52.0 mg (6)Corn starch 39.5 mg (7)Amberlite IRP 88 10.0 mg (8)Magnesium stearate 1.0 mg Total Weight 200.0 mg Some of the corn starch is dissolved in water with heating and ingredient (1), some of (3), (5) and some of (6) are granulated therewith. (2) and the remainder of (3) and (6) are granulated with the aqueous solution of (4). The granules are dried and mixed together. (7) and (8) are added to the mixture of dried granules to form the final mixture. This is then compressed to form tablets 8 mm in diameter and weighing 200 mg.
The active substance and acid are present in separate granulates for ease of manufacture but are subsequently mixed together.
Results:
Time (min) % pimobendan dissolved 7.7 19.2 34.0 40.6 43.0 c) Tablets containing 103 mg of citric acid Each tablet comprises (1) Pimobendan 5.0 mg (2) Citric acid 103.0 mg (3) Microcrystalline cellulose 35.0 mg (4) Collidone 25 1.0 mg (5) Sec. calcium phosphate 31.5 mg (6) Corn starch 81.5 mg ~(1~4569 - to -(7) Amberlite IRP 88 10.0 mg (8) Magnesium stearate 3.0 mg Total Weight 270.0 mg The tablets are produced analogously to those of Example 1b.
The resulting tablets are 9 mm in diameter, and weigh 270 mg.
The active substance and acid are present in separate granulates for ease of manufacture but are subsequently mixed together.
d) Tablets containing 206 mg of citric acid Each tablet comprises (1)Pimobendan 5.0 mg (2)Citric acid 206.0 mg (3)Avicel 50.0 mg (4)Collidone 25 2.0 mg (5)Sec. calcium phosphate 63.0 mg (6)Corn starch 46.0 mg (7)Amberlite IRP 88 20.0 mg (8)Magnesium stearate 3.0 mg Total Weight 395.0 mg The tablets are produced analogously to those of Example lb.
The resulting tablets are 11 mm in diameter, and weigh 395 mg.
The active substance and acid are present in separate granulates for ease of manufacture but are subsequently mixed together.
Results:
Time (min) % pimobendan dissolved 23.8 ~o34ss~
59.0 67.0 30 69.0 Example 2 Tablets containing 2.5 mq-of pimobendan a) Tablets containing 103 mq of citric acid Each tablet comprises (1) Pimobendan 2.5 mg (2) Corn starch 23.0 mg (3) Microcrystalline cellulose 26.0 mg (4) Anhydrous calcium phosphate 31.5 mg (5) Polyplasdone XL 59.0 mg - (6) Citric acid, fine particles (anhydrous) 103.0 mg (7) Compritol 888 5.0 mg Total weight 250.0 mg (1) to (4) are granulated with aqueous starch solution. The other ingredients are added to the dry granules to make the final mixture. This is then compressed to form tablets measuring 9 mm in diameter and weighing 250 mg.
The active substance and acid initially are present separately, for ease of manufacture, but are subsequently mixed together.
Results:
Time (min) % pimobendan dissolved 5 18.7 10 20.5 21.8 22.2 60 22.7 b) Tablets containing 50 mg' of citric acid Each tablet comprises (1)Pimobendan 2.5 mg (2)Anhydrous powdered citric acid 50.0 mg (3)Avicel PH 101 13.0 mg (4)Anhydrous calcium hydrogen phosphate 15.0 mg (5)Undried corn starch 6.0 mg (6)Collidone 25 0.5 mg (7)Insoluble polyvinylpyrrolidone 59.0 mg (8)Compritol 888 3.0 mg (9)Magnesium stearate 1.0 mg Total Weight 150.0 mg (6) is dissolved in ethanol and the mixture of ingredients (1) to (5) is granulated therewith. (7) to (9) are added to the dry granules to form the final mixture. This mixture is compressed to form tablets measuring 8 mm in diameter and weighing 150 mg.
The active substance and acid are present together in the same granulate.
Results:
Time (min) % pimobendan dissolved 15 71.1 30 85.0 Example 3 Capsules containing 5 mg of pimobendan a) Capsules without citric acid Each capsule contains (1) Pimobendan 5.0 mg (2)Lactose 90.25 mg (3}Corn starch 36.0 mg (4}Tween 80 0.5 mg (5)Explotab 8.0 mg (6)Magnesium stearate 0.25 mg Total weight 140.0 mg The individual powders are intensively mixed together and packed into size 4 hard gelatin capsules, the contents of each weighing 140 mg.
b) Capsules containing 230 mg~ of citric acid Each capsule contains (1)Pimobendan 5.0 mg (2)Citric acid 230.45 mg (3)Collidone 25 3.78 mg (4)Magnesium stearate 0.77 mg Total Weight 240.00 mg (1) and (2) are intensively mixed together and granulated with an alcoholic solution of (3). (4) is added to the dried granulate. The final mixture thus obtained is packed into size 1 hard gelatin capsules, the contents of each weighing 240 mg.
The active substance and acid are present together in the same granulate.
Results:
Time (min) % pimobendan dissolved c) Capsules containing 207 mq of citric acid Each capsule contains (1)Pimobendan, finely ground 5.0 mg (2)Citric acid 206.5 mg (3)Microcrystalline cellulose 40.0 mg (4)Aerosil 130 V 11.0 mg (5)Collidone 25 4.0 mg (6)Magnesium stearate 1.5 mg Total Weight 268.0 mg (1) is triturated with (2). (3) and (4) are added to the triturated material. The mixture is granulated with an alcoholic solution of (5). (6) is mixed into the dry granulate. The finished mixture is packed into size 1 capsules, the contents of each weighing 268 mg.
The active substance and acid are present in one and the same granulate.
Results:
Time (min) % pimobendan dissolved 84.1 90.2 91.7 30 92.5 Exampl a 4 Capsules containing 2.5 mq of pimobendan and 209 mg of citric acid Each capsule contains (1) Pimobendan 2.5 mg (2) Powdered citric acid 209.0 mg (3) Microcrystalline cellulose 40.0 mg 2U34 i69 (4) Silicon dioxide 11.0 mg (5) Polyvinylpyrrolidone 4.0 mg (6) Magnesium stearate 1.5 mg Total Weight 268.0 mg The tablets are produced analogously to those of Example 3c.
The active substance and acid are present in the same granulate.
Results:
Time (min) % pimobendan dissolved 15 96.5 30 99.1 Example 5 Film coated tablet containing 2.5 m~~imobendan and 50 ma of citric acid Each tablet comprises (1)Pimobendan 2.5 mg (2)Powdered anhydrous citric acid 50.0 mg (3)Avicel PH 101 13.0 mg (4)Anhydrous calcium hydrogen phosphate 15.0 mg (5)Undried corn starch 6.0 mg (6)Collidone 25 0.5 mg (7)Insoluble polyvinylpyrrolidone 59.0 mg (8)Compritol 888 3.0 mg (9)Magnesium stearate 1.0 mg Total weight 150.0 mg The preparation procedure is as described in Example 2b, but the finished mixture is compressed into biconvex tablets, which are each coated with 5 mg of hydroxypropyl-methylcellulose.
The active substance and acid are together in the same granulate.
Results:
Time (min) % pimobendan dissolved 76.8 30 86.1
Pimobendan and other structurally different substances are described in European Patent No. 8391.
However, unlike other substances described in that patent, the resorption of pimobendan when administered orally is prone to considerable inter- and intra-individual fluctuations when incorporated in known or conventional oral pharmaceutical forms. The reason for this is that pimobendan is characterised by a low and very highly pH-dependent solubility in aqueous media.
Depending on the buffer system used, about 100 to 300 mg of pimobendan dissolve per litre at a pH between 1 and 3 (corresponding to a 0.01 to 0.03% solution), but at pH 5 only about 1 mg/1 will dissolve in water (corresponding to a 0.0001% solution or 1 ppm).
In in vivo tests on humans in which pimobendan was packed into hard gelatin capsules, one test subject showed no detectable blood level of pimobendan, a second test subject showed a very low blood level and a third showed higher blood levels. Overall, the blood levels of pimobendan fluctuated very considerably from one individual to another and the levels were generally too low. These unsatisfactory resorption characteristics can be explained primarily by the high pH-dependency of the solubility of pimobendan in aqueous media and by the fluctuating pH conditions in the gastrointestinal tracts of the test subjects. It is known that the pH of the gastric juices, particularly in patients who have been fasting, can fluctuate between 1 and 6, whereas in patients who have not fasted it is more frequently between 3 and 5 than 1 and 2.
It therefore appeared to be clear that the solubility of pimobendan could be increased by the simultaneous administration of an acid. In vitro tests showed, however, that pimobendan in 0.1 N hydrochloric acid (pH 1.1) dissolved in a quantity of only 100 mg/1 (corresponding to a 0.01% solution). In a fumaric acid solution (pH 2.27) only 50 mg/1 dissolve (corresponding to a 0.005% solution), in a 20% (by weight) tartaric acid solution (pH 1.2) 960 mg/1 dissolve (corresponding to a 0.096% solution), and in a 40% (by weight) tartaric acid solution (pH 0.7) only 3.9 g/1 dissolve (corresponding to a 0.39% solution). None of these levels is sufficient, or the quantity of acid required is no longer practicable for dissolving a sufficient quantity of the active substance and thereby ensuring reliable resorption, even if such quantities of these acids are administered orally simultaneously with the active substance.
Surprisingly, we have now succeeded in overcoming the low solubility and high pH-dependency of the solubility of pimobendan thereby ensuring a very satisfactory and more constant resorption, even when there are considerable pH fluctuations in the gastrointestinal tracts. This is achieved by formulating pimobendan together with citric acid in an acid:pimobendan ratio by weight of at least 5:1.
Thus viewed from one aspect the invention provides an orally administrable pimobendan-containing pharmaceutial composition comprising an intimate mixture of citric acid and pimobendan in a weight ratio of at least 5:1, optionally together with one or more pharmaceutical carriers or excipients.
The compositions of the invention may be produced by intimately mixing pimobendan with citric acid in a ratio of up to 1 part by weight of pimobendan per 5 parts by weight of citric acid, and subsequently processing it with conventional excipients to form a powder, pellets or granules for oral administration.
The granules, powder or pellets may also be compressed with suitable excipients to form tablets which may, if desired, be covered with a flavour-masking coating.
Citric acid is a safe and well tolerated excipient which increases the solubility of pimobendan by a factor of 100, compared with artificial gastric juice (pH 1.2).
Thus, 7.6g of pimobendan will dissolve per litre in an aqueous solution containing 20% by weight of citric acid (pH 1.4), whilst in an aqueous solution containing 40%
by weight of citric acid (pH 1.0) as much as 12.1 g of pimobendan will dissolve per litre. These quantities of dissolved pimobendan are sufficient to ensure adequate resorption of the active substance even in patients who, when given conventional pimobendan preparations by oral route, showed either no detectable blood level or a very low and sharply fluctuating blood level of pimobendan.
Citric acid is difficult to process into solid preparations. To avoid the formation of salts of pimobendan with citric acid, which would increase the hygroscopicity of the formulation, it would appear that one should process the active substance and acid in two separate granulates. However, it has been found (see Examples 1b to 1d and 2a below) that when separated in this way the citric acid is unable to develop its full solubilising activity. However, it has been found that by intimately mixing pimobendan with citric acid to form a powder mixture which may subsequently be processed into granules, pellets or tablets, it is possible to obtain preparations with small amounts of citric acid which ensure adequate dissolution and sufficiently high blood levels of pimobendan.
Thus viewed from a further aspect the invention also provides a process for preparing compositions according to the invention in which citric acid and _ ,1 _ pi_mobeadan i.n a wei_dht rat~:io of at lea~;i: 5:1. :rrr~ broudlai lrlt0 all lrlti_mate.l.y mixed for-m by granm.lai iorr.
Tec)rn_ica_Lly, t~lW s can k>e aclri.evr~cl, I or- exnmpl_e~, lay aqueou~~ or non-aqueous granulation, e.d. k>y dranulat: ion with al_ccohol or by t:he use of suitab l c> rlt-anu_Lati ncl methods which make i.t poss.i ble t:o add the dram.rl at.incl fluid in <3ccurately metered amounts, w_i.t=.Ir sirnul.tanec~m;
dry.i_ng. Another p«;,sibi_7..it=y i s the f~i-~parat i on of granules by dry granulation, t=hese dr_antr l.es conta.i.n i.ocl the active st.rbstanr::e~ and c_itr_ is acjd irrt. i ma t-.e 1y m i xecl .
Owing to the hygro:~copi.c properties of tire cit:r_:ic ac:i.ci, care must be taken t.o ensure that: the composit.i.ons disintegrate rapid_l.y in the re 1. ease mecli_trm; in the c:a<~e of tablets, this may be achieved Por example by the addition of di_sintegrants, e.g. Amberl it~* IF2H F3 t3 (methacryl i_c res in with exchangeable protons ) , Crospovidone* (cros~~7_inked polyvinyl_pyrr_-ol. i.done) and microcrystalline cellulose, which simult~aneotrsl.y improve the compression properties oL c:itric acid.
A weight ratica of pimobendan to c:i t:.r:-ic aci.d of between 1:10 and 1:20 is pr-eferred, the upper li.m:it being defined by the abi_li_ty of the preparations to be swallowed.
Viewed from a still. further aspect the invention also provides a method of treatment of the human or_ non-human animal. body to combat cardlotonlc, hypo tensi.vf=a and anti-thrombotic conditions, said method cornpr:ising orally administering to said body a pharrmaceutical composition according to the invention.
The prevention of sharply fluct:uat.ing blood leve~l_s (both inter- and int:ra-i.Ildiv_i_drrall.y) by t_he addition of:
citric acid can perhaps be explained as follows: when the intimate mixture o1 active sub:~tance and citric acid comes into contact with gastric juices, an acidic . microsphere is formed around the particles due to the high rate of dissolution of the citric acid. This microsphere is a Lway:~ acidic, i rrespect i.ve of the pII of *Trademark A ~4 ~~~
the gastrointestinal juices, and ensures that the finely divided active substance reliably dissolves and is therefore freely available for resorption.
Solubility tests have shown, for pH values between 1 and 6, that the active substance dissolves out of this intimate mixture virtually irrespective of the pH. In addition, the active substance also forms supersaturated solutions with the citric acid which remain stable for hours. This ensures a high level of resorption in any case, even in patients with gastrointestinal juices of abnormally high pH. Of the many acids tested for this purpose, citric acid has unexpectedly proved to be outstanding;
not only does it act as an acid, but it also serves as a solubilizing agent and a stabilizer for the solution of active substance obtained. An important prerequisite for the dissolving of the active substance independently of the local physiological pH value is the intimate mixing of the pimobendan with the citric acid. For this, both substances should be present in powder form or as very small crystals, thereby ensuring contact with each other over a large surface area.
In the following description of the invention reference is made to the accompanying drawings, of which:
Figure 1 is a graph showing the pimobendan plasma level with time, after oral administration of pimobendan in the absence of citric acid to dogs;
Figure 2 is a graph showing the pimobendan plasma level with time, after oral administration of pimobendan and citric acid to dogs;
,, A4a~9 Figures 3 and 4 are graphs showing the pimobendan plasma level with time, after oral administration of pimobendan and citric acid to humans; and Figures 5a, 5b and 5c are graphs showing the pimobendan plasma levels with time, after oral administration of pimobendan in the absence of citric acid to humans.
A comparison of the results from tests on dogs after oral administration of a composition according to Example 1a containing 5 mg of pimobendan, with those from a composition according to Example 1b containing 5 mg of pimobendan and 50 mg of citric acid, showed that the pimobendan plasma level was approximately trebled by the form containing the citric acid compared with the form containing no citric acid. Each test was carried out on 5 experimental animals. The mean curves for the plasma levels of pimobendan found are shown in Figures 1 and 2, in which the plasma level values are given in nanograms per millilitre as a function of time.
Human trials using oral pimobendan compositions according to Examples 3b and 3c (capsules) on 11 test subjects gave the mean curves for the plasma levels of pimobendan shown in Figure 3. The maxima occurred at 1 5a to 1. 5 hours after uc:lministrat.i.on. In add.i ti_Orl to the capsule for-mtrlat.iorm> according to F;xmmpl.~s 11:~ m~cl rtc;, the plasma level curves of pi.mobendan for the tW.~let according to Example 2b and the capsule according t:.o Example 4 were each tested on 11 t=est subjects. It: was found that the tab:.l_ei~ containing only 50 mg of ci.tr-.ic acid according to l~x.ample 2b :i s bi.oec uival.ent to t.t-m capsule formulat1011 contalni ng ?.09 and of c.i.tr is nc ic.l according t;o Example 4. The plasma levels of pimobemlao were obtained by h.i_cltr pressure 1 i_quid chromatogra~luiw methods, resu:Lung i.n the mean curves shown i.n Fi.guro ~1 (mean values ~ standard deviati.ons).
By way of a comparison, a tablet formulation according to Examp:l_c~ 3a, i.e. a formulation with no citric acid, was ac.lministered o.ral_ly. '1'hi.:~ re~~ul_tecl in the curves for_ the plasma 1. evel.s of. pimober~dan i.11 thr-ce test subjects as shown in Figures 5a to 5c. I1: Figures 5a to 5c are compared with Figure 4, the superiority of the citric acid containing composition over a composition without. c:i_tric acid becomes very clear.
This is made apparent by the reduced fluctuations in plasma levels of pi.mobendan.
It goes withor:rt. saying, that instead of using pimobendan, one of it:s pas..>ible enanti.omer_s can also lie used with equal suwc:ess.
The following n.on-limiting Examples are provided to illustrate the preparation of some oral pharmaceutical compositions of pimobendan. All percentages given are by weight. In the~~e Examples Amber:lite I:RP 88 = methacryl_ic resin with exchangeable IlF
Collidone 25 - polyvinylpyrrol.idone, aver_ age molecular weight ?9,000 Avicel - microcrystalline cellulose Polyplasdone XL - crosslinked polyvinylpyrroli.done * polyvinylpolypyrrolic~one Comprit.ol t'.88 - qlyceryl. monobehenate *Trademark Tween F30 _. ~c~l.yoxyethylen~e-(2c>)-sorb.i.ton mf»~o-_ ~oleate Explotah* --- sodium carboxymethyl. starch Aer_osil 130 V - lhighly dispersed, X-.ray amorphou~~
ailicon di_oxic3e.
All measurements of rates of dissolution of pi_mobendan were carried out according t.o iJSP XX:11-I , paddle method, 7_50 rpm, in Mcl:lva:ine buffer, pIt ~: . ~-> ~~toc3 in each case mean v~al_ues were ca:lcul ated from 3 individual measurements.
*Trademark _8_ Example 1 Tablets containing 5 mg of pimobendan a) Tablets without citric acid Each tablet comprises (1)Pimobendan 5.0 mg (2)Microcrystalline cellulose 58.0 mg (3)Sec. calcium phosphate 72.0 mg (4)Corn starch 54.0 mg (5)Amberlite IRP 88 10.0 mg (6)Magnesium stearate 1.0 mg Total weight 200.0 mg Some of the corn starch is dissolved in water with heating and the mixture of ingredients (1) to (4) is granulated therewith. (5) and (6) are added to the dried granules. Tablets 8 mm in diameter and weighing 200 mg are compressed from the finished mixture.
Results:
Time (min) % pimobendan dissolved 8.5 10.2 10.7 10.8 10.8 b) Tablets containing 50 mg of citric acid Each tablet comprises (1) Pimobendan 5.0 mg (2) Citric acid 50.0 mg (3) Microcrystalline cellulose 42.0 mg 2Q3~569 _ g _ (4)Collidone 25 0.5 mg (5)Sec. calcium phosphate 52.0 mg (6)Corn starch 39.5 mg (7)Amberlite IRP 88 10.0 mg (8)Magnesium stearate 1.0 mg Total Weight 200.0 mg Some of the corn starch is dissolved in water with heating and ingredient (1), some of (3), (5) and some of (6) are granulated therewith. (2) and the remainder of (3) and (6) are granulated with the aqueous solution of (4). The granules are dried and mixed together. (7) and (8) are added to the mixture of dried granules to form the final mixture. This is then compressed to form tablets 8 mm in diameter and weighing 200 mg.
The active substance and acid are present in separate granulates for ease of manufacture but are subsequently mixed together.
Results:
Time (min) % pimobendan dissolved 7.7 19.2 34.0 40.6 43.0 c) Tablets containing 103 mg of citric acid Each tablet comprises (1) Pimobendan 5.0 mg (2) Citric acid 103.0 mg (3) Microcrystalline cellulose 35.0 mg (4) Collidone 25 1.0 mg (5) Sec. calcium phosphate 31.5 mg (6) Corn starch 81.5 mg ~(1~4569 - to -(7) Amberlite IRP 88 10.0 mg (8) Magnesium stearate 3.0 mg Total Weight 270.0 mg The tablets are produced analogously to those of Example 1b.
The resulting tablets are 9 mm in diameter, and weigh 270 mg.
The active substance and acid are present in separate granulates for ease of manufacture but are subsequently mixed together.
d) Tablets containing 206 mg of citric acid Each tablet comprises (1)Pimobendan 5.0 mg (2)Citric acid 206.0 mg (3)Avicel 50.0 mg (4)Collidone 25 2.0 mg (5)Sec. calcium phosphate 63.0 mg (6)Corn starch 46.0 mg (7)Amberlite IRP 88 20.0 mg (8)Magnesium stearate 3.0 mg Total Weight 395.0 mg The tablets are produced analogously to those of Example lb.
The resulting tablets are 11 mm in diameter, and weigh 395 mg.
The active substance and acid are present in separate granulates for ease of manufacture but are subsequently mixed together.
Results:
Time (min) % pimobendan dissolved 23.8 ~o34ss~
59.0 67.0 30 69.0 Example 2 Tablets containing 2.5 mq-of pimobendan a) Tablets containing 103 mq of citric acid Each tablet comprises (1) Pimobendan 2.5 mg (2) Corn starch 23.0 mg (3) Microcrystalline cellulose 26.0 mg (4) Anhydrous calcium phosphate 31.5 mg (5) Polyplasdone XL 59.0 mg - (6) Citric acid, fine particles (anhydrous) 103.0 mg (7) Compritol 888 5.0 mg Total weight 250.0 mg (1) to (4) are granulated with aqueous starch solution. The other ingredients are added to the dry granules to make the final mixture. This is then compressed to form tablets measuring 9 mm in diameter and weighing 250 mg.
The active substance and acid initially are present separately, for ease of manufacture, but are subsequently mixed together.
Results:
Time (min) % pimobendan dissolved 5 18.7 10 20.5 21.8 22.2 60 22.7 b) Tablets containing 50 mg' of citric acid Each tablet comprises (1)Pimobendan 2.5 mg (2)Anhydrous powdered citric acid 50.0 mg (3)Avicel PH 101 13.0 mg (4)Anhydrous calcium hydrogen phosphate 15.0 mg (5)Undried corn starch 6.0 mg (6)Collidone 25 0.5 mg (7)Insoluble polyvinylpyrrolidone 59.0 mg (8)Compritol 888 3.0 mg (9)Magnesium stearate 1.0 mg Total Weight 150.0 mg (6) is dissolved in ethanol and the mixture of ingredients (1) to (5) is granulated therewith. (7) to (9) are added to the dry granules to form the final mixture. This mixture is compressed to form tablets measuring 8 mm in diameter and weighing 150 mg.
The active substance and acid are present together in the same granulate.
Results:
Time (min) % pimobendan dissolved 15 71.1 30 85.0 Example 3 Capsules containing 5 mg of pimobendan a) Capsules without citric acid Each capsule contains (1) Pimobendan 5.0 mg (2)Lactose 90.25 mg (3}Corn starch 36.0 mg (4}Tween 80 0.5 mg (5)Explotab 8.0 mg (6)Magnesium stearate 0.25 mg Total weight 140.0 mg The individual powders are intensively mixed together and packed into size 4 hard gelatin capsules, the contents of each weighing 140 mg.
b) Capsules containing 230 mg~ of citric acid Each capsule contains (1)Pimobendan 5.0 mg (2)Citric acid 230.45 mg (3)Collidone 25 3.78 mg (4)Magnesium stearate 0.77 mg Total Weight 240.00 mg (1) and (2) are intensively mixed together and granulated with an alcoholic solution of (3). (4) is added to the dried granulate. The final mixture thus obtained is packed into size 1 hard gelatin capsules, the contents of each weighing 240 mg.
The active substance and acid are present together in the same granulate.
Results:
Time (min) % pimobendan dissolved c) Capsules containing 207 mq of citric acid Each capsule contains (1)Pimobendan, finely ground 5.0 mg (2)Citric acid 206.5 mg (3)Microcrystalline cellulose 40.0 mg (4)Aerosil 130 V 11.0 mg (5)Collidone 25 4.0 mg (6)Magnesium stearate 1.5 mg Total Weight 268.0 mg (1) is triturated with (2). (3) and (4) are added to the triturated material. The mixture is granulated with an alcoholic solution of (5). (6) is mixed into the dry granulate. The finished mixture is packed into size 1 capsules, the contents of each weighing 268 mg.
The active substance and acid are present in one and the same granulate.
Results:
Time (min) % pimobendan dissolved 84.1 90.2 91.7 30 92.5 Exampl a 4 Capsules containing 2.5 mq of pimobendan and 209 mg of citric acid Each capsule contains (1) Pimobendan 2.5 mg (2) Powdered citric acid 209.0 mg (3) Microcrystalline cellulose 40.0 mg 2U34 i69 (4) Silicon dioxide 11.0 mg (5) Polyvinylpyrrolidone 4.0 mg (6) Magnesium stearate 1.5 mg Total Weight 268.0 mg The tablets are produced analogously to those of Example 3c.
The active substance and acid are present in the same granulate.
Results:
Time (min) % pimobendan dissolved 15 96.5 30 99.1 Example 5 Film coated tablet containing 2.5 m~~imobendan and 50 ma of citric acid Each tablet comprises (1)Pimobendan 2.5 mg (2)Powdered anhydrous citric acid 50.0 mg (3)Avicel PH 101 13.0 mg (4)Anhydrous calcium hydrogen phosphate 15.0 mg (5)Undried corn starch 6.0 mg (6)Collidone 25 0.5 mg (7)Insoluble polyvinylpyrrolidone 59.0 mg (8)Compritol 888 3.0 mg (9)Magnesium stearate 1.0 mg Total weight 150.0 mg The preparation procedure is as described in Example 2b, but the finished mixture is compressed into biconvex tablets, which are each coated with 5 mg of hydroxypropyl-methylcellulose.
The active substance and acid are together in the same granulate.
Results:
Time (min) % pimobendan dissolved 76.8 30 86.1
Claims (22)
1. An orally administrable pharmaceutical composition comprising an intimate mixture of citric acid and pimobendan or a stereoisomer of pimobendan, in a weight ratio of at least 5:1.
2. A composition as claimed in claim 1, which composition also contains one or more pharmaceutical carriers or excipients.
3. A composition as claimed in claim 2 in the form of a granulate, powder or pellets.
4. A composition as claimed in claim 3 wherein the granulate, powder or pellets are packed into capsules.
5. A composition as claimed in claim 1, in the form of the granulate, powder or pellets compressed with a suitable excipient into tablets.
6. A composition as claimed in claim 5 wherein the tablets are provided with a flavour-masking coating.
7. A composition as claimed in any one of claims 1 to 6, wherein the weight ratio of pimobendan or a stereoisomer thereof to citric acid is between 1:10 and 1:20.
8. A composition as claimed in any one of claims 1 to 6 further containing a disintegrant.
9. A process for preparing a pharmaceutical composition as claimed in claim 1, wherein citric acid and pimobendan or a stereoisomer thereof in a weight ration of at least 5:1. are brought into an intimately mixed form by granulation.
10. A process as claimed in claim 9 wherein granulation is effected by dry granulation.
11. A process as claimed in claim 9 wherein granulation is effected in the presence of an aqueous granulating fluid with metered addition of granulating fluid and simultaneous drying.
12. A process as claimed in claim 9 wherein granulation is effected in the presence of a non-aqueous granulating fluid with metered addition of granulating fluid and simultaneous drying.
13. A process as claimed in claim 9 wherein the resulting granulate is processed into pellets.
14. A process as claimed in any one of claims 9 to 12 wherein the resulting granulate is compressed with suitable excipients into tablets.
15. A process as claimed in claim 13 wherein the resulting pellets are compressed with suitable excipients into tablets.
16. A process as claimed in claim 14 or 15 wherein the tablets are provided with a flavour-masking coating.
17. A process as claimed in any one of claims 9 to 12 wherein the resulting granulate is packed into capsules.
18 18. A process as claimed in claim 13 wherein the resulting pellets are packed into capsules.
19. A process as claimed in claim 17 or 18 wherein the capsules are provided with a flavour-masking coating.
20. The use of an intimate mixture of citric acid and pimobendan, or a stereoisomer of pimobendan, in a weight ratio of at least 5:1 for cambating cardiotonic, hypotensive and antithrombotic conditions.
21. A commercial package containing as active pharmaceutical ingredient an intimate mixture of citric acid and pimobendan, or a stereoisomer of pimobendan, in a weight ratio of at least 5:1, together with instructions for the use thereof for combating cardiotonic, hypotensive and antithrombotic conditions.
22. Use of a pharmaceutical composition as claimed in any one of claims 1 to 6 as a cardiotonic, hypotensive or antithrombotic agent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4001622.6 | 1990-01-20 | ||
| DE4001622A DE4001622A1 (en) | 1990-01-20 | 1990-01-20 | ORAL DRUGS OF PIMOBENDAN |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2034569A1 CA2034569A1 (en) | 1991-07-21 |
| CA2034569C true CA2034569C (en) | 2002-03-19 |
Family
ID=6398467
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002034569A Expired - Lifetime CA2034569C (en) | 1990-01-20 | 1991-01-18 | Oral pharmaceutical forms of pimobendan |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP0439030B1 (en) |
| JP (1) | JP2608183B2 (en) |
| KR (1) | KR0163056B1 (en) |
| AT (1) | ATE87481T1 (en) |
| AU (1) | AU630536B2 (en) |
| CA (1) | CA2034569C (en) |
| DE (2) | DE4001622A1 (en) |
| DK (1) | DK0439030T3 (en) |
| ES (1) | ES2054379T3 (en) |
| FI (1) | FI96274C (en) |
| HK (1) | HK175796A (en) |
| HU (1) | HU207948B (en) |
| IE (1) | IE64659B1 (en) |
| IL (1) | IL96995A (en) |
| NO (1) | NO176305C (en) |
| NZ (1) | NZ236834A (en) |
| PT (1) | PT96506B (en) |
| ZA (1) | ZA91372B (en) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2753904B1 (en) * | 1996-10-01 | 1998-10-30 | Gattefosse Ets Sa | PHARMACEUTICAL COMPOSITION WITH MODIFIED RELEASE OF ACTIVE SUBSTANCE, INCLUDING A MATRIX, AND MANUFACTURING PROCESS |
| DE102004011512B4 (en) | 2004-03-08 | 2022-01-13 | Boehringer Ingelheim Vetmedica Gmbh | Pharmaceutical preparation containing pimobendan |
| US8980894B2 (en) | 2004-03-25 | 2015-03-17 | Boehringer Ingelheim Vetmedica Gmbh | Use of PDE III inhibitors for the treatment of asymptomatic (occult) heart failure |
| EP1579862A1 (en) | 2004-03-25 | 2005-09-28 | Boehringer Ingelheim Vetmedica Gmbh | Use of PDE III inhibitors for the reduction of heart size in mammals suffering from heart failure |
| WO2005107719A2 (en) * | 2004-05-06 | 2005-11-17 | Sandoz Ag | Pharmaceutical composition comprising hydrophobic drug having improved solubility |
| JP3996626B2 (en) * | 2004-06-22 | 2007-10-24 | 塩野義製薬株式会社 | Orally disintegrating tablets |
| JP2006028130A (en) * | 2004-07-21 | 2006-02-02 | Toa Eiyo Ltd | Pimopendan preparation for oral administration |
| JP4572296B2 (en) * | 2004-07-21 | 2010-11-04 | トーアエイヨー株式会社 | Pimobendan oral dosage formulation |
| JP4572293B2 (en) * | 2004-07-21 | 2010-11-04 | トーアエイヨー株式会社 | Pimobendan oral dosage formulation |
| EP1937270A1 (en) * | 2005-09-21 | 2008-07-02 | Brystol-Myers Squibb Company | Oral administration of n-(2-chloro-6-methylphenyl)-2-[[6-4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-1,3-thiazole-5-carboxamide and salts thereof |
| JP4572300B2 (en) * | 2006-01-19 | 2010-11-04 | トーアエイヨー株式会社 | Pimobendan oral dosage formulation |
| EP1920785A1 (en) | 2006-11-07 | 2008-05-14 | Boehringer Ingelheim Vetmedica Gmbh | Liquid preparation comprising a complex of pimobendan and cyclodextrin |
| PE20081482A1 (en) * | 2006-12-20 | 2008-12-23 | Novartis Ag | GELATINE CAPSULES CONTAINING AN ACID |
| FR2934156B1 (en) * | 2008-07-23 | 2010-09-24 | Virbac | ORAL ADMINISTRATION MEDICAMENT IN SOLID FORM |
| WO2010055119A2 (en) * | 2008-11-17 | 2010-05-20 | Novartis Ag | Pharmaceutical composition comprising pimobendan |
| MX2011005444A (en) | 2008-11-25 | 2011-06-09 | Boehringer Ingelheim Vetmed | PHOSPHODIESTERASE TYPE III (PDE III) INHIBITORS OR CA<sup>2+</sup>-SENSITIZING AGENTS FOR THE TREATMENT OF HYPERTROPHIC CARDIOMYOPATHY. |
| NL1037569C2 (en) | 2009-12-18 | 2011-06-21 | Eurovet Animal Health B V | Crystalline pimobendan, process for the preparation thereof, pharmaceutical composition and use. |
| CN102711763A (en) * | 2009-12-29 | 2012-10-03 | 兴和株式会社 | Pharmaceutical composition for oral administration |
| US20120289517A1 (en) * | 2009-12-29 | 2012-11-15 | Kowa Co., Ltd. | Solid pharmaceutical composition for oral administration |
| EP2825159B1 (en) | 2012-03-15 | 2022-06-22 | Boehringer Ingelheim Vetmedica GmbH | Pharmaceutical tablet formulation for the veterinary medical sector, method of production and use thereof |
| WO2015007760A1 (en) | 2013-07-19 | 2015-01-22 | Boehringer Ingelheim Vetmedica Gmbh | Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition |
| EP3106150B1 (en) | 2013-12-04 | 2021-07-28 | Boehringer Ingelheim Vetmedica GmbH | Improved pharmaceutical compositions of pimobendan |
| US10537570B2 (en) | 2016-04-06 | 2020-01-21 | Boehringer Ingelheim Vetmedica Gmbh | Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease |
| CN106729723A (en) * | 2016-11-21 | 2017-05-31 | 青岛农业大学 | A kind of pharmaceutical composition containing UD-CG115BS.acardi and preparation method thereof |
| WO2024126434A1 (en) | 2022-12-15 | 2024-06-20 | Boehringer Ingelheim Vetmedica Gmbh | Solid dispersions comprising amorphous pimobendan and one or more stabilizing polymers |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES8101067A1 (en) * | 1978-08-25 | 1980-12-01 | Thomae Gmbh Dr K | Benzimidazoles, their preparation and pharmaceutical compositions containing them. |
| DE2837161A1 (en) * | 1978-08-25 | 1980-03-06 | Thomae Gmbh Dr K | 5-Alkyl:pyridazinyl substd. benzimidazole derivs. - useful as cardiovascular agents, antivirals, interferon inducers and ulcer inhibitors |
| JPS56110612A (en) * | 1980-02-08 | 1981-09-01 | Yamanouchi Pharmaceut Co Ltd | Readily disintegrable and absorbable compression molded article of slightly soluble drug |
| JPS60163823A (en) * | 1984-02-03 | 1985-08-26 | Taisho Pharmaceut Co Ltd | Oral administration pharmaceutical |
| DE3776269D1 (en) * | 1986-11-03 | 1992-03-05 | Schering Corp | LABETALOL TABLET WITH DELAYED DELIVERY OF ACTIVE SUBSTANCES. |
| DE3728244A1 (en) * | 1987-08-25 | 1989-03-09 | Thomae Gmbh Dr K | Novel (-)-benzimidazoles, their preparation and medicaments containing these compounds |
| EP0306846A3 (en) * | 1987-09-11 | 1990-05-02 | Dr. Karl Thomae GmbH | Synergistic combination comprising a phosphodiesterase inhibitor and a thromboxane-a2 antagonist, and its use or preparation |
| DE3805635A1 (en) * | 1988-02-24 | 1989-09-07 | Thomae Gmbh Dr K | USE OF BENZIMIDAZOLES FOR THE MANUFACTURE OF A MEDICAMENT WITH ANTI-MIXIC EFFECTS ON THE HEART AND ITS COMBINATIONS WITH SS-BLOCKERS OR BRADYCARDICA |
| JPH01258621A (en) * | 1988-04-06 | 1989-10-16 | Fujimoto Seiyaku Kk | Dilazep tablet with regulated absorption |
| JPH023609A (en) * | 1988-06-21 | 1990-01-09 | Fujimoto Seiyaku Kk | Long-acting drug preparation containing nicardipine hydrochloride as active component |
-
1990
- 1990-01-20 DE DE4001622A patent/DE4001622A1/en not_active Withdrawn
-
1991
- 1991-01-11 EP EP91100309A patent/EP0439030B1/en not_active Expired - Lifetime
- 1991-01-11 ES ES91100309T patent/ES2054379T3/en not_active Expired - Lifetime
- 1991-01-11 AT AT91100309T patent/ATE87481T1/en not_active IP Right Cessation
- 1991-01-11 DE DE9191100309T patent/DE59100067D1/en not_active Expired - Lifetime
- 1991-01-11 DK DK91100309.3T patent/DK0439030T3/en active
- 1991-01-17 PT PT96506A patent/PT96506B/en not_active IP Right Cessation
- 1991-01-18 KR KR1019910000822A patent/KR0163056B1/en not_active IP Right Cessation
- 1991-01-18 AU AU69454/91A patent/AU630536B2/en not_active Expired
- 1991-01-18 HU HU91177A patent/HU207948B/en unknown
- 1991-01-18 NZ NZ236834A patent/NZ236834A/en unknown
- 1991-01-18 JP JP3004069A patent/JP2608183B2/en not_active Expired - Lifetime
- 1991-01-18 FI FI910263A patent/FI96274C/en active
- 1991-01-18 IE IE16591A patent/IE64659B1/en not_active IP Right Cessation
- 1991-01-18 NO NO910213A patent/NO176305C/en not_active IP Right Cessation
- 1991-01-18 ZA ZA91372A patent/ZA91372B/en unknown
- 1991-01-18 CA CA002034569A patent/CA2034569C/en not_active Expired - Lifetime
- 1991-01-22 IL IL9699591A patent/IL96995A/en not_active IP Right Cessation
-
1996
- 1996-09-19 HK HK175796A patent/HK175796A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| NO176305B (en) | 1994-12-05 |
| NO176305C (en) | 1995-03-15 |
| PT96506A (en) | 1991-10-15 |
| FI910263A (en) | 1991-07-21 |
| DE4001622A1 (en) | 1991-07-25 |
| NZ236834A (en) | 1995-10-26 |
| HUT56494A (en) | 1991-09-30 |
| HU207948B (en) | 1993-07-28 |
| EP0439030A2 (en) | 1991-07-31 |
| EP0439030A3 (en) | 1991-10-16 |
| IL96995A (en) | 1994-11-11 |
| DE59100067D1 (en) | 1993-05-06 |
| HK175796A (en) | 1996-09-27 |
| FI96274B (en) | 1996-02-29 |
| HU910177D0 (en) | 1991-08-28 |
| IL96995A0 (en) | 1992-03-29 |
| JPH04210919A (en) | 1992-08-03 |
| AU630536B2 (en) | 1992-10-29 |
| IE910165A1 (en) | 1991-07-31 |
| AU6945491A (en) | 1991-07-25 |
| NO910213D0 (en) | 1991-01-18 |
| ES2054379T3 (en) | 1994-08-01 |
| FI910263A0 (en) | 1991-01-18 |
| ZA91372B (en) | 1992-09-30 |
| FI96274C (en) | 1996-06-10 |
| EP0439030B1 (en) | 1993-03-31 |
| ATE87481T1 (en) | 1993-04-15 |
| NO910213L (en) | 1991-07-22 |
| PT96506B (en) | 1998-06-30 |
| IE64659B1 (en) | 1995-08-23 |
| KR910014120A (en) | 1991-08-31 |
| KR0163056B1 (en) | 1998-12-01 |
| DK0439030T3 (en) | 1993-08-16 |
| JP2608183B2 (en) | 1997-05-07 |
| CA2034569A1 (en) | 1991-07-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2034569C (en) | Oral pharmaceutical forms of pimobendan | |
| US7695735B2 (en) | Fast disintegrating tablet | |
| CA1275933C (en) | Therapeutic composition containing ibuprofen | |
| US5364646A (en) | Oral pharmaceutical forms of pimobendan | |
| IE53543B1 (en) | New oral dipyridamole preparations | |
| HU196708B (en) | Process for producing pharmaceutical composition comprising omeprazol and suitable for treating deseases of the digestive system | |
| EP2147669A2 (en) | Rapidly dissolving robust dosage form | |
| CA2000763C (en) | Dispersable formulation | |
| EP0396972B2 (en) | An aqueous granulation solution and a method of tablet granulation | |
| US5322698A (en) | Process for the preparation of a tablet or dragee composition containing a heat-, light- and moisture-sensitive active ingredient having monoclinic crystal structure | |
| US4863743A (en) | Controlled release potassium chloride | |
| DE69733752T2 (en) | DRUGS CONTAINING OXAPROCINE SODIUM SALT, CALIUM SALT, OR TRIS (HYDROXYMETHYL) AMINOMETHANE SALT | |
| IL99428A (en) | Pharmaceutical compositions containing ranitidine bismuth carboxylate salts | |
| JP2002154948A (en) | Highly disintegrable tablet | |
| US4536511A (en) | Medicaments containing muzolimine, their use and processes for their production | |
| EP0121901A1 (en) | pH independent controlled releasable tablets | |
| AU2004251439A1 (en) | Tablet comprising fluvastatin and carmellose calcium | |
| JP4719899B2 (en) | Orally rapidly disintegrating tablets | |
| JPH02286614A (en) | Acetoaminophene preparation | |
| EP2520300A1 (en) | Pharmaceutical composition for oral administration | |
| NZ260732A (en) | Ipsapirone delayed release compositions | |
| EP3675832A1 (en) | Fast self dispersible dosage forms of deferasirox |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |