CA1228299A - Galenic preparation forms for oral antidiabetic agents and processes for producing them - Google Patents
Galenic preparation forms for oral antidiabetic agents and processes for producing themInfo
- Publication number
- CA1228299A CA1228299A CA000456096A CA456096A CA1228299A CA 1228299 A CA1228299 A CA 1228299A CA 000456096 A CA000456096 A CA 000456096A CA 456096 A CA456096 A CA 456096A CA 1228299 A CA1228299 A CA 1228299A
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- Prior art keywords
- active substance
- basic
- active
- excipient
- pharmaceutical composition
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
-
- 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
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
Abstract
Abstract The specification describes new orally administrable pharmaceutical compositions containing antidiabetic agents having an improved release of active substance and processes for producing these pharmaceutical compositions. The new pharmaceutical compositions are characterised in that the onset of the activity and the duration of activity are adapted to the particular needs of diabetics with regard to proper control of the metabolism and the associated proper release of insulin.
A basic or acidic excipient in a solvent is added to the antidiabetically active substance in a quantity such that the active substance is made soluble, then a solubilising agent is added.
Polyvinylpyrrolidone is dissolved as carrier in this solution, but the carrier may simultaneously serve as the solubilising excipient. This solution is further processed with other excipients to form corresponding pharmaceutical compositions.
A basic or acidic excipient in a solvent is added to the antidiabetically active substance in a quantity such that the active substance is made soluble, then a solubilising agent is added.
Polyvinylpyrrolidone is dissolved as carrier in this solution, but the carrier may simultaneously serve as the solubilising excipient. This solution is further processed with other excipients to form corresponding pharmaceutical compositions.
Description
~.L~ 299 " -- 1Q -7 Z1~4 -941 Pharmaceutical Compositions The invention relates to new orally administrable pharmaceutical compositions containing antidiabetic agents and processes for their preparationO
The said orally administrable compositions may contain as active substances s~lphonylureas, such as gliquidone, or substituted phenylcarboxylic acids. Other preferred sulphonylureas include glibenclamide, glibornuride, glisoxepidl glipizide and gliclazide. Gliquidone is l-cyclohexyl-3-[lp-[2-(3,4-dihydro-7-methoxy-4,4-dimethyl-1,3-dioxo-
The said orally administrable compositions may contain as active substances s~lphonylureas, such as gliquidone, or substituted phenylcarboxylic acids. Other preferred sulphonylureas include glibenclamide, glibornuride, glisoxepidl glipizide and gliclazide. Gliquidone is l-cyclohexyl-3-[lp-[2-(3,4-dihydro-7-methoxy-4,4-dimethyl-1,3-dioxo-
2(lH)-isoquinolyl)-ethyl]-phenyl]sulfonyl]urea, and exhibits a hypoglycaemic effect. However, other antidiabetic substances which may be used are 4-12-(aroylamino)ethyl~benzoic acids of general formula (I) ~ CO-NH-CH2-CH2- ~ -COOH 5I) wherein Rl represents a halogen atom, preferably a chlorine atom, and ~ represents an alkoxy group with l to 3 carbon atoms or a piperidin-l-yl or octamethyleneimino group, and also substituted 4-(aralkylaminocarbonylmethyl)-benzoic acids of general formula (II) ., . ~ .
5 ~ C~-NH C~CH2 ~ COOH (II j wherein R3 represents an alkyl group with 1 to 4 carbon atoms (preferably an n-propyl group) or a phenyl group, ~4 represents a piperidin-l-yl, pyrrolidin-l-yl or hexamethyleneimino group and R5 represents a hydrogen or halogen atom, preferably a chlorine or fluorine atom, or a methyl or methoxy group. However, mixtures of these active substances may also be used.
Micronised gliquidone is contained in a commercially available preparation consisting additionally of corn starch, lactose and magnesium stearate. This preparation containing gliquidone has already proved satisfactory as a reliable antidiabetic agent, with the great advantage that it is not contraindicated when there is restricted kidney function.
Generally, in the oral administration of substances which are difficultly soluble in the digestive fluids, and these include the substances mentioned above, the following problems arise: in many cases the active substance can only be partly reabsorbed and greatly fluctuating blood levels of the active substance may occur inter- and intra-individually.
However, in oral an~idiabetic agents, the start of the activity and the duration of the activity are also of particular importance since the activity sho~ d be matched to the blood sugar levels caused by the intake of food. This is not the case with the hitherto ava~ able preparations of antidiabetic ~2~
5 ~ C~-NH C~CH2 ~ COOH (II j wherein R3 represents an alkyl group with 1 to 4 carbon atoms (preferably an n-propyl group) or a phenyl group, ~4 represents a piperidin-l-yl, pyrrolidin-l-yl or hexamethyleneimino group and R5 represents a hydrogen or halogen atom, preferably a chlorine or fluorine atom, or a methyl or methoxy group. However, mixtures of these active substances may also be used.
Micronised gliquidone is contained in a commercially available preparation consisting additionally of corn starch, lactose and magnesium stearate. This preparation containing gliquidone has already proved satisfactory as a reliable antidiabetic agent, with the great advantage that it is not contraindicated when there is restricted kidney function.
Generally, in the oral administration of substances which are difficultly soluble in the digestive fluids, and these include the substances mentioned above, the following problems arise: in many cases the active substance can only be partly reabsorbed and greatly fluctuating blood levels of the active substance may occur inter- and intra-individually.
However, in oral an~idiabetic agents, the start of the activity and the duration of the activity are also of particular importance since the activity sho~ d be matched to the blood sugar levels caused by the intake of food. This is not the case with the hitherto ava~ able preparations of antidiabetic ~2~
3 -agents in which the effect of the substance and physiological insulin requirements in accordance with the intake of food cannot be reliably m~tched to one another in terms of time. The activity of the substance often occurs too late. frequently the maximum effect is only achieved at a time at which the blood glucose values are already dropping even without medication after the intake of food.
Then the activity of the substance continues even when the blood glucose concentration has returned to its initial level (cf. Berger, in Pelzer and Froesch, Diabetische Enteropathie, ~Iypoglykamien, Verlag Hans H~ber, Bern-Stuttgart-Wien 1974).
Attempts have also been made to synchronise the hypoglycaemic activity of a sulphonylurea with the increase in blood sugar caused by food intake by taking the sulphonylurea at a suitable time before the meal. However, it was then found ~hat administration of the active substance thirty minutes before the meal did not res ~ t in a satisfactory improvement in activity (cf. Sartor et al., Eur.
J. Clin. Pharmacolog. 21, 403 to 408 (1982)), partly because of the longer duration of activity mentioned above. Furthermore, a specific time difference between the taking of the medicine and the taking of food can onl~ be reliably monitored in a clinic.
Attempts were made to solve these problems in the case of substances which are diffic~ tly soluble in the digestive fluids by attempting to optimise the dissolution ra~e of the active substance difficultly soluble ~ se in the development of the galenic preparationsO This was donel for example, by increasing the surface area of the active substance.
Thus, a pharmaceutical composition has been described (German Patent 27348,334) in which the active s~bstance (also a hypoglycaemic substance) is present with a particle surface area of from 3 ~o 10 m2/g in -- d" --the presenee of a wetting agent.
However, this objective was ~ so supposed to be achieved by applying the active substance in dissolved form to a substrate or carrier with the largest possible surface area and then eliminating the solvent (cf. H. Rupprecht, Acta Pharm. Technol.
26/1, pages 13 ff. (1980))o Furthermore, attempts have been made to improve the dissolution rate by adding salt forming agents (cf~ German Offenlegungsschrift 31 24 090~9).
Moreover, in order to improve the solubility and the dissolution rate, solid dispersions have also been produced. They consist of the active substance and one or more water-soluble carriers, possibly combined with surface-active substances. In order to prepare these dispersions, a homogeneous melt is prepared ~rom the active substance or possibly a salt thereof and a carrier (cf. German Offenlegungs-schrift 23 55 743). In another process, the active substance and carrier are dissolved in a common solvent and then the solvent is eliminated. The water soluble carriers used are, inter alia, polyvinyl-pyrrolidone or polyethylene glycols (cf~ ~.R.
Mer ~ e, Acta Pharm. Technol. 27/4, pages 193 ff.
(1981) and W.L. Chiou and S. Riegelmann, J. Pharm~
Sci~ 60/9, 1281 ff. (1971)).
If the following methods described in the literature are used to produce preparations containing the compounds mentioned hereinbefore, a better dissolution rate for the active substance, e.g.
the gliquidone, is scarcely obtained- the salt formation itself does no~ res ~ t in an increase in the dissolution rate (cf. Table 3, Example 6), and the application of active substance, e.g. gliquidone, to a carrier alone (cf. Example 1~ comparison part) does not produce the desired result either. In corresponding tests, which will be described in more detail hereinafter, the dissolution rate was determined an~ in the case of gliquidone it was found to be no greater than the dissolution rates shown by gli~uidone-containing preparations known per se.
It has now been found that, surprisingly, pharrnaceutic~ compositions according to the invention having a very rapid and total release of active substance can be produced by dissolving (a) acidically reacting active substances by means of basic excipients, ~b) amphoterically reacting active substances by means of basic or acidic excipients or (c) basically reacting active substances by means of acidic excipients in a solvent in the presence of one or more solubi-lising substances. The solubilising substance used is polyvinylpyrrolidone and, optionally, other solubilising substances. The solution is evaporated to dryness and the product thereby obtained is, if required,processed further to produce the desired preparation. The molar ratio of active substance to basic or acidic excipient must be selected so that there is an excess of basic or acidic excipient.
Hence, according to one feature of the present invention there is provided a process for producing orally administrable pharmaceutical compositions containing antidiabetically active substances, wherein an acidically reacting active substance is dissolved in a solvent with the aid of at least one basic excipient, an amphoterically reactiny active substance is dissolved in a solvent with the aid of at least one basic or acidic excipient or a basically reacting active substance is dissolved in a solvent with the aid of at least one acidic excipient, the said dissolution being effected in the presence of polyvinylpyrrolidone , and optionally one or more other solubilising or emulsifying sub-stances and the molar ratio of ac-tive substance -to basic or acidic excipient being less than 1:1; the solution is evaporated to dryness;
and the product thereby obtained is, if required, further processed op-tionally with the addition of further excipients to produce the required pharmaceutical composi-tions.
Pharmaceutical compositions thereby obtained constitute a further feature of the present invention.
According to a still further fea-ture of the presen-t in-vention -there is provided orally administrable pharmaceutical com-positions in solid form containiny: an acidically reacting anti-diabetically active substance together with a basic excipient, an amphoterically reac-ting an-tidiabetically active substance together with a basic or acidic excipien-t or a basically reacting an-tidiabe-tically ac-tive substance together with an acidic excipient; to-gether with polyvinylpyrrolidone and optionally one or more other solubilising or emulsifying substances and, if required, one or more further excipients, the molar ratio of active substance to basic or acidic excipient being less -than 1:1.
It is important that sufficient basic or acidic excipient is added to the ac-tive substance to ensure rapid and complete dissolu-tion _ vivo. This is only possible wi-th a molar ratio of active substance to basic or acidic excipien-t of less -than 1:1.
In order -to dissolve 2.5 parts by weigh-t of gliquidone, for example, in 50 parts by weight of water, 0.7 parts by weigh-t of ethylenediamine. lH20, 3.0 parts by weight of N-methylgluca-mine or 3.5 parts by weight of diethanolamine are required. If we ~ b ~ 3 3 ~L~ .~.
- 6a -compare the molar ratios which are absolutely necessary for rapid ancl complete dissolution of -the ac-tive subs-tance, the followiny picture is obtained:
gliquidone (molecular weight 527.6): e~hylenediamine.lH20 (molecular weight 7~.1) is 1.1.89;
gliquidone: N-methylglucamine (molecular weight 195.21) is 1:3.24;
gliquidone: diethanolamine (molec~ ar weight 105.1~) is 1:7003;
gliquidone L~lysine (molecular weight 1~6.2) is 1:4.33.
This Einding cannot be explained by mere salt formation of the gliquidone with the basic excipients in question; it appears that the excess base has an additional stabilising effect. The same phenomena also apply to the other active substances.
This effect was not ~oreseeable even by someone skilled in the art.
The solutions are prepared wi-th polyvinylpyr-rolidone as solubilising agent; after evaporation, this substance also acts as carrier at the same time. It is not possible to incorporate the active substance and basic excipient directly in a melt of polyvinylpyrrolidone since this carrier decomposes even before reaching the melting point.
Suitable basic excipients include a number of inorganic or or~anic bases which are physiologically harmless at least in the dosage ranges used, such as sodium hydroxide solution, potassium hydroxide solution, ammonia, tert. sodium phosphate, diethanolamine, ethylenediamine, N-methylglucamine or L-lysine.
The molar ratio of active subs~ance to basic excipient or mixtures of excipients is pre~erably from 1:1.1 to 1:10, but a greater excess of base may be advantageous in some cases.
Suitable acidic excipients include sulphuric and phosphoric acid: the acid must be present in excess.
In order to stabilise highly concentrated solutions such as those which are clearly obtained d~
when ~sing a preparation according to ~he invention, it is necessary to add sol~ilising and/or emulsifying substance. ~n addition, other such substances may be added, such as polyoxyethylene polyoxypropylene polymers, polyethylene glycol 4000 or 6000 , polyethoxy-lated sorbitan mono-oleates; sorbitol, glycerol polyethylene glycoloxy stearates and polyoxyethylene fatty alcohol ethers. Both the nature of the solubilising substance and also the proportions used are important in determining the dissolution rate of the active substance. The preferred ratio of active substance, e.g. gliquidone, to the total quantity of solubilising substances is from 1:1 to 1~10.
The solution of the active substance~ basic or acidic excipients ard solubilising and/or emulsifying substances is prepared primarily using water or other polar solvents such as lower alcohols, e.g.
ethanol, isopropanol, ketones such as acetone or mixtures of these substances with water.
By using the method of solution according to the invention instead of the melting process known from German Offenlegungsschrift 23 55 743 for incorporating the active sobstance, the non~
fusible solubilising substance polyvinylpyrrolidone can be processed in molecular dispersion together with the active substances.
The solution to the problem described above is surprising for the following reasons:
The methods for incorporation of substances which are difficultly soluble in the digestive fluids, described in the literature and listed hereinafter, do not result in a significant increase in the dissolution rate of the active substances when applied to the production of pharmaceutical compositions containing the above mentioned active substances; nor can they improve the dissolution rate found for the commercially available preparations which contain, for example, gliq~idone. Some _ relevant tests are described below. The dissolution rates were determined after 5 and 30 minutes by the USP XX Paddle Method in 900 ml of McIlvaine-Buffer, at pH 7.0, at 37C and at 100 rpm. For each measurement, a quantity of preparation corresponding to 40.0 my of active substance was used and each measurement was repeated twice and the average was calculated from the results obtained.
In order to determine the dissolution rate with an increase in the surface area of gliquidone, 30 parts by weight of the active substance was dissolved in 150 parts by weight of methylene chloride and the solution was applied to 210 parts by weight of a tablet carrier. After drying, the treated tablet carrier was compressed to form tablets and the dissolution rate of the gliquidone from these tablets was determined; 5% of the active substance dissolved after 5 minutes and 7% dissolved after 30 minutes. In the case of micronised gliquidone with no excipients, 0~ dissolved after 5 and 30 minutes. When the micronised gliquidone was compressed to form tablets (see the comparison preparation in Example 1) 5.8% of active substance dissolved after 5 minutes and 7.2% after 30 minutes.
No better dissolution rate was obtained by forminc gliquidone salts. 5.0 parts by weight of gliquidone was dissolved in an aqueous solution of 1.9 parts by weight of ethylenediamine=lH2O, with heating and stirring; this solution was dried in vacuo in a rotary evaporator and the solid product was passed through a 1.0 mm mesh screen.
This product also yielded a quantity of only 4%
of dissolved active substance after 5 minutes and 30 minutes.
Not even the use of a gliquidone-containing dispersion produced any better dissolution rates.
Analogously to the method described in German Offenlegungs-schrift 23 55 743, 1.47 parts by weight of gliquidone .
was dissolved in a melt consisting of 79.1 parts by weight of polyethylene glycol 4000 and 5.0 parts by weight oE polyoxyethylene-40-stearate and then 14.43 parts by weight of potassium bicarbonate was dispersed therein. The solidified melt was rubbed through a screen with a mesh size of 1.0 mm.
The measurement of the dissolution rate gave a result of 10% of active substance after 5 minutes and 7% after 30 minutes.
A further series of tests was carried out to check whether the use of gliquidone salts in the process described in German Offenlegungsschrift 23 55 743 leads to better dissolution rates. Again, a melt consisting of 79.1 parts by weight of polyethylene glycol 4000 and 5.0 parts by weight of polyoxyethylene-40-stearate was used, in which a saturated solution of the gliquidone salt in question was prepared.
Then 14.43 parts by weight of potassium hydrogencarbonate was dispersed in this solution. The solidified melt was passed through a screen with a mesh size of 1Ø
3~3 T~BLE
____ Gliquidone Maximum active Quantity of Salt containing substance (calc~ ated solidified melt as base) soluble in required for a melt consisting of 30 mg dose of PEG 4000 and Polyoxy- gliquidone:
ethylene-40-stearateo Ethylenediamine 0.65% 4.6 g 10 NH~OH 2.40% 1.25 g N~Methylglucamine 0.54% 5.54 g Piperidine 2.15~ 1.395 g Na~I 1.99% 1.51 g _ _ (PEG 4000 = polyethylene ~lycol 4000) It is easy to see from these results that ~he quantity o~ melt required for a 30 mg dose of gliquidone cannot be contained in a disintegrating tablet which can be swallGwed. Thus, the process according to German Offenlegungsschrift 23 55 743 is unsuitable for gliquidone salts and also for the similarly added salts of the other active substances mentioned hereinbefore.
It is not therefore possible to achieve rapid and total dissolution of the active .substances using the known methods which are described as suitable for such purposes, as can be seen from the tests described aboveO
When developing pharmaceutical preparations, optimisation is carried out using in vitro me~hodsO
The release and dissolution of the active substance are determined using dissolution testsu In order to create conditions comparab~e to those which obtain in vivo, these tests are normally carried out in an acidic medium at pH 1.2. IE this pH
is used with the preparations according to the invention, no measurable release rates are obtained.
q~
In vitro dissolution tests must therefore be carried out at pH 7 (or above). This is due to the fact that the solubility of the active substance is no longer suf~icient at pH levels below 7. It would therefore be expected that there would be only a slight release of active substance in vivo ln the acidic range of the intestinal tract. The rapid and total reabsorption of the active substance even in the upper region of the intestinal tract is therefore surprising to anyone skilled in the artO It is also surprising that, despite the difference between in vivo conditions and those conditions which are created for the measurement of the dissolution rate in vitro, there is considerable concord between the in vitro and in vivo results This is shown _ by a comparison of the dissolution rates of Example 2 in Table 1 with the curve in Fig. 1, on the one hand, and by a comparison of the curve for a preparation according to the present invention (Example 2) with the curves for the preparations of Examples 6 and 8, which are not according to the present invention, on the other hand.
If the hypoglycaemically active substances mentioned hereinbefore are formulated by the processes according to the present invention described hereinbe~ore, pharmaceutical compositions are obtained wherein the action of the active substance is matched to the physiological requirement o~ the patient for this medicament. These special pharmaceutical products ensure rapid and complete reabsorption o~ the active substance. Rapid reabsorption shortens the time which must elapse between taking the medicament and taking a meal in order to synchronise the hypo-glycaemic activity of the sulphonylurea with the increase in blood sugar caused by ~ood intake.
Rapid and total reabsorption reduces intra- and inter-individual fluctuations in the blood glucose level, minimizes the dependence of reabsorption on the state of the gastrointestin~ tract or on the nature or quantit~ of food taken and thus ensures the correct metabolic pattern and consequently a correct insulin release. The disadvantages described above relating to the preparations known at present are avoided by using the process according to the invention.
Trials on humans (see Fig. 1 ) demonstrate the rapid onset of activity of the preparation according to the invention (Example 2) and the slight activity of Examples 6 and 8, which are not according to the invention. It is also found that the values obtained in vitro and in vivo correspond well.
The findings mentioned above show that the medical objective:
a) avoiding a non-physiological rise in blood sugar after the intake of food and b) avoiding a massive drop in blood sugar some hours after food intake, is achieved with the preparations according to the invention.
The methods of measuring used will now be described:
Determining the blood_~ucose .
The blood sugar was measured in whole venous blood. 50 ul of blood were freed from protein with 500 ul of 0.32 M perchloric acid. After centrifuging, the glucose in the supernatant was measured by the hexokinase method using an automatic substrate.
~uman trials Blood samples were taken through long-term catheters with heparinised disposable syringes.
After a preliminary period of 15 minutes in which the course of the blood sugar level and of the ins ~ in level without any medicament was measured, the preparation was administered in the form of a granulate or in tablet form in the appropriate dosage with 70 ml of water.
The essence of the invention will be investigated more closely hereinafter in a discussion of the res ~ ts obtained in the tests described in the Examples.
Table 1 shows the correlation between the quan~ity of polyvinylpyrrolidone and the dissolution rate.
Table 2 shows that the presence of a basic excipient is absolutely necessary not only for dissolving the gliquidone but also for obtaining rapid release of the active substance. In order to achieve an equally high dissolution rate solely by using the solubilisin~ carrier Kollidon 25(R) and without using a basic excipient, the quantity of Kollidon 25(R) in this Example would have to be increased by approximately a power of 10. ~owever, such a high proportion of polyvinylpyrrolidone is impossible for practical reasons (the preparations would no longer be manageable as oral preparations and in any case such forms would not be viable from the point of view of manufacture and cost).
The Examples on which ~hese observations are based now follow, with precise numerical data:
In the Examples:
Kollidon 2s(R) is a poly-N-vinylpyrrolidone (-2)7 PEG 4000 = polyethylene glycol 4000 Pluronic F 68 (R) is a polyoxyethylene polyoxypropylene polymer, Avicel ( ) is a microcrystalline cellulose, Explotab (R) is sodium carboxymethyl starch and -- 15 ~
Amberlite IRP 88 is the potassium salt of a polymer of methacrylic acid ~ith divinylbenzene.
7~r~;~le l)lr~rK
~ 16 -Examples 1 to 3 Table 1 contains Examples 1 to 3 with their dissolution rates.
Table 1:
Examples 1 to 3 have the foll ~7ing compositions in common:
5mg of gliquidone, 1.9mg of ethylenediamine.lH2O
Example Kollidon 25(R) Dissolution Rate in percent mg of the active substance which has gone into solution after 5 and 30 minutes The pharmaceutical compositions in the Examples were produced as follows:
The basic excipient i5 dissolved in 100 parts by weight of water at 70C w-th stirring. The active substance is added; the mixture is stirred until the latter is completely dissolved. Polyvinyl~
pyrrolidone is dissolved in this solution. The solution is evaporated to dryness in vacuo with stirring and the product is rubbed through a screen with a mesh size of 1 mm.
A comparison with a known gliquidone-containing preparation of the following composition:
micronised gliquidone 30 parts by weight corn starch 75 parts by weight lactose 132 parts by weight magnesium stearate 3 parts by weight showed the following dissolution rate:
after 5 minutes : 5.8~ gliquidone after 30 minutes : 7.2~ gliquidone Examples 4 and 5 The pharmaceutical compositions shown in Table 2 which follows comprise, in addition to 5 mg of gliquidone, increasing quantities of polyvinylpyrrolidone (Kollidon 25(R)) but no basic excipient and no carrier. A useful dissolution rate is achieved only wi-th upwards of 12 times the quantity of Kollidon 25 (R)o The pharmaceutical compos itions in these Examples were produced by dissolving the active substance and solubilising substance together in ethanol; the solution was then evaporated to dryness and the product was rubbed through a screen with a mesh size of 1 mm.
Table 2:
Example Kollidon 25( ) Dissolution Rate in percent mg of the active substance ~ which has gone into solution after 5 and 30 minutes Examples 6 to 8 The pharmaceutical composition in Example 3S 7 was prepared as described in Example 1. The ~ 8~
pharmaceutical compo~itions in Examples 6 and 8 were produced analogously to the method described in Examples 4 and 5.
Table 3 shows the compositions and the dissolution rates meas~red. As can be seen from Table 3, the presence of a basic excipient alone does not lead to a useful dissolution rate nor does the sole presence of a solubilising substance (without a basic excipient and a carrier) lead to a product with a useful dissol.ution rate. This shows that the combination of gli.quidone with a basic excipient and sol~bilising agent in the presence of a soluble carrier yields the best results in terms of rapid and fulles~ possible dissolution of the active 15 substance.
Table 3:
Exa- Gliqui- Basic 30 mg of Dissolution Rate mple done mg Excip- Kollidon in per cent of ient mg 25(R) the active sub-stance which has gone in~o solution after 5 and 30 minutes _ _ 25 6 5 l.9~Ethylene no 4 4 7 25 6.5)diamine yes 88 94 . lH2 0 8 25 - yes 12 24 9 30 36.0 L-lysine yes * 91 *(Kollidon 25 *
Pluronic F 68) Example 9 35 1 Tablet contains:
,~ -- 19 -- `
30.0 mg gliquidone 36.0 mg L-lysine 20.0 mg Kollidon 25 24.0 mg Pluronic F 68 Processing analogously to Examples 1 to 3, but with the solution being evaporated in a spray dryer.
The Eollowing are added per tablet:
105.0 mg Avicel 105.0 mq Explotab 320.0 mg From this mixture round biconvex tablets weighing 320 mg and measuring 10 mm in diameter are compressed and coated with hydroxypropylmethyl-cellulose to mask the flavour.
Dissolution rateO after 5 minutes : 91%
Example 10 Film-coated tablets containing 4-[(1-(2-piperidino-phen~ butyl)-aminocarbonylmethyl]-benzoic acid Example 10a:
1 Tablet contains:
30 mg 4~(1-(?.-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid 134 mg ~nberlite IRP 88 134 mg Avicel 2 m~ magnesium stearate 300 mg The tablet constituents are mixed together, compressed to form round biconvex tablets weighiny 300 mg and measuring 10 mm in diameter and then coated with hydroxypropylmethylcellulose to mask the flavour.
d~9 Dissolution rate: after 5 minutes: 25.6 after 30 minutes: 36.3 Example lOb:
Granulat.e of active substance.
30 mg of the active substance of Example lOa 36 mg L-lysine 30 mg Xollidon 25 24 mg Pluronic F 68 Processing is carried out analogously to Examples 1 to 3. The following are added to this granulate:
gO mg Avicel 90 mg Amberlite IRP 88 300 mg Round biconvex tablets weighing 300 mg and measuring 10 mm in diameter are compressed from this mixture and coated with hydroxypropylmethylcellulose to mask the flavour.
Dissolution rate~ after 5 minutes : 48.7%
after 30 minutes : 81.3%
Example 11 - Film-coated tablets contai_ing 4-~N-(a-phenyl-2-p~eridino-benzyl~-aminocarbonylmethyl L-benzoic acid . .
Example lla:
1 Tablet contains:
30 mg of active subs~ance 134 mg Amberlite IRP 88 134 mg Avicel 2'mg magnesium stearate 300 mg ~ he tablet ingredients are mixed together, compressed to form round biconvex tablets weighing 300 mg and measuring 10 mm in diameter and coated with hydroxypropylmethylcell~ose to mask the flavour.
Dissolution rate: 1508% after 5 minutes 20.9% after 3Q minutes Example llb:
Granulate of active substance 30 mg of active substance of Example lla 30 mg L-lysine 30 mg Kollidon 25 24 mg Pluronic F 68 Processing analogously to Examples 1 to 3.
The following are added to this granulate:
93 mg Avicel 93 mg .Amberlite IRP 88 300 mg Round biconvex tablets weighing 300 mg and measuring lO mm in diameter are compressed from this mix~ure and coated with hydroxypropylmethylcellulose to mask the flavour~
Dissolution rate: af~er 5 minutes: 58.4%
after 30 minutes: 33~4%
Example 12 - Film-coated_tablets containing 4-[2-(5-chloro-2-octamethyleneimino-benzoyl-amino)ethyl]-benzoic acid Example 12a:
l Tablet containsr ~9i - 22 ~
30 mg of active substance 134 my Amberlite IRP 88 134 mg Avicel 2 m~ magnesium stearate 300 mg The tablet ingredients are mixed together7 compressed to form round biconvex tablets weighing 300 mg and measuring 10 mm in diameter and then coated with hydroxypxopylmethylcellulose to mask the flavourO
Dissolution rateo 18.4% after 5 minutes 27.2% after 30 minutes Example 12b_ Granulate of active substance 30 mg of active substance of Example 12a 36 mg L-lysine 30 mg Kollidon 25 24 mg Pluronic F 63 Processing is carried out analogously to Examples 1 to 3.
The following are added to the granulate.
90.0 mg Avicel 90.0 mq Amberlite IRP 88 300.0 mg Round biconvex tablets weighing 300 mg and measuring 10 mm in diameter are compressed from this mixture and coated with hydroxypropylmethylcellulose to mask the flavour.
Dissolution rate: 96.2~ after 5 minutes 99.9% after 30 minutes There now follows an Example of the production of a pharmaceutical composition.
Example 13 Capsules A quantity of granulate from Example 1 corresponding to 10 mg of gliquidone is mixed with a corresponding quantity of corn starch and magnesium stearate and then packed into size 5 hard gelatine capsulesO
Then the activity of the substance continues even when the blood glucose concentration has returned to its initial level (cf. Berger, in Pelzer and Froesch, Diabetische Enteropathie, ~Iypoglykamien, Verlag Hans H~ber, Bern-Stuttgart-Wien 1974).
Attempts have also been made to synchronise the hypoglycaemic activity of a sulphonylurea with the increase in blood sugar caused by food intake by taking the sulphonylurea at a suitable time before the meal. However, it was then found ~hat administration of the active substance thirty minutes before the meal did not res ~ t in a satisfactory improvement in activity (cf. Sartor et al., Eur.
J. Clin. Pharmacolog. 21, 403 to 408 (1982)), partly because of the longer duration of activity mentioned above. Furthermore, a specific time difference between the taking of the medicine and the taking of food can onl~ be reliably monitored in a clinic.
Attempts were made to solve these problems in the case of substances which are diffic~ tly soluble in the digestive fluids by attempting to optimise the dissolution ra~e of the active substance difficultly soluble ~ se in the development of the galenic preparationsO This was donel for example, by increasing the surface area of the active substance.
Thus, a pharmaceutical composition has been described (German Patent 27348,334) in which the active s~bstance (also a hypoglycaemic substance) is present with a particle surface area of from 3 ~o 10 m2/g in -- d" --the presenee of a wetting agent.
However, this objective was ~ so supposed to be achieved by applying the active substance in dissolved form to a substrate or carrier with the largest possible surface area and then eliminating the solvent (cf. H. Rupprecht, Acta Pharm. Technol.
26/1, pages 13 ff. (1980))o Furthermore, attempts have been made to improve the dissolution rate by adding salt forming agents (cf~ German Offenlegungsschrift 31 24 090~9).
Moreover, in order to improve the solubility and the dissolution rate, solid dispersions have also been produced. They consist of the active substance and one or more water-soluble carriers, possibly combined with surface-active substances. In order to prepare these dispersions, a homogeneous melt is prepared ~rom the active substance or possibly a salt thereof and a carrier (cf. German Offenlegungs-schrift 23 55 743). In another process, the active substance and carrier are dissolved in a common solvent and then the solvent is eliminated. The water soluble carriers used are, inter alia, polyvinyl-pyrrolidone or polyethylene glycols (cf~ ~.R.
Mer ~ e, Acta Pharm. Technol. 27/4, pages 193 ff.
(1981) and W.L. Chiou and S. Riegelmann, J. Pharm~
Sci~ 60/9, 1281 ff. (1971)).
If the following methods described in the literature are used to produce preparations containing the compounds mentioned hereinbefore, a better dissolution rate for the active substance, e.g.
the gliquidone, is scarcely obtained- the salt formation itself does no~ res ~ t in an increase in the dissolution rate (cf. Table 3, Example 6), and the application of active substance, e.g. gliquidone, to a carrier alone (cf. Example 1~ comparison part) does not produce the desired result either. In corresponding tests, which will be described in more detail hereinafter, the dissolution rate was determined an~ in the case of gliquidone it was found to be no greater than the dissolution rates shown by gli~uidone-containing preparations known per se.
It has now been found that, surprisingly, pharrnaceutic~ compositions according to the invention having a very rapid and total release of active substance can be produced by dissolving (a) acidically reacting active substances by means of basic excipients, ~b) amphoterically reacting active substances by means of basic or acidic excipients or (c) basically reacting active substances by means of acidic excipients in a solvent in the presence of one or more solubi-lising substances. The solubilising substance used is polyvinylpyrrolidone and, optionally, other solubilising substances. The solution is evaporated to dryness and the product thereby obtained is, if required,processed further to produce the desired preparation. The molar ratio of active substance to basic or acidic excipient must be selected so that there is an excess of basic or acidic excipient.
Hence, according to one feature of the present invention there is provided a process for producing orally administrable pharmaceutical compositions containing antidiabetically active substances, wherein an acidically reacting active substance is dissolved in a solvent with the aid of at least one basic excipient, an amphoterically reactiny active substance is dissolved in a solvent with the aid of at least one basic or acidic excipient or a basically reacting active substance is dissolved in a solvent with the aid of at least one acidic excipient, the said dissolution being effected in the presence of polyvinylpyrrolidone , and optionally one or more other solubilising or emulsifying sub-stances and the molar ratio of ac-tive substance -to basic or acidic excipient being less than 1:1; the solution is evaporated to dryness;
and the product thereby obtained is, if required, further processed op-tionally with the addition of further excipients to produce the required pharmaceutical composi-tions.
Pharmaceutical compositions thereby obtained constitute a further feature of the present invention.
According to a still further fea-ture of the presen-t in-vention -there is provided orally administrable pharmaceutical com-positions in solid form containiny: an acidically reacting anti-diabetically active substance together with a basic excipient, an amphoterically reac-ting an-tidiabetically active substance together with a basic or acidic excipien-t or a basically reacting an-tidiabe-tically ac-tive substance together with an acidic excipient; to-gether with polyvinylpyrrolidone and optionally one or more other solubilising or emulsifying substances and, if required, one or more further excipients, the molar ratio of active substance to basic or acidic excipient being less -than 1:1.
It is important that sufficient basic or acidic excipient is added to the ac-tive substance to ensure rapid and complete dissolu-tion _ vivo. This is only possible wi-th a molar ratio of active substance to basic or acidic excipien-t of less -than 1:1.
In order -to dissolve 2.5 parts by weigh-t of gliquidone, for example, in 50 parts by weight of water, 0.7 parts by weigh-t of ethylenediamine. lH20, 3.0 parts by weight of N-methylgluca-mine or 3.5 parts by weight of diethanolamine are required. If we ~ b ~ 3 3 ~L~ .~.
- 6a -compare the molar ratios which are absolutely necessary for rapid ancl complete dissolution of -the ac-tive subs-tance, the followiny picture is obtained:
gliquidone (molecular weight 527.6): e~hylenediamine.lH20 (molecular weight 7~.1) is 1.1.89;
gliquidone: N-methylglucamine (molecular weight 195.21) is 1:3.24;
gliquidone: diethanolamine (molec~ ar weight 105.1~) is 1:7003;
gliquidone L~lysine (molecular weight 1~6.2) is 1:4.33.
This Einding cannot be explained by mere salt formation of the gliquidone with the basic excipients in question; it appears that the excess base has an additional stabilising effect. The same phenomena also apply to the other active substances.
This effect was not ~oreseeable even by someone skilled in the art.
The solutions are prepared wi-th polyvinylpyr-rolidone as solubilising agent; after evaporation, this substance also acts as carrier at the same time. It is not possible to incorporate the active substance and basic excipient directly in a melt of polyvinylpyrrolidone since this carrier decomposes even before reaching the melting point.
Suitable basic excipients include a number of inorganic or or~anic bases which are physiologically harmless at least in the dosage ranges used, such as sodium hydroxide solution, potassium hydroxide solution, ammonia, tert. sodium phosphate, diethanolamine, ethylenediamine, N-methylglucamine or L-lysine.
The molar ratio of active subs~ance to basic excipient or mixtures of excipients is pre~erably from 1:1.1 to 1:10, but a greater excess of base may be advantageous in some cases.
Suitable acidic excipients include sulphuric and phosphoric acid: the acid must be present in excess.
In order to stabilise highly concentrated solutions such as those which are clearly obtained d~
when ~sing a preparation according to ~he invention, it is necessary to add sol~ilising and/or emulsifying substance. ~n addition, other such substances may be added, such as polyoxyethylene polyoxypropylene polymers, polyethylene glycol 4000 or 6000 , polyethoxy-lated sorbitan mono-oleates; sorbitol, glycerol polyethylene glycoloxy stearates and polyoxyethylene fatty alcohol ethers. Both the nature of the solubilising substance and also the proportions used are important in determining the dissolution rate of the active substance. The preferred ratio of active substance, e.g. gliquidone, to the total quantity of solubilising substances is from 1:1 to 1~10.
The solution of the active substance~ basic or acidic excipients ard solubilising and/or emulsifying substances is prepared primarily using water or other polar solvents such as lower alcohols, e.g.
ethanol, isopropanol, ketones such as acetone or mixtures of these substances with water.
By using the method of solution according to the invention instead of the melting process known from German Offenlegungsschrift 23 55 743 for incorporating the active sobstance, the non~
fusible solubilising substance polyvinylpyrrolidone can be processed in molecular dispersion together with the active substances.
The solution to the problem described above is surprising for the following reasons:
The methods for incorporation of substances which are difficultly soluble in the digestive fluids, described in the literature and listed hereinafter, do not result in a significant increase in the dissolution rate of the active substances when applied to the production of pharmaceutical compositions containing the above mentioned active substances; nor can they improve the dissolution rate found for the commercially available preparations which contain, for example, gliq~idone. Some _ relevant tests are described below. The dissolution rates were determined after 5 and 30 minutes by the USP XX Paddle Method in 900 ml of McIlvaine-Buffer, at pH 7.0, at 37C and at 100 rpm. For each measurement, a quantity of preparation corresponding to 40.0 my of active substance was used and each measurement was repeated twice and the average was calculated from the results obtained.
In order to determine the dissolution rate with an increase in the surface area of gliquidone, 30 parts by weight of the active substance was dissolved in 150 parts by weight of methylene chloride and the solution was applied to 210 parts by weight of a tablet carrier. After drying, the treated tablet carrier was compressed to form tablets and the dissolution rate of the gliquidone from these tablets was determined; 5% of the active substance dissolved after 5 minutes and 7% dissolved after 30 minutes. In the case of micronised gliquidone with no excipients, 0~ dissolved after 5 and 30 minutes. When the micronised gliquidone was compressed to form tablets (see the comparison preparation in Example 1) 5.8% of active substance dissolved after 5 minutes and 7.2% after 30 minutes.
No better dissolution rate was obtained by forminc gliquidone salts. 5.0 parts by weight of gliquidone was dissolved in an aqueous solution of 1.9 parts by weight of ethylenediamine=lH2O, with heating and stirring; this solution was dried in vacuo in a rotary evaporator and the solid product was passed through a 1.0 mm mesh screen.
This product also yielded a quantity of only 4%
of dissolved active substance after 5 minutes and 30 minutes.
Not even the use of a gliquidone-containing dispersion produced any better dissolution rates.
Analogously to the method described in German Offenlegungs-schrift 23 55 743, 1.47 parts by weight of gliquidone .
was dissolved in a melt consisting of 79.1 parts by weight of polyethylene glycol 4000 and 5.0 parts by weight oE polyoxyethylene-40-stearate and then 14.43 parts by weight of potassium bicarbonate was dispersed therein. The solidified melt was rubbed through a screen with a mesh size of 1.0 mm.
The measurement of the dissolution rate gave a result of 10% of active substance after 5 minutes and 7% after 30 minutes.
A further series of tests was carried out to check whether the use of gliquidone salts in the process described in German Offenlegungsschrift 23 55 743 leads to better dissolution rates. Again, a melt consisting of 79.1 parts by weight of polyethylene glycol 4000 and 5.0 parts by weight of polyoxyethylene-40-stearate was used, in which a saturated solution of the gliquidone salt in question was prepared.
Then 14.43 parts by weight of potassium hydrogencarbonate was dispersed in this solution. The solidified melt was passed through a screen with a mesh size of 1Ø
3~3 T~BLE
____ Gliquidone Maximum active Quantity of Salt containing substance (calc~ ated solidified melt as base) soluble in required for a melt consisting of 30 mg dose of PEG 4000 and Polyoxy- gliquidone:
ethylene-40-stearateo Ethylenediamine 0.65% 4.6 g 10 NH~OH 2.40% 1.25 g N~Methylglucamine 0.54% 5.54 g Piperidine 2.15~ 1.395 g Na~I 1.99% 1.51 g _ _ (PEG 4000 = polyethylene ~lycol 4000) It is easy to see from these results that ~he quantity o~ melt required for a 30 mg dose of gliquidone cannot be contained in a disintegrating tablet which can be swallGwed. Thus, the process according to German Offenlegungsschrift 23 55 743 is unsuitable for gliquidone salts and also for the similarly added salts of the other active substances mentioned hereinbefore.
It is not therefore possible to achieve rapid and total dissolution of the active .substances using the known methods which are described as suitable for such purposes, as can be seen from the tests described aboveO
When developing pharmaceutical preparations, optimisation is carried out using in vitro me~hodsO
The release and dissolution of the active substance are determined using dissolution testsu In order to create conditions comparab~e to those which obtain in vivo, these tests are normally carried out in an acidic medium at pH 1.2. IE this pH
is used with the preparations according to the invention, no measurable release rates are obtained.
q~
In vitro dissolution tests must therefore be carried out at pH 7 (or above). This is due to the fact that the solubility of the active substance is no longer suf~icient at pH levels below 7. It would therefore be expected that there would be only a slight release of active substance in vivo ln the acidic range of the intestinal tract. The rapid and total reabsorption of the active substance even in the upper region of the intestinal tract is therefore surprising to anyone skilled in the artO It is also surprising that, despite the difference between in vivo conditions and those conditions which are created for the measurement of the dissolution rate in vitro, there is considerable concord between the in vitro and in vivo results This is shown _ by a comparison of the dissolution rates of Example 2 in Table 1 with the curve in Fig. 1, on the one hand, and by a comparison of the curve for a preparation according to the present invention (Example 2) with the curves for the preparations of Examples 6 and 8, which are not according to the present invention, on the other hand.
If the hypoglycaemically active substances mentioned hereinbefore are formulated by the processes according to the present invention described hereinbe~ore, pharmaceutical compositions are obtained wherein the action of the active substance is matched to the physiological requirement o~ the patient for this medicament. These special pharmaceutical products ensure rapid and complete reabsorption o~ the active substance. Rapid reabsorption shortens the time which must elapse between taking the medicament and taking a meal in order to synchronise the hypo-glycaemic activity of the sulphonylurea with the increase in blood sugar caused by ~ood intake.
Rapid and total reabsorption reduces intra- and inter-individual fluctuations in the blood glucose level, minimizes the dependence of reabsorption on the state of the gastrointestin~ tract or on the nature or quantit~ of food taken and thus ensures the correct metabolic pattern and consequently a correct insulin release. The disadvantages described above relating to the preparations known at present are avoided by using the process according to the invention.
Trials on humans (see Fig. 1 ) demonstrate the rapid onset of activity of the preparation according to the invention (Example 2) and the slight activity of Examples 6 and 8, which are not according to the invention. It is also found that the values obtained in vitro and in vivo correspond well.
The findings mentioned above show that the medical objective:
a) avoiding a non-physiological rise in blood sugar after the intake of food and b) avoiding a massive drop in blood sugar some hours after food intake, is achieved with the preparations according to the invention.
The methods of measuring used will now be described:
Determining the blood_~ucose .
The blood sugar was measured in whole venous blood. 50 ul of blood were freed from protein with 500 ul of 0.32 M perchloric acid. After centrifuging, the glucose in the supernatant was measured by the hexokinase method using an automatic substrate.
~uman trials Blood samples were taken through long-term catheters with heparinised disposable syringes.
After a preliminary period of 15 minutes in which the course of the blood sugar level and of the ins ~ in level without any medicament was measured, the preparation was administered in the form of a granulate or in tablet form in the appropriate dosage with 70 ml of water.
The essence of the invention will be investigated more closely hereinafter in a discussion of the res ~ ts obtained in the tests described in the Examples.
Table 1 shows the correlation between the quan~ity of polyvinylpyrrolidone and the dissolution rate.
Table 2 shows that the presence of a basic excipient is absolutely necessary not only for dissolving the gliquidone but also for obtaining rapid release of the active substance. In order to achieve an equally high dissolution rate solely by using the solubilisin~ carrier Kollidon 25(R) and without using a basic excipient, the quantity of Kollidon 25(R) in this Example would have to be increased by approximately a power of 10. ~owever, such a high proportion of polyvinylpyrrolidone is impossible for practical reasons (the preparations would no longer be manageable as oral preparations and in any case such forms would not be viable from the point of view of manufacture and cost).
The Examples on which ~hese observations are based now follow, with precise numerical data:
In the Examples:
Kollidon 2s(R) is a poly-N-vinylpyrrolidone (-2)7 PEG 4000 = polyethylene glycol 4000 Pluronic F 68 (R) is a polyoxyethylene polyoxypropylene polymer, Avicel ( ) is a microcrystalline cellulose, Explotab (R) is sodium carboxymethyl starch and -- 15 ~
Amberlite IRP 88 is the potassium salt of a polymer of methacrylic acid ~ith divinylbenzene.
7~r~;~le l)lr~rK
~ 16 -Examples 1 to 3 Table 1 contains Examples 1 to 3 with their dissolution rates.
Table 1:
Examples 1 to 3 have the foll ~7ing compositions in common:
5mg of gliquidone, 1.9mg of ethylenediamine.lH2O
Example Kollidon 25(R) Dissolution Rate in percent mg of the active substance which has gone into solution after 5 and 30 minutes The pharmaceutical compositions in the Examples were produced as follows:
The basic excipient i5 dissolved in 100 parts by weight of water at 70C w-th stirring. The active substance is added; the mixture is stirred until the latter is completely dissolved. Polyvinyl~
pyrrolidone is dissolved in this solution. The solution is evaporated to dryness in vacuo with stirring and the product is rubbed through a screen with a mesh size of 1 mm.
A comparison with a known gliquidone-containing preparation of the following composition:
micronised gliquidone 30 parts by weight corn starch 75 parts by weight lactose 132 parts by weight magnesium stearate 3 parts by weight showed the following dissolution rate:
after 5 minutes : 5.8~ gliquidone after 30 minutes : 7.2~ gliquidone Examples 4 and 5 The pharmaceutical compositions shown in Table 2 which follows comprise, in addition to 5 mg of gliquidone, increasing quantities of polyvinylpyrrolidone (Kollidon 25(R)) but no basic excipient and no carrier. A useful dissolution rate is achieved only wi-th upwards of 12 times the quantity of Kollidon 25 (R)o The pharmaceutical compos itions in these Examples were produced by dissolving the active substance and solubilising substance together in ethanol; the solution was then evaporated to dryness and the product was rubbed through a screen with a mesh size of 1 mm.
Table 2:
Example Kollidon 25( ) Dissolution Rate in percent mg of the active substance ~ which has gone into solution after 5 and 30 minutes Examples 6 to 8 The pharmaceutical composition in Example 3S 7 was prepared as described in Example 1. The ~ 8~
pharmaceutical compo~itions in Examples 6 and 8 were produced analogously to the method described in Examples 4 and 5.
Table 3 shows the compositions and the dissolution rates meas~red. As can be seen from Table 3, the presence of a basic excipient alone does not lead to a useful dissolution rate nor does the sole presence of a solubilising substance (without a basic excipient and a carrier) lead to a product with a useful dissol.ution rate. This shows that the combination of gli.quidone with a basic excipient and sol~bilising agent in the presence of a soluble carrier yields the best results in terms of rapid and fulles~ possible dissolution of the active 15 substance.
Table 3:
Exa- Gliqui- Basic 30 mg of Dissolution Rate mple done mg Excip- Kollidon in per cent of ient mg 25(R) the active sub-stance which has gone in~o solution after 5 and 30 minutes _ _ 25 6 5 l.9~Ethylene no 4 4 7 25 6.5)diamine yes 88 94 . lH2 0 8 25 - yes 12 24 9 30 36.0 L-lysine yes * 91 *(Kollidon 25 *
Pluronic F 68) Example 9 35 1 Tablet contains:
,~ -- 19 -- `
30.0 mg gliquidone 36.0 mg L-lysine 20.0 mg Kollidon 25 24.0 mg Pluronic F 68 Processing analogously to Examples 1 to 3, but with the solution being evaporated in a spray dryer.
The Eollowing are added per tablet:
105.0 mg Avicel 105.0 mq Explotab 320.0 mg From this mixture round biconvex tablets weighing 320 mg and measuring 10 mm in diameter are compressed and coated with hydroxypropylmethyl-cellulose to mask the flavour.
Dissolution rateO after 5 minutes : 91%
Example 10 Film-coated tablets containing 4-[(1-(2-piperidino-phen~ butyl)-aminocarbonylmethyl]-benzoic acid Example 10a:
1 Tablet contains:
30 mg 4~(1-(?.-piperidino-phenyl)-l-butyl)-aminocarbonylmethyl]-benzoic acid 134 mg ~nberlite IRP 88 134 mg Avicel 2 m~ magnesium stearate 300 mg The tablet constituents are mixed together, compressed to form round biconvex tablets weighiny 300 mg and measuring 10 mm in diameter and then coated with hydroxypropylmethylcellulose to mask the flavour.
d~9 Dissolution rate: after 5 minutes: 25.6 after 30 minutes: 36.3 Example lOb:
Granulat.e of active substance.
30 mg of the active substance of Example lOa 36 mg L-lysine 30 mg Xollidon 25 24 mg Pluronic F 68 Processing is carried out analogously to Examples 1 to 3. The following are added to this granulate:
gO mg Avicel 90 mg Amberlite IRP 88 300 mg Round biconvex tablets weighing 300 mg and measuring 10 mm in diameter are compressed from this mixture and coated with hydroxypropylmethylcellulose to mask the flavour.
Dissolution rate~ after 5 minutes : 48.7%
after 30 minutes : 81.3%
Example 11 - Film-coated tablets contai_ing 4-~N-(a-phenyl-2-p~eridino-benzyl~-aminocarbonylmethyl L-benzoic acid . .
Example lla:
1 Tablet contains:
30 mg of active subs~ance 134 mg Amberlite IRP 88 134 mg Avicel 2'mg magnesium stearate 300 mg ~ he tablet ingredients are mixed together, compressed to form round biconvex tablets weighing 300 mg and measuring 10 mm in diameter and coated with hydroxypropylmethylcell~ose to mask the flavour.
Dissolution rate: 1508% after 5 minutes 20.9% after 3Q minutes Example llb:
Granulate of active substance 30 mg of active substance of Example lla 30 mg L-lysine 30 mg Kollidon 25 24 mg Pluronic F 68 Processing analogously to Examples 1 to 3.
The following are added to this granulate:
93 mg Avicel 93 mg .Amberlite IRP 88 300 mg Round biconvex tablets weighing 300 mg and measuring lO mm in diameter are compressed from this mix~ure and coated with hydroxypropylmethylcellulose to mask the flavour~
Dissolution rate: af~er 5 minutes: 58.4%
after 30 minutes: 33~4%
Example 12 - Film-coated_tablets containing 4-[2-(5-chloro-2-octamethyleneimino-benzoyl-amino)ethyl]-benzoic acid Example 12a:
l Tablet containsr ~9i - 22 ~
30 mg of active substance 134 my Amberlite IRP 88 134 mg Avicel 2 m~ magnesium stearate 300 mg The tablet ingredients are mixed together7 compressed to form round biconvex tablets weighing 300 mg and measuring 10 mm in diameter and then coated with hydroxypxopylmethylcellulose to mask the flavourO
Dissolution rateo 18.4% after 5 minutes 27.2% after 30 minutes Example 12b_ Granulate of active substance 30 mg of active substance of Example 12a 36 mg L-lysine 30 mg Kollidon 25 24 mg Pluronic F 63 Processing is carried out analogously to Examples 1 to 3.
The following are added to the granulate.
90.0 mg Avicel 90.0 mq Amberlite IRP 88 300.0 mg Round biconvex tablets weighing 300 mg and measuring 10 mm in diameter are compressed from this mixture and coated with hydroxypropylmethylcellulose to mask the flavour.
Dissolution rate: 96.2~ after 5 minutes 99.9% after 30 minutes There now follows an Example of the production of a pharmaceutical composition.
Example 13 Capsules A quantity of granulate from Example 1 corresponding to 10 mg of gliquidone is mixed with a corresponding quantity of corn starch and magnesium stearate and then packed into size 5 hard gelatine capsulesO
Claims (28)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing an orally administrable pharm-aceutical composition containing an antidiabetically active sub-stance, wherein an acidically reacting active substance is dis-solved in a solvent with the aid of at least one basic excipient, an amphoterically reacting active substance is dissolved in a solvent with the aid of at least one basic or acidic excipient or a basically reacting active substance is dissolved in a solvent with the aid of at least one acidic excipient, the said dissolution being effected in the presence of polyvinylpyrrolidone and op-tionally one or more other solubilising or emulsifying substances and the molar ratio of active substance to basic or acidic exci-pient being less than 1:1; the solution is evaporated to dryness;
and the product thereby obtained is, if required, further processed optionally with the addition of further excipients to produce the required pharmaceutical composition.
and the product thereby obtained is, if required, further processed optionally with the addition of further excipients to produce the required pharmaceutical composition.
2. A process as claimed in claim 1, wherein the active sub-stance comprises an orally administrable antidiabetically active sulphonylurea.
3. A process as claimed in claim 1, wherein the active sub-stance comprises at least one substance selected from:
a) 4-[2-(aroylamino)ethyl]-benzoic acids of general formula (I) (I) (wherein R1 represents a halogen atom and R2 represents an alkoxy group with 1 to 3 carbon atoms or a piperidin-1-yl or octa-methyleneimino group) and b) substituted 4-(aralkylaminocarbonylmethyl)-benzoic acids of general formula (II) (II) (wherein R3 represents an alkyl group with 1 to 4 carbon atoms or a phenyl group, R4 represents a piperidin-1-yl, pyrrolidin-1-yl or hexamethyleneimino group and R5 represents a hydrogen or halogen atom or a methyl or methoxy group).
a) 4-[2-(aroylamino)ethyl]-benzoic acids of general formula (I) (I) (wherein R1 represents a halogen atom and R2 represents an alkoxy group with 1 to 3 carbon atoms or a piperidin-1-yl or octa-methyleneimino group) and b) substituted 4-(aralkylaminocarbonylmethyl)-benzoic acids of general formula (II) (II) (wherein R3 represents an alkyl group with 1 to 4 carbon atoms or a phenyl group, R4 represents a piperidin-1-yl, pyrrolidin-1-yl or hexamethyleneimino group and R5 represents a hydrogen or halogen atom or a methyl or methoxy group).
4. A process as claimed in claim 3 wherein the active sub-stance comprises at least one compound of formula I in which R1 represents a chlorine atom.
5. A process as claimed in claim 3 wherein the active sub-stance comprises at least one compound of formula II in which R3 represents an n-propyl group.
6. A process as claimed in claim 3 or claim 5 wherein the active substance comprises at least one compound of formula II
in which R5 represents a fluorine or chlorine atom.
in which R5 represents a fluorine or chlorine atom.
7. A process as claimed in claim 2 wherein gliquidone is used as the active substance.
8. A process as claimed in claim 3 wherein 4-[2-(5-chloro-2-octamethyleneimino-benzoylamino)ethyl]benzoic acid is used as the active substance.
9. A process as claimed in claim 3 wherein 4-[N-(.alpha.-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid is used as the active substance.
10. A process as claimed in claim 3 wherein 4-[[1-(2-piperidino-phenyl)-1-butyl]-aminocarbonylmethyl]-benzoic acid is used as the active substance.
11. A process as claimed in claim 1, 2 or 3, wherein a mixture of orally administrable antidiabetically active substance is used.
12. A process as claimed in claim 1, 2 or 3, wherein a basic excipient is used and the molar ratio of active substance to basic excipient is from 1:1.1 to 1:10.
13. A process as claimed in claim 1, 2 or 3, wherein a mixture of basic excipients is used.
14. A process as claimed in claim 1, 2 or 3, wherein the ratio of active substance or mixture of active substances to the total quantity of solubilising substances is from 1:1 to 1:10 parts by weight.
15. A process as claimed in claim 1, 2 or 3, wherein the dissolution is effected in the presence of one or more other solubilising or emulsifying substance which is or are selected from polyoxyethylene polyoxypropylene polymers, polyethylene glycols, polyethoxylated sorbitan mono-oleates, sorbitol, glycerol polyethylene glycoloxy stearates, polyoxyethylene fatty alcohol ethers and mixtures of these substances.
16. A process as claimed in claim 1, 2 or 3, wherein the solvent used is water or is a lower alcohol or ketone or a mixture thereof with water.
17. A process as claimed in claim 1, 2 or 3, wherein at least one basic excipient selected from sodium hydroxide solution, potassium hydroxide solution, ammonia, tert. sodium phosphate, diethanolamine, L-lysine, ethylenediamine or N-methylglucamine is used.
18. A process as claimed in claim 1, 2 or 3 wherein at least one acidic excipient selected from sulphuric acid and phosphoric acid is used.
19. An orally administrable pharmaceutical composition in solid form containing: an acidically reacting antidiabetically active substance together with a basic excipient, an amphoterically reacting antidiabetically active substance together with a basic or acidic excipient or a basically reacting antidiabetically active substance together with an acidic excipient; together with poly-vinylpyrrolidone and optionally one or more other solubilising or emulsifying substances and, if required, one or more further excipients, the molar ratio of active substance to basic or acidic excipient being less than 1:1.
20. A pharmaceutical composition as claimed in claim 19 containing an antidiabetically active sulphonylurea together with a basic excipient.
21. A pharmaceutical composition as claimed in claim 19, wherein the active substance comprises at least one substance selected from:
a) 4-[2-(arolylamino)ethyl] -benzoic acids of general formula (I) (I) (wherein R1 represents a halogen atom and R2 represents an alkoxy group with 1 to 3 carbon atoms or a piperidin-1-yl or octamethyleneimino group) and b) substituted 4-(aralkylaminocarbonylmethyl)-benzoic acids of general formula (II) (II) (wherein R3 represents an alkyl group with 1 to 4 carbon atoms or a phenyl group, R4 represents a piperidin-1-yl, pyrrolidin-1-yl or hexamethyleneimino group and R5 represents a hydrogen or halogen atom or a methyl or methoxy group).
a) 4-[2-(arolylamino)ethyl] -benzoic acids of general formula (I) (I) (wherein R1 represents a halogen atom and R2 represents an alkoxy group with 1 to 3 carbon atoms or a piperidin-1-yl or octamethyleneimino group) and b) substituted 4-(aralkylaminocarbonylmethyl)-benzoic acids of general formula (II) (II) (wherein R3 represents an alkyl group with 1 to 4 carbon atoms or a phenyl group, R4 represents a piperidin-1-yl, pyrrolidin-1-yl or hexamethyleneimino group and R5 represents a hydrogen or halogen atom or a methyl or methoxy group).
22. A pharmaceutical composition as claimed in claim 21 wherein the active substance comprises at least one compound of formula I in which R1 represents a chlorine atom.
23. A pharmaceutical composition as claimed in claim 21 wherein the active substance comprises at least one compound of formula II in which R3 represents an n-propyl group.
24. A pharmaceutical composition as claimed in claim 21 wherein the active substance comprises at least one compound of formula II in which R3 represents an n-propyl group and R5 represents a fluorine or chlorine atom.
25. A pharmaceutical composition according to claim 19 wherein the active substance is gliquidone.
26. A pharmaceutical composition according to claim 19 wherein the active substance is 4-[2-(5-chloro-2-octamethylene-imino-benzoylamino)-ethyl]benzoic acid.
27. A pharmaceutical composition according to claim 19 wherein the active substance is 4-[N-(.alpha.-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoic acid.
28. A pharmaceutical composition according to claim 19 wherein the active substance is 4-[[1-(2-piperidino-phenyl)-1-butyl]-aminocarbonylmethyl]-benzoic acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19833320582 DE3320582A1 (en) | 1983-06-08 | 1983-06-08 | METHODS OF PREPARATION WITH GLIQUIDONE AND METHOD FOR THE PRODUCTION THEREOF |
| DEP3320582.5 | 1983-06-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1228299A true CA1228299A (en) | 1987-10-20 |
Family
ID=6200885
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000456096A Expired CA1228299A (en) | 1983-06-08 | 1984-06-07 | Galenic preparation forms for oral antidiabetic agents and processes for producing them |
Country Status (25)
| Country | Link |
|---|---|
| US (2) | US4696815A (en) |
| EP (1) | EP0128483B1 (en) |
| JP (1) | JPS6069038A (en) |
| KR (1) | KR910004571B1 (en) |
| AT (1) | ATE56365T1 (en) |
| AU (1) | AU563642B2 (en) |
| CA (1) | CA1228299A (en) |
| DD (1) | DD224216A5 (en) |
| DE (2) | DE3320582A1 (en) |
| DK (1) | DK162019C (en) |
| ES (1) | ES8506446A1 (en) |
| FI (1) | FI85217C (en) |
| GB (1) | GB2142236B (en) |
| GR (1) | GR82362B (en) |
| HK (1) | HK72387A (en) |
| HU (1) | HU193932B (en) |
| IE (1) | IE57793B1 (en) |
| IL (1) | IL72034A (en) |
| MY (1) | MY100795A (en) |
| NO (1) | NO168628C (en) |
| NZ (1) | NZ208417A (en) |
| PH (1) | PH24567A (en) |
| PT (1) | PT78710B (en) |
| SG (1) | SG48187G (en) |
| ZA (1) | ZA844296B (en) |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3320582A1 (en) * | 1983-06-08 | 1984-12-13 | Dr. Karl Thomae Gmbh, 7950 Biberach | METHODS OF PREPARATION WITH GLIQUIDONE AND METHOD FOR THE PRODUCTION THEREOF |
| DE3320583A1 (en) * | 1983-06-08 | 1984-12-13 | Dr. Karl Thomae Gmbh, 7950 Biberach | NEW GALENIC PREPARATION FORMS OF ORAL ANTIDIABETICS AND METHOD FOR THE PRODUCTION THEREOF |
| US5312924A (en) | 1983-12-30 | 1994-05-17 | Dr. Karl Thomae Gmbh | Phenylacetic acid benzylamides |
| US4819238A (en) * | 1987-10-26 | 1989-04-04 | Hughes Aircraft Company | Wide band free electron laser with variable phase and frequency |
| US5258185A (en) * | 1989-08-23 | 1993-11-02 | Bauer Kurt H | Highly active, rapidly absorbable formulations of glibenclamide, processes for the production thereof and their use |
| US5024843A (en) * | 1989-09-05 | 1991-06-18 | Alza Corporation | Oral hypoglycemic glipizide granulation |
| CH678920A5 (en) * | 1989-11-14 | 1991-11-29 | Gergely Gerhard | |
| US5455046A (en) * | 1993-09-09 | 1995-10-03 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems for insoluble drugs |
| US5773025A (en) | 1993-09-09 | 1998-06-30 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems--amorphous drugs |
| US6726930B1 (en) * | 1993-09-09 | 2004-04-27 | Penwest Pharmaceuticals Co. | Sustained release heterodisperse hydrogel systems for insoluble drugs |
| ES2322405T3 (en) | 1996-07-08 | 2009-06-19 | Penwest Pharmaceuticals Co. | CONTROLLED LIBERATION MATRIX FOR INSOLUBLE DRUGS IN HIGH DOSE. |
| WO1999004818A1 (en) * | 1997-07-24 | 1999-02-04 | Eisai Co., Ltd. | Preparation composition and process for producing the same |
| US6056977A (en) | 1997-10-15 | 2000-05-02 | Edward Mendell Co., Inc. | Once-a-day controlled release sulfonylurea formulation |
| US6099859A (en) * | 1998-03-20 | 2000-08-08 | Andrx Pharmaceuticals, Inc. | Controlled release oral tablet having a unitary core |
| US6099862A (en) | 1998-08-31 | 2000-08-08 | Andrx Corporation | Oral dosage form for the controlled release of a biguanide and sulfonylurea |
| IL143375A0 (en) * | 1999-09-30 | 2002-04-21 | Penwest Pharmaceuticals Co | Sustained release matrix systems for highly soluble drugs |
| US6703045B2 (en) | 2001-08-21 | 2004-03-09 | Council Of Scientific & Industrial Research | Composition and method for maintaining blood glucose level |
| JP2005508331A (en) * | 2001-09-28 | 2005-03-31 | サン・ファーマシューティカル・インダストリーズ・リミテッド | Dosage preparation for the treatment of diabetes |
| WO2004050068A1 (en) * | 2002-11-29 | 2004-06-17 | Janssen Pharmaceutica N.V. | Pharmaceutical compositions comprising a basic respectively acidic drug compound, a surfactant and a physiologically tolerable water-soluble acid respectively base |
| AU2003269481A1 (en) * | 2003-09-10 | 2005-03-29 | Biocon Limited | (s)-(+)-2-ethoxy-4-{(3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl)-methyl}-benzoic acid sodium salt |
| AU2003269480A1 (en) * | 2003-09-10 | 2005-03-29 | Biocon Limited | Phosphoric acid salt of (s)-(+)-2-ethoxy-4-{(3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl)-methyl}-benzoic acid |
| TR200704897A1 (en) | 2007-07-13 | 2009-02-23 | Sanovel �La� Sanay� Ve T�Caret Anon�M ��Rket� | Glyclazide formulations providing extended release @ |
| EP2181705A1 (en) | 2008-10-31 | 2010-05-05 | Disphar International B.V. | Sustained-release formulation of gliclazide |
| EP2468268B1 (en) | 2010-12-21 | 2017-12-13 | Sanovel Ilaç Sanayi Ve Ticaret Anonim Sirketi | Combination composition of vildagliptin and gliclazide |
| TR201107482A1 (en) | 2010-12-21 | 2012-07-23 | Sanovel İlaç San.Ve Ti̇c.A.Ş. | The bilayer combination composition of vildagliptin and glyclazide. |
| TR201103946A1 (en) | 2011-04-22 | 2012-11-21 | Sanovel İlaç Sanayi̇ Ve Ti̇caret Anoni̇m Şi̇rketi̇ | Glyclazide formulations for controlled release. |
| RU2014124118A (en) | 2011-11-15 | 2015-12-27 | Др. Редди'С Лабораторис Лтд. | PHARMACEUTICALS, INCLUDING ATORVASTATIN AND GLIMEPIRIDE |
| EP2958548A1 (en) | 2013-02-19 | 2015-12-30 | Sanovel Ilac Sanayi ve Ticaret A.S. | A production process for gliclazide formulations |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1187259A (en) * | 1967-10-23 | 1970-04-08 | Hexachimie | New Aminoalkyl Esters of 2-Anilino-Nicotinic Acids and process for their manufacture |
| US3668215A (en) * | 1967-11-25 | 1972-06-06 | Bayer Ag | Aryl-sulphonyl-semicarbazides containing heterocyclic acylamino groups |
| NL138933B (en) * | 1969-03-26 | 1973-05-15 | Erba Carlo Spa | PROCEDURE FOR PREPARING BENZENE SULPHONYLUREA DERIVATIVES WITH BLOOD SUGAR-MIRROR-LOWERING ACTION. |
| NL7314765A (en) * | 1972-10-31 | 1974-05-02 | ||
| DE2657382A1 (en) * | 1976-12-17 | 1978-06-29 | Thera Ges Fuer Patente | ORAL ANTIDIABETIC |
| EP0045238B1 (en) * | 1980-07-29 | 1986-10-01 | Sanofi S.A. | Acid stabilized compositions of thieno-pyridine derived compounds and process for preventing degradation of such compounds |
| US4430399A (en) * | 1980-09-25 | 1984-02-07 | Duracell Inc. | Method of electrode formation and article |
| DE3100535A1 (en) * | 1981-01-10 | 1982-08-12 | Dr. Karl Thomae Gmbh, 7950 Biberach | "NEW CARBONIC ACID DERIVATIVES, THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS" |
| DE3225188A1 (en) * | 1982-07-06 | 1984-01-12 | Dr. Karl Thomae Gmbh, 7950 Biberach | Novel phenylacetic acid derivatives, their preparation and pharmaceuticals containing these compounds |
| DE3124090A1 (en) * | 1981-06-19 | 1983-01-05 | Dr. Karl Thomae Gmbh, 7950 Biberach | NEW ORAL DIPYRIDAMOL FORMS |
| DE3126703A1 (en) * | 1981-07-07 | 1983-01-27 | Dr. Karl Thomae Gmbh, 7950 Biberach | BROMHEXIN RETARD FORM AND METHOD FOR THEIR PRODUCTION |
| GB2118040A (en) * | 1982-02-15 | 1983-10-26 | Hoechst Uk Ltd | Oral anti-diabetic preparation |
| DE3320582A1 (en) * | 1983-06-08 | 1984-12-13 | Dr. Karl Thomae Gmbh, 7950 Biberach | METHODS OF PREPARATION WITH GLIQUIDONE AND METHOD FOR THE PRODUCTION THEREOF |
-
1983
- 1983-06-08 DE DE19833320582 patent/DE3320582A1/en not_active Ceased
-
1984
- 1984-05-31 US US06/615,892 patent/US4696815A/en not_active Expired - Fee Related
- 1984-06-01 AT AT84106272T patent/ATE56365T1/en not_active IP Right Cessation
- 1984-06-01 EP EP84106272A patent/EP0128483B1/en not_active Expired - Lifetime
- 1984-06-01 DE DE8484106272T patent/DE3483175D1/en not_active Expired - Fee Related
- 1984-06-05 IL IL72034A patent/IL72034A/en unknown
- 1984-06-06 GR GR74942A patent/GR82362B/el unknown
- 1984-06-06 DD DD84263871A patent/DD224216A5/en not_active IP Right Cessation
- 1984-06-07 IE IE1423/84A patent/IE57793B1/en not_active IP Right Cessation
- 1984-06-07 GB GB08414529A patent/GB2142236B/en not_active Expired
- 1984-06-07 NZ NZ208417A patent/NZ208417A/en unknown
- 1984-06-07 KR KR1019840003188A patent/KR910004571B1/en not_active IP Right Cessation
- 1984-06-07 ZA ZA844296A patent/ZA844296B/en unknown
- 1984-06-07 NO NO842290A patent/NO168628C/en unknown
- 1984-06-07 ES ES533208A patent/ES8506446A1/en not_active Expired
- 1984-06-07 HU HU842206A patent/HU193932B/en not_active IP Right Cessation
- 1984-06-07 JP JP59117432A patent/JPS6069038A/en active Granted
- 1984-06-07 FI FI842294A patent/FI85217C/en not_active IP Right Cessation
- 1984-06-07 CA CA000456096A patent/CA1228299A/en not_active Expired
- 1984-06-07 DK DK281184A patent/DK162019C/en not_active IP Right Cessation
- 1984-06-08 PT PT78710A patent/PT78710B/en unknown
- 1984-06-08 PH PH30794A patent/PH24567A/en unknown
- 1984-06-08 AU AU29240/84A patent/AU563642B2/en not_active Ceased
-
1987
- 1987-05-30 SG SG48187A patent/SG48187G/en unknown
- 1987-07-06 MY MYPI87000951A patent/MY100795A/en unknown
- 1987-07-23 US US07/076,697 patent/US4863724A/en not_active Expired - Lifetime
- 1987-10-07 HK HK723/87A patent/HK72387A/en not_active IP Right Cessation
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