KR20000076107A - Dosage forms comprising separate portions of R- and S-Enantiomers - Google Patents

Abstract

The present invention consists of a substantially single (+)-enantiomer of a chiral agent other than verapamil in one part and a substantially single (-)-enantiomer of the agent in another part thereof, wherein, in use, the other Thiomers are directed to pharmaceutical formulations which are released at different rates from the formulation. Such formulations are useful for the administration of chiral agents in which both enantiomers have an effective pharmacological dosage and clinical benefit can be realized by controlling the release rate of these enantiomers. Examples of such agents are especially tramadol and warfarin.

Description

Dosage forms comprising separate portions of R- and S-Enantiomers

Isolation of some chiral agents Enantiomers have other therapeutic properties and / or mechanisms of action, and in some cases it may still be desirable to administer all of the enantiomers together. However, if the pharmacological rate characteristics of the separated enantiomers are different (eg, due to different rates of metabolism), the proportion of other enantiomers changes over time after the initial administration, which is Reduce the efficacy of the agent. The actual ratio of enantiomers may depend on many factors at any time and will be more complicated if different formulations provide different enantiomer ratios. This effect has been observed with other verapamil enantiomers (Longstreth, JA Clin. Pharmacol. (1993) 18 (2nd Edition): 315-336 and Gupta et al., Eur. J. Pharm. Biopharm. (1996) 42 (1): 74-81).

The present invention relates to novel pharmaceutical formulations of chiral drugs.

1 is a graph showing drug release from immediate-release tablets.

2 is a graph showing drug release from controlled release tablets.

3 is a graph showing percent drug release from controlled release tablets.

4 is a graph showing the dissolution profile of a two-layered tablet.

According to the invention, the pharmaceutical formulation consists of a substantially single (+)-enantiomer of a chiral agent other than verapamil in one part and a substantially single (-)-enantiomer of the agent in another separate part, Here, in use, different enantiomers are released from the formulation at different rates.

When different enantiomers of chiral agents are absorbed, metabolized, dispensed or secreted at different rates by the body, their rate of release from the formulation is determined by their initial ratio (50:50 or non-racemic ratio). It may be adjusted to remain ideal throughout. By regulating the administration of other enantiomers in this manner, it optimizes the provision of the desired enantiomer to the target organ, thereby increasing the clinical efficacy of the drug throughout the administration period.

The invention may also be advantageous for administering chiral agents in which individual enantiomers have different efficacy, different mode of action, different selectivity, for example, different selectivity for receptors or enzymes, or different toxicity.

The present invention may also be beneficial for administering chiral agents which have side effects associated with chiral agents, but where the side effects remain only in one of the two enantiomers of the chiral agent. In this case, depending on the nature of the side effects, it may be desirable to have different release rates for the enantiomers that cause the side effects.

Examples of chiral agents, in which all enantiomers have an effective pharmacological input, and whose clinical advantages can be implemented by controlling the release rate of these enantiomers are warfarin, tramadol, Mianserin, carvedilol, citalopram, citalopram, dobutamine, aminoglutethimide, alfuzosin, celiprolol, cisapride ), Disopyramide, fenoldopam, flecainide, hydroxychloroquine, ifosfamide, labetolol, mexiletine, propapepe Including propafenone, tegafur, terazosin, thioctic acid, thiopental and zacopride, in particular warfarin and tramadol, Most preferred is tramadol The.

The present invention includes formulations in which two enantiomers of a chiral agent are physically separated or separated to achieve different release rates of different enantiomers. Such separation or separation may be on a large scale, such that other enantiomers may be incorporated into separate formulations, for example as kits, for simultaneous or sequential administration, or the separation of other enantiomers may be small. For example, other enantiomers may be present in the same formulation and, despite their physical segregation, may be intimately mixed or in some cases both.

In the context of the present specification, substantially single enantiomer means that one enantiomer is at least 70% by weight relative to the other enantiomer, preferably at least 80% by weight, more preferably 90% by weight or It means more than that. In addition, the non-racemic ratio of enantiomers means that two enantiomers are present and (-)-enantiomers are present in excess of (+)-enantiomers, or vice versa.

Multiple release profiles for other enantiomers of chiral agents can be implemented with the formulations of the present invention. For example, the formulation can be designed such that one enantiomer is released immediately and the release of another enantiomer is delayed or controlled. In this case, immediate release means that the release of each enantiomer occurs substantially immediately or after only a short time delay, generally not more than 5-10 minutes after administration of the formulation, over a period of up to 1-2 hours It means to go on. Delayed or controlled release means that the release of each enantiomer is generally delayed for at least 1 hour and often longer, for example, 2 hours or more after administration of the formulation. Delayed or controlled release can be constant or varied throughout the treatment period.

The formulations of the present invention may be designed such that one of the enantiomers is released before or before the other, depending on the condition or type of patient being treated. It is preferred that the separated enantiomer is maintained at a constant rate in the target tissue for a specific time period, for example at least 8 hours per day, preferably at least 12 hours per day, more preferably 24 hours per day. The ratio maintained can be 50:50 or it can be a non-racemic ratio in which the amount of (+)-enantiomer is greater than the amount of (-)-enantiomer or vice versa.

Another option is that the ratio of the two enantiomers may change throughout the treatment period, or for at least some time of that period. For example, the release rate of either or both enantiomers can be adjusted such that the relative proportion of (+)-enantiomers or the relative proportion of (-)-enantiomers will increase or decrease over time. Can be. The latter can be accomplished, for example, by using a number of different release coatings for each enantiomer.

As above, the present invention can be particularly applied to the administration of tramadol and warfarin. Tramadol is formulated as a racemate for use as a high potency analgesic with opioid-like properties. The analgesic efficacy and stability of racemates and individual enantiomers was investigated in a randomized double-blind study using patient-controlled analgesia intravenously in gynecological patients (Grond, S, et al. Pain (1995) 62 (3): 313-320). Although (+)-tramadol appears to have more pain in the patient, this causes more nausea and nausea. Because racemates have more efficacy than (-)-tramadol and have fewer side effects than (+)-tramadol, the authors concluded that racemates are more clinically useful. In another study, it was found that there is complementarity and synergistic antinociceptive interactions between the individual enantiomers of tramadol (Raffa, RB et al. J. Pharmacol. Exp. Ther. (1993) 267 (1): 331-340). Enantiomers have different efficacy in opioid receptors and in inhibiting serotonin reuptake and noradrenaline reuptake. Thus, it has been found that both enantiomers of tramadol contribute to analgesic effects. Thus, all of the tramadol enantiomers have been shown to contribute to analgesic effects. Thus, controlled administration of individual enantiomers at different rates, facilitated by the formulations embodied by the present invention, can result in more useful analgesics without additional side effects.

Preferred formulations for the administration of tramadol are those in which the (-)-tramadol is immediately-released and the (+)-tramadol is in the delayed- or controlled-release form. In this case, the release rate of (+)-enantiomer can be adjusted in such a way as to reduce the adverse side effects of nausea and / or dizziness believed to be associated with this enantiomer.

In the case of the anticoagulant drug warfarin formulated as a clinical racemate, (S)-(-)-and (R)-(+)-enantiomers exhibit the desired hypoprothrombinemic activity, (S) -Warfarin has been shown to be more potent (see Hyneck, M. et al, Chirality in Drug Design and Synthesis (1990), p. 17-18, ed. C. Brown, Academic Press, London). However, the use of warfarin as this form, for example racemate, is weakened by a delay of several days before the onset of the desired anticoagulant effect. Thus, once treatment is initiated, careful monitoring is needed to balance the under-dose and over-dose. Overdose can cause bleeding and can sometimes be fatal. This effect can be attributed to the individual enantiomers of warfarin with different affinity for albumin binding, which in turn are metabolized by other pathways that can affect the relative clearance rate. Thus, administration of separate formulations of individual enantiomers, or simple formulations with separate individual enantiomers, can achieve a more controllable therapeutic regimen.

Many different types of formulations can be drawn for administration by various routes, such as oral, rectal, transdermal, nasal, eye, lung, injection (subcutaneous or intravenous).

Applicant's co-pending application WO 97/33570 describes formulations in which the individual enantiomers of verapamil are released at different rates, some of which may be used with any of the above agents.

For example, one type of formulation consists of a capsule comprising two sets of multi-particulates with different release rates, one set comprising (+)-enantiomers, and the other set (-) Contains enantiomers. Multi-particulates can be made by any of the conventional methods themselves, including extrusion spheronisation, high shear granulation, non-pareil seeds and the like. The rate at which other enantiomers are released from the multi-particulates can be achieved using any conventional controlled-release mechanism such as matrix (eg, corrosion diffusion), coating or osmosis. This type of formulation is suitable for oral or rectal use.

Another type of formulation consists of two tablets, a combined product (kit), one tablet containing (+)-enantiomers, the other tablet containing (-)-enantiomers, two Tablets have different release rates. Again, conventional controlled-release techniques can be used to achieve the desired effect. For example, two tablets with different release coatings or metrics can be used, or two osmotic pump tablets with different pumping rates can be used. The tablets may then be administered sequentially, or they may be filled into capsules for simultaneous administration.

Another type of formulation consists of an osmotic pump tablet having two separate parts, typically two layers, one part comprising (+)-enantiomer, pumping at one speed, and the other part (- ) -Enantiomers are included and pumped at different rates.

Another type of formulation consists of two-layered tablets, one layer comprising (+)-enantiomers, the other layer containing (-)-enantiomers, and the two layers of their respective Have different release rates for enantiomers. Again, conventional controlled-release techniques can be used to achieve the desired effect.

One example of a two-layered tablet has (-)-tramadol in the outer layer as an initial therapeutic agent and induces release of (+)-tramadol from the center providing continuous therapy. Another example of a two-layer tablet may have (S) -warfarin in the outer layer as the initial therapeutic agent and (R) -tramadol in the center for sustained treatment. Different percentages of the individual enantiomers can be used in other tablet formulations so that the dosage can be titrated against the individual enantiomers.

Another type of formulation is a shell comprising a core comprising one of (+)-and (-)-enantiomers and the other of (+)-and (-)-enantiomers surrounding the core. Consisting of compressed coated tablets with the core and the shell having different release rates for their respective enantiomers.

Another type of formulation consists of a patch that attaches near the patient's skin, the patch consisting of two separate portions, one portion comprising (+)-enantiomers and the other portion (-) -Enantiomers, the two parts having different release rates for their respective enantiomers. Alternatively, two separate patches can be used, for example, as a combined product (kit), one patch containing (+)-enantiomer, the other patch containing (-)-enantiomer, The two patches have different release rates.

Another type of formulation consists of a polymer implant consisting of two separate parts, one part containing (+)-enantiomers, the other part containing (-)-enantiomers, The two parts have different release rates for their respective enantiomers. Alternatively, two separate polymer implants can be used, for example, as a combined product (kit), one implant comprising a (+)-enantiomer and the other implant a (-)-enantiomer The two implants have different release rates.

Another type of formulation consists of an aerosol comprising two sets of particulates with different release rates, one set comprising (+)-enantiomers, and the other set containing (-)-enantiomers. Include. Alternatively, two separate aerosol agents can be used, one for each enantiomer, for example as a combined product (kit), with each aerosol particulate having a different release rate.

Other types of formulations can be administered by injection. With this type of formulation, different release rates of different enantiomers can be achieved, for example, by liposomes or small particles.

In the present invention, it is important that two enantiomers are effectively separated and administered, and that they are provided in a form that does not harm a prospective patient. If they are provided in salt form, it is preferred that the salts are all stable and nonhygroscopic.

The formulations of the present invention can be used for the treatment of symptoms to which chiral agents are generally administered, especially to patients exposed to harmful side effects or to patients who may be at risk from exposure to harmful side effects.

The invention is illustrated by the following examples.

In the following, tablets use a Universal Testing Instrument (Instron floor model, Instron Limited, High Wycombe, United Kingdom) and at a compression rate of 1 mm / min, a flat-faced punch with a compression pressure of 200 MPa and 8 mm Formulated using

The disintegration characteristics of the tablets were evaluated by disintegration tester (Erweka GmbH, Heusenstamm Germany) according to BP with water at 37 ° C. ± 0.2K. The dissolution profile of the tablets was evaluated using the USP XXIII paddle method (Pharmatest, Hamburg, Germany) and 1000 ml of distilled water and a paddle speed of 100 rpm at 37 ° C. ± 0.5K. The dissolved amount of the drug was measured by online UV (Phillips PU 8620, Hamburg, Germany) at a wavelength of 220 nm, regardless of whether it was (+)-or (-)-tramadol hydrochloride.

In the accompanying drawings, reference numeral ■ denotes (+)-tramadol hydrochloride, and ▩ denotes (-)-tramadol hydrochloride.

Example 1

Immediate-release tablets were obtained from a powder mixture of 50.0 mg of (+)-or (-)-tramadol hydrochloride, 46.5 mg of microcrystalline cellulose, 3.0 mg of croscarmellose sodium and 0.5 mg of magnesium stearate, using a tableting pressure of 200 MPa. Formulated.

Drug release from immediate-release tablets is shown in FIG. 1. Here, the Y-axis represents the concentration of the individual enantiomers in the dissolution medium. The dissolution patterns observed ensure the rapid pharmaceutical utility of the medicament.

Example 2

Release controlled tablets were prepared from a powder mixture of 50.0 mg of (+)-or (-)-tramadol hydrochloride, 119.15 mg of hydroxypropyl methyl cellulose (HPMC) and 0.5 mg of magnesium stearate, using tableting pressure 200 MPa. Disintegration was monitored after 7 hours.

Drug release of controlled release tablets is shown as the dissolution profile in FIG. 2, where the Y-axis represents the concentration of the individual enantiomers in the dissolution medium and is shown as a percentage of drug release in FIG. 3. 12 hour release control was achieved with this formulation. After 6 hours, (-)-enantiomers are released slightly faster than (+)-enantiomers, achieving nearly 100% drug release at 12 hours, whereas only 86% of (+)-enantiomers are 12 hours It was released later. At 6 hours or less, the drug release profiles of the two enantiomers were very similar.

Example 3

Two-layer tablets were prepared by prepressing the powder mixture of Example 2 to form a release control layer at a compression pressure of 20 MPa. Then, the powder mixture of Example 1 containing the opposite enantiomer of tramadol hydrochloride for that used in the release control layer was filled on top of the release control layer and the whole tablet was compressed using tableting pressure 200 MPa.

Dissolution profiles of the individual layers of the two-layered tablets were obtained by chiral HPLC analysis of tramadol free base using Chiralpak AD Column (eluent: 90% heptane, 9.99% isopropanol, 0.01% diethylamine), where (+)- Tramadol had a residence time of 4.5 minutes and (-)-tramadol had a residence time of 5.6 minutes, which is shown in FIG. 4. Here, the Y-axis represents the concentration of the individual enantiomers in the dissolution medium.

Short release profiles from the release control layer can be achieved simply by changing the amount of excipient used, in this case lowering the amount of HPMC. In addition, when increased dosages are required, the tablet diameter may be increased.

Claims (35)

Consisting essentially of a single (+)-enantiomer of a chiral agent other than verapamil in one part and a (-)-enantiomer of the agent in another part thereof, where, in use, the other enantiomer has a different rate from the formulation. Pharmaceutical formulation. The pharmaceutical formulation of claim 1, wherein the chiral agent is a drug whose other enantiomers are absorbed, metabolized, dispensed or secreted by the body at different rates. The pharmaceutical formulation according to claim 1 or 2, wherein the chiral agent is any agent whose other enantiomers have different efficacy or different mode of action. The pharmaceutical formulation according to claim 1 or 2, wherein the chiral agent is a drug having adverse side effects on one of its two enantiomers. The pharmaceutical formulation according to any one of claims 1 to 4, wherein the release rate of the other enantiomers is selected to obtain a substantially constant proportion of these enantiomers in the target tissue for at least 8 hours per day. . 6. The pharmaceutical formulation of claim 5, wherein the ratio of enantiomers in the target tissue is about 50:50. 6. The pharmaceutical formulation of claim 5, wherein the proportion of enantiomers in the target tissue is a non-racemic proportion in which excess (+)-enantiomer is present relative to (-)-enantiomer. 6. The pharmaceutical formulation of claim 5, wherein the proportion of enantiomers in the target tissue is a non-racemic proportion in which excess (-)-enantiomer is present relative to (+)-enantiomer. The pharmaceutical formulation of claim 1, wherein the release rate of at least one of the enantiomers changes over time. The pharmaceutical formulation of claim 9, wherein the release rate of the (+)-enantiomer increases or decreases over time. 13. The pharmaceutical formulation of claim 12, wherein the release rate of the (-)-enantiomer increases or decreases over time. The pharmaceutical formulation of claim 1, wherein the (+)-enantiomer is released faster than the (-)-enantiomer. The pharmaceutical formulation of claim 1, wherein the (-)-enantiomer is released faster than the (+)-enantiomer. The method according to any one of claims 1 to 13, comprising a plurality of first particles containing (+)-enantiomers and a plurality of second particles containing (-)-enantiomers. Pharmaceutical formulation wherein the first and second particles consist of capsules having different release rates for their respective enantiomers. The method according to any one of claims 1 to 13, comprising a first tablet containing (+)-enantiomer and a second tablet containing (-)-enantiomer, wherein the first and second 2 tablets having different release rates for their respective enantiomers. The pharmaceutical formulation of claim 15, wherein the first and second tablets are encapsulated. 14. An osmotic pump tablet according to any one of claims 1 to 13, comprising a first portion containing (+)-enantiomer and a second portion containing (-)-enantiomer, Wherein the first and second portions have different pumping rates for their respective enantiomers. 14. A tablet according to any one of claims 1 to 13, consisting of two-layered tablets with one layer containing (+)-enantiomers and the other layer containing (-)-enantiomers, Wherein said two layers have different release rates for their respective enantiomers. 14. The core according to any one of claims 1 to 13, comprising a central portion containing one of (+)-and (-)-enantiomers and surrounding (+)-and (-)-enantiomers Pharmaceutical formulation consisting of a compression coated tablet having a shell containing the other one of the. 14. The composition of any one of claims 1 to 13, wherein the patch consists of a patch that adheres closely to the patient's skin, wherein the patch comprises a first portion containing (+)-enantiomer and (-)-enantio And a second portion containing a mer, wherein said first and second regions have different release rates for their respective enantiomers. The method according to any one of claims 1 to 13, wherein each butt in proximity to the patient's skin consists of two patches, one patch containing (+)-enantiomer and the other patch (-) The pharmaceutical formulation containing enantiomers, the two patches having different release rates. 14. A polymer implant according to any one of claims 1 to 13, consisting of a polymer implant having a first portion containing (+)-enantiomer and a second portion containing (-)-enantiomer, wherein , Wherein the first and second portions have different release rates for their respective enantiomers. The method of claim 1, wherein one implant contains two polymer implants containing (+)-enantiomers and the other implant contains (-)-enantiomers, Wherein the two implants have different release rates. 14. Aerosols according to any of claims 1 to 13, comprising aerosols containing two sets of small particles with different release rates, one set containing (+)-enantiomers, and the other set ( -)-Pharmaceutical formulation containing enantiomers. The method according to any one of claims 1 to 13, wherein one comprises small particles containing (+)-enantiomers, and the other comprises small particles containing (-)-enantiomers. A pharmaceutical formulation consisting of two aerosols, wherein the small particles in the two aerosols have different release rates for their respective enantiomers. The pharmaceutical formulation according to any one of claims 1 to 25, wherein the chiral agent is selected from warfarin, tramadol, myanserine, carvedilol, citalopram, dobutamine and aminoglutetimide. The pharmaceutical formulation of claim 26, wherein the chiral agent is warfarin. The pharmaceutical formulation of claim 26, wherein the chiral agent is tramadol. The pharmaceutical formulation of claim 28, wherein the (-)-tramadol is in immediate release form and the (+)-enantiomer is in sustained release form. The pharmaceutical formulation according to claim 28 or 29, wherein the outer layer consists of (-)-tramadol and the central part is a two-layer tablet consisting of (+)-tramadol. 26. The method according to any one of claims 1 to 25, wherein the chiral agent is alfzosin, celiprolol, cisapride, disopyramid, phenodofam, plecainide, hydroxychloroquine, ifosfamide, lavetolol, Pharmaceutical formulations selected from mexyltine, propofenone, tegapur, terrazosin, thioctynic acid, thiopental and jacobopride. The pharmaceutical formulation according to any one of claims 1 to 25, wherein the chiral agent is a drug with different enantiomers having different selectivity. The pharmaceutical formulation according to any one of claims 1 to 25, wherein the chiral agent is a drug with which other enantiomers have different toxicity. 34. A pharmaceutical formulation according to any one of claims 1 to 27 and 31 to 33 wherein one enantiomer is in immediate release form and the other enantiomer is in sustained release form. 35. A therapeutic agent for a symptom in a patient exposed to or at risk of being exposed to harmful side effects by administering a substantially single enantiomer of a chiral agent in racemic form to the preparation of a formulation according to any one of claims 1 to 34.