CN1820783A - Thyroid hormone medicinal preparation - Google Patents

Abstract

The present invention provides the medicine recipe based on thyroid hormone, and the medicine may be used to treat thyroid gland dysfunction through safe and stable oral taking within strict therapeutic index frame.

Description

Thyroid hormone medicinal preparation

Invention field

The present invention relates to the thyroxin pharmaceutical composition.

Prior art

T3 is to be used for the thyroxin that different treatments are used with T4.T3 (trilute ≡ O-(4-hydroxyl-3-iodophenyl)-3,5-two iodo-L-tyrosine) and T4 (levothyroxine ≡ O-(4-hydroxyl-3,5-diiodo-phenyl)-3,5-two iodo-L-tyrosine), itself or sodium salt or hydrate forms, be extensively known, they can pass through synthetic and/or (for example: pig etc.) extraction obtains from the animal body of gland.

Especially, these thyroxins have two kinds of critical functions: they are relevant with growth, particularly central nervous system's growth is relevant, and for the adult, they are by keeping metabolic homoiostasis and working by the function that influences all organs in fact.Thyroxin concentration in the serum obtains strict adjusting by the hormone thyrotropin that flows through typical degeneration factor.In any case by administration T3 and T4 (or their sodium salt), the treatment that lacks for these hormones can obtain good result, many patients obtain curing by taking these hormones.

Especially, T3 and T4 are main is to be used for the treatment of hypothyroidism.Hypothyroidism is a kind of very common disease.In the U.S., be the hypothyroidism patient with regard to a baby among every 4000-5000, hyperthyroidism then can be attacked the adult of 0.5-1.3%.In greater than sexagenarian crowd, hypothyroid sickness rate, the man is up to 2.7%, and the woman is up to 7.1%.Because congenital hypothyroidism can cause irreversible mental retardation, though it can obtain prevention by diagnosis and the treatment in its initial period,, the generaI investigation of baby's this disease in the North America, Europe and Japan then is enforceable.

Except the treatment hypothyroidism, for example, T4 (sodium salt of levothyroxine) is used in the secretion that suppresses thyrotropin in treatment non-endemicity simple goiter, chronic lymphocytic thyroiditis and the thyroid carcinoma.The sodium salt of levothyroxine also can use with antithyroid drug, is used for the treatment of thyrotoxicosis, with prevention goiter and hypothyroid generation.

Thyroxin supply therapy, usually be accompanied by patient's whole all one's life.And dosage should be determined separately at each patient.Initial consumption generally is very little.Afterwards, this quantity just improves gradually, no longer shows best response up to clinical assessment and laboratory inspection in the organ of treatment.Obtain this and respond necessary consumption, thereby be held.The order of severity and the persistent period of patient's age and his/her comprehensive physical state and hypothyroid symptom, determine this initial dosage and the described dose of speed that can reach its terminal level.In order to prevent angina pectoris, myocardial infarction or to beat, can only very little by little improve consumption for the patient who suffers from myxedema and cardiovascular disease, be particular importance.

Owing to these reasons, T3 and T4, their sodium salt and their combination (Liotrix) are normally with the oral way medication, especially adopt the tablet mode, the picked-up frequency by controlling them and by selecting dosage unit for use, it can make supplies the individual state that is suitable for patient.

In fact, thereby, underdosage also causes hypothyroidism, so accurate dose is extremely critical owing to will causing the response of suboptimum.On the other hand, contingent overdose will cause hyperthyroid poisoning symptom, as pained, cardiopalmus or arrhythmia.For the patient who suffers from coronary disease, the consumption of levothyroxine is even a very little increment all is a danger close.

More accurately, hyperthyroidism is a known risk factor for osteoporosis.In fact, some studies show that women's subclinical hyperthyroidism before the menstrual period that the sodium salt that adopts levothyroxine is treated runs off relevant with osseous tissue.For osteoporosis danger is minimized, this consumption of titration is desirable up to the consumption that reaches minimum effect as much as possible.Especially, referring to Paul, " the united states drug association magazine " 259:3137-3141 of " the hipbone density of women's reduction is relevant before long-term Levothyroxinnatrium treatment and the menopause " such as T., 1988 and Kung, " united states drug association magazine " 265:2688-2691 that A.W etc. " accept the preceding women's of menopause of levothyroxine physiology dosage bmd " for a long time, 1991.

So, because the sodium salt that is present in levothyroxine is not only in the danger relevant with overdose or underdosage, also be present in common thyroxin, so patient can rely on drug products (they are dependable) with regard to titer and bioavailability, be definitely critical.Reach and keep these strict especially standards especially, thereby become maximum difficulty.

For example, between 1987 and 1994, the irregular experience of the potential (titer) of 58 parts of relevant levothyroxine sodium products based on oral medication is received by the food and drug administration of the U.S. (FDA).47 parts in the described report show, bulletin declares that pharmaceutical preparation has lower titer, and 9 parts show that this titer is higher.There is contradiction in 2 parts of blood levels for thyroxin in these reports.4 parts in these reports cause hospitalization, and wherein 2 parts is owing to the titration deficiency, and 2 parts is owing to overtitration in addition.The most numbers of whole 58 parts of reports are to be supported by the blood test of thyroid function.In hypothyroid specific symptoms, report has a following symptom: seriously dejected, and fatigue, weight increase, constipation, cold resistant not, edema is difficult to focus one's attention on.Hyperthyroid specific symptoms comprises atrial fibrillation, cardiopalmus and insomnia.

Although some problems in these problems are to cause when changing the kind of drug products, but, having in them severally only bought the product of other quantity patient (it before taken for a long time, and having a good curative effect) time will take place, thereby show between the different batches of identical producer with regard to stability, titer and bioavailability to have very low concordance.

Although knew already, for instance, from " total drug reference " " medicine news (Pharmaceutical Press) " 1498 pages in 1999, can know, it may be irregular that thyroxine in the intestines and stomach zone absorbs, itself can cause very big difficulty when preparation has the dosage unit of predictable and reproducible release, it shows and takes particularly some problems in relevant these problems of T3 and/or T4 (or their sodium salt) of thyroxin, not only with the medicament forms of medication and patient's metabolism between interaction relevant, and, relevant with interaction between the adjuvant that contains in active component and the given dose unit mainly.

In fact, verified, for example, levothyroxine sodium is highstrung for the influence that exists owing to excipient, though these excipient are in fact through selecting in advance and having carried out purposive widely test at their inertia.So, the suitable preparation of levothyroxine sodium, normally a problem.

For instance, as Hennessy, " internal medicine annual (Annals of Internal the Medicine) " 102:770-773 of " two L thyroxine preparations of equal value " such as J.V.K., 1985 are discussed, a producer is arranged by removing two kinds of non-active ingredients simply and changing the coloring agent physical form in nineteen eighty-two, prepared its product again based on levothyroxine.Find that in a research product of preparing again like this shows titer and improves a lot, only because this new product contains 100% bulletin content, and previous product only reaches 78% (Stoffer, S.S. with " potential of levothyroxine product " " united states drug association magazine " 251:635-636 of W.E.Szpunar, 1984).On the other hand, find in another research that the levothyroxine content of old-fashioned preparation reaches about 70% (Fish, " alternative dosage, metabolism and biological activity of levothyroxine in the hypothyroidism treatment such as L.H. of bulletin numerical value; The effect of trilute in people's hypophysis feedback " " Britain's new drug magazine (The New EnglandJournal of Medicine) " 316:764-770,1987).Obviously, with regard to contingent clinical problem, this raising of titer exists serious risk.

In order to obtain stable formulation, people further attempt improving the preparation that contains the levothyroxine drug products.A research (Das Gupta who carried out from 1991, " pharmacy,clin and therapeutics magazine (Journal of Clinical Pharmacy and the Therapeutics) " 15:331-336 of " excipient is to the influence of the stability of levothyroxine sodium tablet " such as V., 1990) can clearly be seen that, the levothyroxine sodium tablet that still is selected from different production batch of same producer, on their chromatogram, exist variation, show and in pharmaceutical tablet, used different excipient.

What should be mentioned in that is, in nineteen eighty-two, American Pharmacopeia conference (United StatesPharmacopeial Convention) has proposed the standard that HPLC analyzes, the stability of quality control that contains the drug products of thyroxin in order to expression, particularly T3 and T4 (Garnick, R.I. wait " stability that is used for the high pressure lipuid chromatography (HPLC) of thyronine sodium and Syroxine Tablets quality control " in " hormone medicine ", J.L.Gueriguian, E.D.Bransome and A.S.Outschoorn editors, the American Pharmacopeia conference, the 504-516 page or leaf, Rockville, 1982), the delivered product of multiple industry, the objection that often causes owing to Food and Drug Administration is called back unexpectedly.

The stability problem that all these are extensively write down and argue repeatedly by Food and Drug Administration, it shows, in view of high susceptibility for accelerated degradation (degraded of active component it feels like experience), in numerous these packings of product announce popular 2 years and shelf-life, be exactly inappropriate at all.For example, levothyroxine is unsettled (Won in the presence of light, high temperature, air and dampness, C.M. " levothyroxine liquid solution and solid-state under degradation kinetics " " drug research (Pharmaceutical Research) ", 9:131-137,1992).And, in another research, some excipient that discovery is used with levothyroxine sodium, serve as catalyst again and quickened its degraded (Das Gupta, " pharmacy,clin and the therapeutics magazine " 15:331-336 of " excipient is to the influence of Syroxine Tablets stability " such as V., 1990).In addition, the kinetics of levothyroxine sodium degraded is complicated.Show for Study on Stability, levothyroxine sodium has two sections degradeds of one-level profile, has high degradation rate at first, be lower degradation rate (Won afterwards, C.M. " levothyroxine liquid solution and solid-state under degradation kinetics " " drug research ", 9:131-137,1992).Initial degradation rate depends on temperature.In order to compensate initial degraded, some producers use excessive active component in their preparation, thereby cause the case of accidental overtitration therein.

At last, without doubt, thyroxin is T3, T4 and their combination particularly, do not have can accept to substitute in the case of medicine existence many, and be a kind of essential therapy.However, because the strict therapeutic index that thyroxin dosage bears, so, can utilize the quantity of effective agent absolute reliable for given pharmaceutical dosage unit, be particular importance.Even the reality of effective ingredient can be utilized the very little variation of quantity, all can influence its safety and effect.Accept the patient of overtitration dosage unit, exist angina pectoris, tachycardia or ARR danger.In contrast, the not enough dosage unit of titration is invalid for overcoming hypothyroidism shape or side effect then.

Knew already that levothyroxine sodium was in environmental factors and be unsettled in the presence of some common drug tax table agent at least.However, as explained above, obtainable popular prescription on the market, really seem not address these problems, this is because based on the current production of levothyroxine and oral medication, before their expiry date shown on its packing, has experienced the titer variation, perhaps, be because their can owing between the different batches and and then Different Package between change.Because the time that treatment can last for several years usually is so described deviation means titanic peril with regard to safety and effect.

Therefore, as if at least since nineteen eighty-two, people just know exist for thyroxin particularly the more desirable oral medication of T3 or T4 and their combination supply with the demand of pharmaceutical formulation (they are more reliable with regard to titer and bioavailability).Especially, for a long time since, just exist for thyroxin particularly the more desirable oral medication of T3 or T4 and their combination supply with the demand of pharmaceutical formulation (they are stable on time, and for example, they have at least two years effectively shelf-lifeing).And, exist for thyroxin particularly the medication of T3 or T4 and their combination supply with pharmaceutical formulation (they can obtain splendid uniform dose, not only do not need to consider producer batch, and also be preferably in pharmaceutical dosage unit self) demand.

So, the present invention seeks to satisfy these and other demand, it will become more cheer and bright in following detailed description.

Summary of the invention

In framework of the present invention, have been found that the shortcoming of prior art can be by being overcome with preferred soft capsule of capsule or the pharmaceutical composition supplied with based on thyroxin with (being tablet type or capsule-type) the even soft gel-type vehicle form of can swallowing.

Detailed description of the Invention

Especially, have been found that, contain being the preferred soft capsule of capsule or being the pharmaceutical composition that to swallow (being tablet type or capsule-type) even soft gel-type vehicle form of preferred T3 of thyroxin and/or T4,, can allow to obtain a plurality of benefits with respect to normal medication with known pharmaceutical forms.

Although, studied for a long time by different authors already with the degraded of the thyroxin of conventional solid form administration, especially, can referring to Richheimer, S.L.﹠amp; Amer, " pharmaceutical science magazine (the Journal of Pharmaceutical Sciences) " 72 (11) of T.M. " the stable phenetic analysis of levothyroxine sodium tablet, dissolving and content uniformity ", 1349-1351; Brower, J.F.Tolier, D.Y.﹠amp; Reepmayer J.C. " measures large quantities of levothyroxine sodium tablets and ejection preparation by the high speed liquid chromatography method " " pharmaceutical science magazine " 73 (9), 1315-1317; Chong Min Wong, " levothyroxine liquid solution and solid-state under degradation kinetics " " drug research " Vol.9, No.1,1992, " pharmacy,clin and therapeutics magazine " 15:331-336 of 131-137 and Das Gupta etc. " excipient is to the influence of Syroxine Tablets stability ", 1990, as previously mentioned, up to now, solid composite medicament and its preparation method that represent to overcome foregoing problems are impossible one because exist numerous possible influence factors.For example, although propose, according to deamination (Won, referring to above), the decomposition of some drugs excipient catalysis effective ingredient (Das Gupta etc., referring to above), but we also know, another kind of decomposition path-ways be with specified criteria under the deiodination of first reacting phase competition.In the practice, because the thyroxin multiple sensitivity of T3 or T4 and their combination particularly, the solid form of prior art administration (they are made up of tablet), neither one are gratifying especially.

Carry out in the research work in the present invention, have been found that, known some excipient, light, humidity, temperature, contact with oxygen, degradation factors that negative effect such as pH is confirmed and described as prior art, by the manufacture method (it has cancelled the compacting of the pharmaceutical formulation that typically characterizes the tablet manufacturing) that adopts a kind of form of medication, just can be reduced significantly, even be eliminated.Foregoing theoretical explanation; be provided among the present patent application; be intended to without any binding character; only be for purpose of explanation; and do not limit by the applicant the protection domain of requirement of the present invention (it is only limited by subsequently claims); industry has report; as if the result who is obtained by the applicant show; very possibly; by the thyroxin Degradation of T3 and/or T4 experience particularly; at the stress that causes owing to the stage that compresses that is the semi-finished product product of acquisition finished product tablet; can cause being converted into a kind of intermediate products to the initial thyroxin of small part; it is in case form, and will self-catalysis conventional solid medicament forms is the decomposition in turn of the residual activity composition that contains in the tablet.

In fact, have been found that the medicament forms that is used for oral administration that obtains according to the present invention, the multiple degraded influence for description of the Prior Art and discussion all has significantly lower sensitivity.Especially, the invention provides be the preferred soft capsule of capsule or be (being tablet type or capsule-type) the even soft gel-type vehicle form of can swallowing based on the thyroxin pharmaceutical composition of T3 and/or T4 particularly, they are not except containing the trace contaminant that may self-catalysis further decomposes, can also determine the higher and more direct bioavailability of active component in other advantage such as stomach and/or the intestinal environment, this is because described active component had been the dissolution form already, in any case perhaps it does not compress.

On the other hand; the tradition tablet; except the low titer stability shortcoming of describing in the scientific and technical literature as mentioned above; they also can cause other problem; this be since when they when the liquid with the gastrointestinal inner chamber contacts, they dissolve very slowly, and; rate of dissolution also is subjected to the very big influence of tablet property except that the pH condition that is subjected to inner chamber with whether with the influence of food administration.

(they can be coated with the enteric solubility layer swallowing even soft gel-type vehicle or the medicament forms in the preferred soft capsule of capsule, promptly it is decomposable in the gastrointestinal conduit region of wanting according to pH value), if it is formed by containing a shell, this shell contains thyroxin particularly T3 and/or T4, (for example be solid form with possible inert matter, for so-called " hard gelatin capsule " o DFC, " the dried capsule that fills ", as " Lei Mingdun pharmaceutical science " nineteen ninety the 18th edition, Alfonso R.Gennaro chief editor, Mack publishing company, Easton Pennsylvania18042, ISBN 0-912734-04-3 is described, perhaps, for SEC " SEC ", as " Lei Mingdun pharmaceutical science " nineteen ninety the 18th edition, Alfonso R.Gennaro chief editor, Mack publishing company, Easton Pennsylvania 18042, ISBN 0-912734-04-3 is described, the latter is also contained solid for mulation), perhaps at liquid, or in the semiliquid carrier, also has other excipient (being preferred SEC: " SEC ") possibly, perhaps (according to other embodiment) if medicament forms form by swallowing (being tablet type or capsule-type) even soft gel-type vehicle, wherein saidly swallow soft gel-type vehicle and contain thyroxin and possible excipient and/or plasticizer, then no matter be hard or soft, rapid release goes out the inclusions in described shell or the described substrate respectively, thereby and this active component of instant-free, active component is by efflorescence (for hard capsule-DFC-with solid contents or SEC) or dissolved and/or disperse (maybe can swallow even soft gel-type vehicle for soft capsule).

Enteric solubility layer (they are preferred in framework of the present invention) can be applicable to the capsule of form of ownership described herein maybe can swallow even gel-type vehicle, and they are prepared according to known technique, thereby make it (this place is the absorbed main positions of thyroxin) basic decomposition in the small intestinal zone.

Except (or substituting) possible enteric solubility layer, maybe can swallow even soft gel-type vehicle according to capsule of the present invention and also can adopt other skin to provide, they can simplify picked-up, promptly form by reducing the excipient that rubs between capsule and patient's esophagus.

Can be used to obtain the material that capsule of the present invention maybe can be swallowed even soft gel-type vehicle, be the common gelatin (so-called A and Type B) that uses of drug world or methylcellulose, hydroxypropyl emthylcellulose, the known suitable substance of calcium alginate or other medicines field, they also can be used for this purpose.

And, capsule of the present invention maybe can be swallowed the hardness of even soft gel-type vehicle, can control according to the type that capsule maybe can be swallowed even soft gel-type vehicle, they must adopt known drug can accept the capsule plasticizer and obtain, polyhydroxy-alcohol for example, preferably glycerine, 1,2-propylene glycol, Sorbitol/sorbitan solution etc.

Other common optional member that capsule of the present invention maybe can be swallowed even soft gel-type vehicle is water and antiseptic (as antibacterial agent, antifungal etc.), with those skilled in the art by oneself.

Especially; according to first preferred implementation of the present invention; it provides a kind of so-called hard gelatin capsule; by sleeve pipe interconnective " housing " (half capsule) being installed by two forms; and contain the thyroxin that is solid form; preferably contain T3 and/or T4 or its drug acceptable salt, particularly their sodium salt, and be mixed with and be powder, granule or other non-common drug excipient that compresses particulate form.According to various different needs, described granule or microgranule also can be according to known method successively by microencapsulated, to control the release of the thyroxin that they contain.Just can be used for the application's solid excipient, exist drug world diluent, buffer agent, binding agent or disintegrating agent commonly used.For example, the excipient that adds to obtain tablet usually also can use.Some preferred embodiments of described excipient are as follows: Tri-Compress, carboxymethyl starch sodium, microcrystalline Cellulose, a hydration lactic acid, sodium carboxymethyl cellulose, corn starch, magnesium stearate etc.

According to second preferred implementation of the present invention; it provides a kind of soft capsule (" SEC "); it contains the thyroxin that is solid form; preferably contain T3 and/or T4 or its drug acceptable salt; their sodium salt particularly, and be mixed with and be powder, granule or other non-common drug excipient that compresses particulate form.According to various different needs, described granule or microgranule also can be according to known method successively by microencapsulated, to control the release of the thyroxin that they contain.Just can be used for the application's solid excipient, exist drug world diluent, buffer agent, binding agent or disintegrating agent commonly used.For example, the excipient that adds to obtain tablet usually also can use.Some preferred embodiments of described excipient are as follows: Tri-Compress, carboxymethyl starch sodium, microcrystalline Cellulose, a hydration lactic acid, sodium carboxymethyl cellulose, corn starch, magnesium stearate etc.

According to " Lei Mingdun pharmaceutical science " nineteen ninety the 18th edition, edit by Alfonso R.Gennaro, Mack publishing company, Easton Pennsylvania 18042, ISBN0-912734-04-3, the soft capsule that contains solid for mulation of the present invention can adopt what is called " Accogel capsule machine " or " Stern " machine (by the Lederle exploitation) to obtain.Another kind of acquisition machine and the method that contains the solid for mulation soft capsule of the present invention is as the US5 of Scherer Corp., described in 740,660.

According to particularly preferred the 3rd embodiment of the present invention, it also provides a kind of soft capsule (SEC), it is made up of the gelatin mass shell, contains the thyroxin that is present in liquid or the semiliquid carrier, preferably contains T3 and/or T4 or its drug acceptable salt, particularly their sodium salt and possible excipient.Especially, described soft capsule contains a kind of inner phase, is made up of liquid, semiliquid, paste, gel, emulsion or suspension, contains this liquid (or semiliquid) carrier and thyroxin and possible excipient in suspension or solution.

As previously mentioned, the preferable production process of soft capsule, provide active component and possible excipient in this liquid or semiliquid carrier dissolving and suspend to obtain inner phase, it then is injected among the melted gelatin semi-finished product product, to obtain finished capsule product.In any case, the acquisition of describing in the Drugdoc has any known method of liquid or semiliquid inclusions SEC, for example, " plate method ", " rotating mould method " or use " Norton capsule machine " or " Accogel capsule machine ", as " Lei Mingdun pharmaceutical science " nineteen ninety the 18th edition, edit by Alfonso R.Gennaro, Mack publishing company, Esaton Pennsylvania 18042, ISBN0-912734-04-3, all can adopt, to obtain to contain the soft capsule of the present invention of thyroxin in liquid or the semiliquid carrier and possible excipient.

Should be noted that, be dissolved in the case that the thyroxin solution in this liquid in the soft capsule or the semiliquid carrier uses in specific providing, if this preferred implementation of the present invention is obtaining one with another identical dosage unit, especially compare with the very effort method that is used for preparing identical solid mixture, also has other advantage, promptly relative case.In fact, the known machine that is used to produce the SEC with liquid or semiliquid inclusions, the accuracy that little dosage of this inclusions (being the inner phase inclusions) is had satisfy content deviation between capsule and the capsule within 1% or littler.

Can be used in the excipient that liquid-carrier uses, the common drug that has all can be used, disperse or dissolve that can mention can be accepted solid additive, to improve the viscosity or the release profile of thyroxin in this carrier of capsule contents.The excipient that other can be added to carrier in this soft capsule is an antiseptic, as parabens, and preferably methyl parahydroxybenzoate, ethylparaben or propyl p-hydroxybenzoate or their salt.

In these liquid or semiliquid carrier, only as example, that can mention has glycerol, ethanol, Polyethylene Glycol (particularly having the Polyethylene Glycol that molecular weight is 200-800), a glycerol furfuryl alcohol (tetrahydrofurfuryl alcohol polyglycol ether; Sigma T3396), 1, it (is trioleate or the tristearate such as the Tween  80 of monolaurate, monoleate, monopalmitate, monostearate, polyoxyethylene sorbitan that 2-propylene glycol, medicine can be accepted oils or non-ionic surface active agent such as polysorbate (polysorbate20 or 80) or multiple different Tweens , Sigma P1754) or other carrier (or their mixture), they are usually used in drug world and are used for preparing the SEC with liquid or semiliquid inclusions.

A preferred embodiment of this capsule material is that gelatin (comprises A type gelatin, it obtains from Corii Sus domestica, animal bone or fish by acid treatment, with the Type B gelatin, it obtains from animal bone and skin by alkali treatment), and can be used to control the elastic forming agent of this capsule, can be glycerol, 1,2-propylene glycol, Sorbitol/sorbitan solution of 85% etc.Known as drug world, liquid in gelatin mass and the capsule or semiliquid inclusions should be compatible, so, with regard to capsule material, preferably use the plasticizer that also is present in (possibly with various different weight percentage) this liquid or the semiliquid carrier, for example glycerol.In these possible prescriptions of the third embodiment of the present invention, containing the thyroxin that is present in liquid or the semiliquid carrier (it is made up of the mixture of ethanol or glycerol or a kind of ethanol and glycerol) or its drug acceptable salt particularly their sodium salt and the possible SEC capsule that is present in excipient in suspension or the solution, is particularly preferred.

First optimization formula that comprises according to the third embodiment of the present invention, a kind of SEC capsule is provided, it comprises a kind of liquid or semiliquid inner phase, contains particularly their sodium salt of the thyroxin that is present in liquid or the semiliquid carrier (it is made up of the mixture of ethanol or glycerol or a kind of ethanol and glycerol) or its drug acceptable salt.

Second optimization formula that comprises according to the third embodiment of the present invention, a kind of SEC capsule is provided, it comprises the inner phase of being made up of paste or gel, contains particularly their sodium salt of the thyroxin that is present in liquid or the semiliquid carrier (it is made up of the mixture of ethanol or glycerol or a kind of ethanol and glycerol) or its drug acceptable salt.

According to the 4th embodiment of the present invention, it provides a kind of swallows (being tablet type or capsule-type) even soft gel-type vehicle, wherein, described soft gel-type vehicle contains particularly particularly their sodium salts separately and possible excipient and/or plasticizer of T3 and/or T4 or its drug acceptable salt of thyroxin.Therefore, these can swallow the present invention invalid soft gel-type vehicle and be made of mutually single, and, itself do not have the shell that can distinguish over this soft gel-type vehicle bulk phase (except that the layer that the external additive of generally acknowledging such as enteric solubility layer or promotion are swallowed).The manufacture method of even soft gel-type vehicle is suitable for drug technique and/or food technology.

Make a described preferred but not exclusive method of swallowing even soft gel-type vehicle, comprise active component and possible excipient and/or the dissolving/suspension of plasticizer in liquid-carrier (being preferably selected from glycerol or glycerol/alcohol mixture), they are the gelling by adding gelatin (or a kind of carrier of high gelatine content/gelatin pre-composition) then, to obtain a kind of gum material, preferably, make finished product tablet type or capsule-type substrate from it by heat fusing and molding subsequently injection molding for example.Through this described other useful feature of swallowing even soft gel-type vehicle that obtains, be to cause by such fact, promptly according to doctor's suggestion, identical soft gel-type vehicle can be by patient oneself separately (for example dimidiation or be divided into three parts), at least the situation that does not have enteric solubility coating or analog for identical soft gel-type vehicle, except that the standard dose unit that medicine producer provides, can allow other fine setting of dosage every day like this.And, as pointing out before this, be used for obtaining the situation of gel-type vehicle at all employing active ingredient solutions, it is very easy producing complete uniform dose unit.

May participate in preparation at these and can swallow in the optional excipient of even soft gel-type vehicle, can enumerate have " using always " medicine can accept composition as the solid additive of thickening agent (they before this substrate gelling or among be dissolved or dispersed among this liquid-carrier) and/or antiseptic such as p-Hydroxybenzoate be preferably methyl parahydroxybenzoate, ethylparaben or propyl p-hydroxybenzoate or their salt.

Preferred carrier is selected from glycerol, ethanol, Polyethylene Glycol or their mixture, and glycerol and glycerol/alcohol mixture are particularly preferred.Non-limiting example as for gelatin, A or Type B are preferred, and plasticizer (as Sorbitol/sorbitan or glycerol) can add improving the elasticity of this soft gel, in case above-mentioned this carrier mentioned and/or excipient only are not enough to the result that obtains to want.

Especially, for swallowing even soft gel-type vehicle, can provide the material such as the glycerol (as carrier or/or plasticizer) of multiple function, be particularly preferred.

Experimental section

Following table has been listed some examples of the present invention's prescription:

I, hard capsule with solid contents:

Embodiment 1: hard gelatin capsule, contain the granule of being made up of T4, Tri-Compress, carboxymethyl starch sodium, microcrystalline Cellulose and magnesium stearate.

Embodiment 2: hard hydroxypropyl methylcellulose capsules (+optional colorant), contain by T3, Tri-Compress (CaHPO ₄2H ₂O), the granule of carboxymethyl starch sodium, microcrystalline Cellulose and magnesium stearate composition.

Embodiment 3: hard gelatin capsule (+optional colorant), contain the granule of being made up of T4, a hydration lactic acid, sodium carboxymethyl cellulose, microcrystalline Cellulose and magnesium stearate.

Embodiment 4: hard gelatin capsule (+optional colorant), contain the granule of being made up of T3 and T4, corn starch sodium carboxymethyl cellulose, microcrystalline Cellulose and magnesium stearate.

II. the soft capsule (SEC) that has solid contents:

These capsular solid contents are identical with above-mentioned described hard capsule situation.

III. the soft capsule (SEC) that has liquid, semiliquid, paste class or gel-like inner phase:

Following compositions and percentage ratio are soft shell and its inclusions at whole dry capsule:

Embodiment 1	Weight %
		T 3Na	0.001-1％
Glycerol	5-30％
		Ethanol	1-15％
PEG400	20-90％
		Gelatin	3-40％
Water	1-10％
		85% Sorbitol/sorbitan solution	0.5-30％

Embodiment 2	Weight %
		T 4Na	0.001-1％
Glycerol	5-30％
		Ethanol	1-15％
PEG400	20-90％
		Gelatin	3-40％
Water	1-10％
		85% Sorbitol/sorbitan solution	0.5-30％

Embodiment 3	Weight %
		T 3Na	0.001-1％
Glycerol	5-30％
		Ethanol	5-15％
Tween 80	20-90％
		Gelatin	3-40％
Water	1-10％
		85% Sorbitol/sorbitan solution	0.5-30％

Embodiment 4	Weight %
		T 4Na	0.001-1％
Glycerol	5-30％
		Ethanol	5-15％
Tween 80	20-90％
		Gelatin	3-40％
Water	1-10％
		85% Sorbitol/sorbitan solution	0.5-30％

Embodiment 5	Weight %
		T 3Na	0.001-1％
Glycerol	1-30％
		Ethanol	1-10％
Water	1-10％
		Liquid Macrogol	15-90％
Gelatin	3-40％
		85% Sorbitol/sorbitan solution	0.5-30％

Embodiment 6	Weight %
		T 4Na	0.001-1％
Glycerol	1-30％
		Ethanol	1-10％
Water	1-10％
		Liquid Macrogol	15-90％
Gelatin	3-40％
		85% Sorbitol/sorbitan solution	0.5-30％

Embodiment 7	Weight %
		T 3Na	0.001-1％
Glycerol	1-30％
		Ethanol	1-10％
Water	1-10％
		Gelatin	3-40％
Macrogol 600	10-60％

Embodiment 8	Weight %
		T 4Na	0.001-1％
Glycerol	1-30％
		Ethanol	1-10％
Water	1-10％
		Gelatin	3-40％
Macrogol 600	10-60％

Embodiment 9	Weight %
		T 3Na	0.001-1％
T 4Na	0.001-1％
		Glycerol	1-30％
Ethanol	1-10％
		Gelatin	3-40％
PEG400	20-80％
		Water	1-10％
Methyl parahydroxybenzoate	0.01-1％
		Propyl p-hydroxybenzoate	0.01-1％

Embodiment 10	Weight %
		T 3Na	0.001-1％
T 4Na	0.001-1％
		Glycerol	1-30％
Ethanol	1-10％
		Gelatin	3-40％
PEG400	20-80％

Embodiment 11	Weight %
		T 3Na	0.001-1％
T 4Na	0.001-1％
		Glycerol	1-30％
Ethanol	1-10％
		Gelatin	3-40％
Macrogol 600	10-90％
		Water	1-10％
85% Sorbitol/sorbitan solution	0.5-30％

Embodiment 12	Weight %
		T 4Na	0.001-1％
Tween 80	20-95％
		Gelatin	3-40％
85% Sorbitol/sorbitan solution	1-30％
		Glycerol	1-30％
Water	1-10％
		Methyl parahydroxybenzoate	0.01-1％
Propyl p-hydroxybenzoate	0.01-1％

Embodiment 13	Weight %
		T 4Na	0.001-1％
Gelatin	20-95％
		Glycerol	1-40％
Water	1-30％

Embodiment 14	Weight %
		T 4Na	0.001-1％
Gelatin	20-95％
		Glycerol	1-40％
Ethanol	0.1-50％
		Water	1-10％

Embodiment 15	Weight %
		T 3Na	0.001-1％
Gelatin	20-95％
		Glycerol	1-40％
Ethanol	0.1-50％
		Water	1-10％

Following compositions and percentage ratio are meant the inner phase that is injected in the SEC capsule:

Embodiment A	Weight %
		T 4Na	0.001-1％
Ethanol	1-10％
		Glycerol	1-30％
PEG400	Reach 100% capacity

Embodiment B	Weight %
		T 4Na	0.001-1％
Ethanol	1-10％
		Glycerol	1-30％
Tween 80	Reach 100% capacity

Embodiment C	Weight %
		T 4Na	0.001-1％
Tween 80	Reach 100% capacity

Embodiment B	Weight %
		T 4Na	0.001-1％
PEG400	Reach 100% capacity

Embodiment E	Weight %
		T 4Na	0.001-1％
Ethanol	1-10％
		Propylene glycol	1-30％
PEG400	Reach 100% capacity

Embodiment F	Weight %
		T 4Na	0.001-1％
Glycerol	1-20％
		PEG400	Reach 100% capacity

Embodiment G	Weight %
		T 4Na	0.001-1％
The glycerol furfural	Reach 100% capacity

Embodiment H	Weight %
		T 4Na	0.001-1％
Liquid Macrogol	Reach 100% capacity

Example I	Weight %
		T 4Na	0.001-1％
Ethanol	0.1-50％
		Glycerol	Reach 100% capacity

Embodiment K	Weight %
		T 3Na	0.001-1％
Ethanol	0.1-50％
		Glycerol	Reach 100% capacity

Embodiment L	Weight %
		T 4Na	0.001-1％
Ethanol	0.1-50％
		Gelatin	0.1-20％
Glycerol	Reach 100% capacity

Embodiment M	Weight %
		T 3Na	0.001-1％
Ethanol	0.1-50％
		Gelatin	0.1-20％
Glycerol	Reach 100% capacity

Embodiment N	Weight %
		T 4Na	0.001-1％
T 3Na	0.001-1％
		Ethanol	0.1-50％
Gelatin	0.1-30％
		Glycerol	Reach 100% capacity

Embodiment O	Weight %
		T 3Na	0.001-1％
Gelatin	0.1-30％
		Glycerol	Reach 100% capacity

Embodiment P	Weight %
		T 4Na	0.001-1％
Gelatin	1-30％
		Glycerol	Reach 100% capacity

Embodiment Q	Weight %
		T 4Na	0.001-1％
Water	0.1-40％
		Ethanol	0.1-50％
Glycerol	Reach 100% capacity

Embodiment R	Weight %
		T 4Na	0.001-1％
Gelatin	1-30％
		Water	0.1-40％
Glycerol	Reach 100% capacity

Embodiment S	Weight %
		T 4Na	0.001-1％
Gelatin	1-30％
		Water	0.1-40％
Ethanol	0.1-50％
		Glycerol	Reach 100% capacity

Embodiment T	Weight %
		T 3Na	0.001-1％
Gelatin	1-30％
		Water	0.1-40％
Ethanol	0.1-50％
		Glycerol	Reach 100% capacity

Embodiment U	Weight %
		T 3Na	0.001-1％
T 4Na	0.001-1％
		Gelatin	1-30％
Water	0.1-40％
		Ethanol	0.1-50％
Glycerol	Reach 100% capacity

IV. following compositions and percentage ratio are meant according to being the of the present invention of drying regime and gulp down

Swallow even soft gel-type vehicle:

EXAMPLE V	Weight %
		T 4Na	0.001-1％
Glycerol	1-30％
		Gelatin	Reach 100% capacity

Claims (20)

1, is the pharmaceutical composition that contains thyroxin or its salt that to swallow even soft gel-type vehicle form, preferably forms by gelatin.

2, according to the described pharmaceutical composition of claim 1, be to be form of hard gelatin capsules.

3,, be to be the soft capsule form according to the described pharmaceutical composition of claim 1.

4, according to the arbitrary described pharmaceutical composition of claim 1-3, wherein, thyroxin is to be selected from T3 and/or T4 or its sodium salt.

5, according to the arbitrary described pharmaceutical composition of claim 1-4, wherein, described capsule maybe can be swallowed even soft gel-type vehicle and be made up of A type or Type B gelatin or methylcellulose, hydroxypropyl cellulose or calcium alginate.

6, according to claim 2,4 or 5 described pharmaceutical compositions, wherein, described hard capsule contains the thyroxin that is solid form, and is mixed with and is powder, granule or other non-common drug excipient that compresses particulate form.

7, according to the described pharmaceutical composition of claim 6, wherein, described drug excipient is to be selected from Tri-Compress, carboxymethyl starch sodium, microcrystalline Cellulose, a hydration lactic acid, sodium carboxymethyl cellulose, corn starch, magnesium stearate and antiseptic or their compositions.

8, according to claim 3,4 or 5 described pharmaceutical compositions, wherein, described soft capsule contains the thyroxin that is solid form, and is mixed with and is powder, granule or other non-common drug excipient that compresses particulate form.

9, described according to Claim 8 pharmaceutical composition, wherein, described drug excipient is to be selected from Tri-Compress, carboxymethyl starch sodium, microcrystalline Cellulose, a hydration lactic acid, sodium carboxymethyl cellulose, corn starch, magnesium stearate and antiseptic or their compositions.

10, according to claim 3,4 or 5 described pharmaceutical compositions, wherein, described soft capsule is made up of a shell, contains the thyroxin that is present in liquid or the semiliquid carrier and possible excipient.

11, according to the described pharmaceutical composition of claim 10, wherein, described soft capsule contains a kind of inner phase, and this inner phase is made up of liquid, semiliquid, paste, gel, emulsion or suspension, contains described liquid-carrier, thyroxin and possible excipient in suspension or solution.

12, according to the described pharmaceutical composition of claim 11, wherein, described liquid or semiliquid carrier are selected from glycerol, ethanol, Polyethylene Glycol (particularly having the Polyethylene Glycol that molecular weight is 200-800), glycerol furfural (tetrahydrofurfuryl alcohol polyglycol ether; Sigma T3396), 1,2-propylene glycol, medicine can be accepted oils or non-ionic surface active agent such as polysorbate (polysorbate20 or 80) or multiple different Tweens  (being trioleate or the tristearate such as the Tween  80 of monolaurate, monoleate, monopalmitate, monostearate, polyoxyethylene sorbitan, Sigma P1754) or their mixture.

13, according to the described pharmaceutical composition of claim 12, wherein, described SEC contains a kind of liquid or semiliquid inner phase, contains a kind of carrier of being made up of ethanol, glycerol or its mixture.

14, according to the described pharmaceutical composition of claim 12, wherein, described SEC contains a kind of inner phase and a kind of liquid or semiliquid carrier of being made up of paste that contains gelatin or gel of being made up of ethanol, glycerol or its mixture.

15,, wherein, describedly swallow even soft gel-type vehicle and contain glycerol, ethanol or its mixture according to claim 1 or 5 described pharmaceutical compositions.

16,, wherein, describedly swallow even soft gel-type vehicle and contain glycerol/alcohol mixture according to the described pharmaceutical composition of claim 15.

17, according to the arbitrary described pharmaceutical composition of aforementioned claim, has the enteric solubility coating that in small intestinal, can discharge thyroxin.

18, according to the arbitrary described pharmaceutical composition of aforementioned claim, has the external coating that to simplify picked-up.

19,, wherein, form described capsule and maybe can swallow the material of even soft gel-type vehicle and contain plasticizer and be used for controlling its hardness according to the arbitrary described pharmaceutical composition of aforementioned claim.

20, according to the described pharmaceutical composition of claim 19, wherein, described plasticizer is selected from glycerol, 1,2-propylene glycol, Sorbitol/sorbitan or its compositions.