CN101305099A - Prodrugs of T3 and T4 with enhanced bioavailability - Google Patents

Abstract

The invention relates to compositions of amino acid and peptide conjugates comprising T3 and/or T4. The T3 or T4 is covalently attached to at least one amino acid via the N-terminus, the C-terminus, a side chain of the peptide carrier, and/or interspersed within the peptide chain. Also discussed are methods for protecting and administering active agents and methods for treating thyroid disorders.

Description

Have the T3 of bioavailability of raising and the prodrug of T4

The cross reference of related application

According to 35U.S.C 119 (e), the application requires the U.S. Provisional Application 60/714,859 submitted on September 8th, 2005 and the rights and interests of the U.S. Provisional Application 60/786,695 submitted on March 29th, 2006; According to 35U.S.C 120, the application requires in the U. S. application 10/136 of submission on May 2nd, 2002,433 and in rights and interests that submit to, U. S. application that title is same as above, application number the unknown on September 8th, 2006, these apply for that integral body is incorporated herein by reference separately.

Invention field

The present invention relates to comprise medical compounds, the compoistion and method of use of the chemical part that is connected with T4 with T3.These inventions provide the effect of multiple beneficial, and comprising provides fast or slowly discharge and reduce the side effect relevant with composition with using iodine thyronine (iodothyronine) compound.The invention still further relates to protection and use the method for T3 and/or T4 and the method for treatment thyroid disease.The invention still further relates to the amount of available in vivo T3 of raising and/or T4 and avoid discharging the T3 of toxic level and the prodrug of T4 simultaneously.In addition, the invention still further relates to the composition of T3 prodrug, T4 prodrug and multiple combination thereof, described combination for example has T3 prodrug and T4, T3 prodrug and T3, T3 prodrug and T4 prodrug and T4 and T4 prodrug and T3, T4 prodrug and T4.

Background of invention

Triiodothyronine thyroxine (T4) and triiodothyronine (T3) are the hormones based on tyrosine that is produced by Tiroidina, and they play keying action and influence the almost function of each tract in the metabolism homeostasis.Thyroxine (T4) and triiodothyronine (T3) work to increase basal metabolic rate(BMR), influence protein synthesis and to increase the susceptibility of health to catecholamines (for example suprarenin) to health.Important component is an iodine in synthetic.

In healthy individual, the serum-concentration of Triiodothyronine is controlled by the classical degeneration factor that comprises Tiroidina, pituitary gland, hypothalamus and peripheral tissues such as liver.Thyroid disease not only can be caused by the defective of Tiroidina self, but also can be caused by hypophysis or hypothalamic unusual institute.In response to the thyrotropic hormone (TSH that produces by hypophysis; Also be called thyrotropin), the T4 of Tiroidina common every day of release estimation 70 to 90mg and 15 to 30mg T3 are in blood flow.Though healthy Tiroidina secretion T3, the most of T3 in the circulation are considered to take off the iodine generation by T4 by peripheral tissues, particularly liver.In response to by the caused metabotic change of low-level Triiodothyronine, TSH is subjected to the stimulation of thyroid releasing hormone (TRH, a kind of tripeptides that is produced by hypothalamus) by the synthetic and release of hypophysis.

Thyroid disease is common, and it comprises hyperthyroidism and hypothyroidism.It is feature that hypothyroidism raises with the TSH level usually, but its clinical manifestation changes extensively.In addition, although some patients show tangible clinical symptom, other needs of patients uses biochemical test to measure the state of thyroid function.Therefore, just can think hypothyroidism after diagnosing usually.In recent years, discerned multiple hypothyroidism syndrome with trickle performance.It is the illness of feature that subclinical hypothyroidism refers to raise with the normal and TSH of T4 and T3 level." the normal ill syndrome of thyroid function " and " low T3 syndrome " refer to wherein exist the T3 of low serum level but observe normal TSH and the illness of T4 level.These illnesss with multiple non-thyroid disease, comprise that congestive heart failure, clinical depression, mood disorder are relevant.

Hypothyroidism is modal thyroid disease, and it shows as Tiroidina and can not produce enough Triiodothyronines, mainly be triiodothyronine (also being called T3).The symptom relevant with hypothyroidism comprises that cold intolerance, burnout, fatigue, chronic constipation and multiple hair and skin change.Though these illnesss are not life-threatening, can not cause myxedema, stupor or death if do not treat disease.Be 1 to 10% significantly among the adult with subclinical hypothyroid morbidity scope.

Thereby T3 is by the syncaryon Thyroid Hormone Receptors and to regulate transcribing of specific gene be activated aspect the metabolism.T4 is at adjusting active much lower aspect transcribing, and it is considered to prohormone usually.In case T4 enters target cell, to be taken off the iodine enzymatic conversion be T3 to T4 in peripheral tissues and on subcellsular level, caused the metabolism of T4.As mentioned previously such, the T3 in the circulation mainly is the result that T4 transforms to T3 in liver.

That hypothyroid early symptom comprises is weak, tired, cold intolerance, constipation, weight increase (non-have a mind to), depressed, joint or myalgia, nail crisp fritter, hair crisp fritter, pale.Hypothyroid late period symptom comprise that bradyphrasia, xerosis cutis are easily peeled off, pachyderma, face, hand and sufficient edema, taste and smell reduce, eyebrow is thinning, trachyphonia, menstrual period are unusual.

Hypothyroid other symptom can comprise whole body swelling, muscle spasm (cramp), myalgia, amyotrophy, locomotor ataxia, lack menstruation (amenorrhoea, menstruation lacks), joint stiffness, xerasia, trichomadesis, edema of the face, drowsiness, appetite stimulator, ankle, foot and leg swelling, of short and small stature, seam separates and the tooth generation delays or absence of tooth.

Hypothyroidism is diagnosed by physical examination usually, and physical examination shows can notice of flaccid muscles delaying in the mirrored text process; The ochrodermia jaundice; Eyebrow outer rim disappearance; The hair crisp fritter; Facial characteristics is coarse; Nail is crisp; Stiffness of limbs swelling; And intelligence is slow.Vital sign can show heart rate slowly, ypotension and hypothermia.Chest x-ray can show cardiac dilatation.

The laboratory test of measuring thyroid function comprises: T4 test (low), serum TSH (high in primary hypothyroidism, low or low in secondary hypothyroidism-normal).Other laboratory abnormalities can comprise the mensuration thyroid function: cholesterol levels raises, the liver enzyme increases, the serum prolactin increases, hang down serum sodium and/or complete blood count (CBC) shows anaemia.

The overall goal of hypothyroidism treatment is to substitute insufficient Triiodothyronine.Levothyroxine is the medicine of normal use.Can use effectively mitigation symptoms and make the normal lowest dose level of TSH.Need treatment throughout one's life.Even when going down, symptom also must continue the use medicine.Should annual monitoring thyroid hormones level after the dosage of determining medicine is stable.Usually need to use throughout one's life medicine.

In the hypothyroidism illness, use active hormones T3 as an alternative therapy originally obtained limited success, because raising rapidly or " spike " level appears in the serum-concentration of this hormone occasionally in the serum, it will prove that for the impaired patient of cardiac status be dangerous.For this reason, the treatment of carrying out with prohormone T4 has become hypothyroid treatment option, just can have activity because T4 at first must be converted into T3 in vivo, this conversion process has been eliminated the possibility that makes the T3 serum level form spike and any serious sequela.But recently to studies show that of T4, it is relevant with aging that the patient is converted into T4 the general decline of ability of T3, and also observed the decline of this conversion capability when having stress disease or complication.In addition, can also exist certain organs or tract with the deficiency of T4 to the ability of T3 conversion.

Consider with use T3 or T4 as the Triiodothyronine surrogate relevant, as those problems that this paper discerned, need be used to transmit Triiodothyronine and derivative thereof efficient, effective, cost is low and the mechanism that can adopt easily.In addition, also need to treat hypothyroidism illness and control systemic composition of T3 body and method.

In addition, relevant with using synthetic Triiodothyronine FAQs is the amount of Triiodothyronine in the control volume.T3 (T3) can be used or administered several times with single dose every day, but these two kinds of methods all can cause high-caliber T3 after using this hormone.That the T3 of a large amount can cause is too fast such as heartbeat, the symptom of insomnia and anxiety.The synthesising preparation of the sodium salt levothyroxine sodium of T4 (

Deng) can be used as tablet and obtain.The sodium salt Cyronine of T3 can be used as tablet (

) and injectable forms (

) obtain.4: 1 mixtures of levothyroxine sodium and Cyronine also as liotrix (liotrix) (

) go on the market with tablet form.

And importantly, it is constant in to prevent bad side effect that the level of Triiodothyronine keeps.A kind of method of the per-cent of T3 and T4 is that amino acid and peptide are connected also thus interior T3 that is discharged of control volume and/or the amount of T4 with T3 (T3) or thyroxine (T4) in the control agent.The appearance of this method is because amino acid or peptide prodrug are limited by the amido linkage cracking to the transformation of its activity form, has therefore reduced the possibility that discharges the active medicine of toxic level.

Used transfer system is crucially depended in effective transmission of T3 and/or T4 usually.When the conformability of considering the patient and iodine thyronine stable, these systems become even more important.As mentioned above such, the preparation that is conditioned by release makes T3 " spike " rust will significantly improve the security of this medicine.Usually, improve the stability of iodine thyronine, for example prolong the circulation ratio that storage period or preservation under one's belt will be guaranteed dosage, and may even can reduce required dosage number, this can improve patient's conformability.

Find in the U. S. application 10/136,433 that can for example be to submit on May 2nd, 2002 about the other information of T3 and T4 compound and composition, this application integral body is incorporated herein by reference.Similarly, T4 and T3 mixture are discussed also has discussion to the information of the effect that had each other in U. S. application 10/701,173, and this application is incorporated herein by reference.

Still need to transmit effectively the composition of triiodothyronine (T3) and thyroxine (T4).Also still need protection and control triiodothyronine (T3) and/or the transmission of thyroxine (T4) and/or the method for release.

Therefore, still need to use the drug delivery system of recruit T3 and T4 composition, it can reduce the technical risk relevant with iodine thyronine material, regulation and control risk and fiscal risk, improves its circulation ratio, bioavailability, reliability and slowly-releasing simultaneously.

Compound of the present invention can provide with several useful forms.Therefore, the method for need improving effective iodine thyronine compound, compoistion and method of use aspect medicinal that prepare dosage excessive possibility is lowered and/or that have low side effect.

The accompanying drawing summary

Be appreciated that above general introduction and following detailed description all are illustrative, and not restrictive to the present invention.

Fig. 1 has illustrated iodine thyronine compound and the terminal schema that is connected by the acid functional group of iodine thyronine of the N-of peptide;

Fig. 2 has illustrated iodine thyronine and the terminal schema that is connected by the amine functional group of iodine thyronine of the C-of peptide;

Fig. 3 has illustrated the synthetic of T3 amino acid and peptide binding substances;

Fig. 4 has illustrated Orally administered T3 sodium or G-T3 (12mg/kg T3 content; HED～120mg T3 sodium) the total T3-time-concentration curve after;

Fig. 5 has illustrated Orally administered T3 sodium or G-T3 (12mg/kg T3 content; HED～120mg T3 sodium) the total T3 Δ-time-concentration curve after;

Fig. 6 has illustrated Orally administered T3 sodium or G-T3 (12mg/kg T3 content; HED～120mg T3 sodium) total T3-time-concentration curve of each animal of back;

Fig. 7 has illustrated Orally administered T3 sodium or G-T3 (12mg/kg T3 content; HED～120mg T3 sodium) total T3 Δ-time-concentration curve of each animal of back;

Fig. 8 has illustrated Orally administered T3 sodium or G-T3 (12mg/kg T3 content; HED～120mg T3 sodium) the TSH-time-concentration curve after;

Fig. 9 has illustrated Orally administered T3 sodium or V-T3 (12mg/kg T3 content; HED～120mg T3 sodium) the total T3-time-concentration curve after;

Figure 10 has illustrated Orally administered T3 sodium or V-T3 (12mg/kg T3 content; HED～120mg T3 sodium) the total T3 Δ-time-concentration curve after;

Figure 11 has illustrated Orally administered T3 sodium or I-T3 (12mg/kg T3 content; HED～120mg T3 sodium) the total T3-time-concentration curve after;

Figure 12 has illustrated Orally administered T3 sodium or I-T3 (12mg/kg T3 content; HED～120mg T3 sodium) the total T3 Δ-time-concentration curve after;

Figure 13 has illustrated Orally administered T3 sodium or Y-T3 (12mg/kg T3 content; HED～120mg T3 sodium) the total T3-time-concentration curve after;

Figure 14 has illustrated Orally administered T3 sodium or Y-T3 (12mg/kg T3 content; HED～120mg T3 sodium) the total T3 Δ-time-concentration curve after;

Figure 15 has illustrated Orally administered T3 sodium or A2-T3 (12mg/kg T3 content; HED～120mgT3 sodium) the total T3-time-concentration curve after;

Figure 16 has illustrated Orally administered T3 sodium or A2-T3 (12mg/kg T3 content; HED～120mgT3 sodium) the total T3 Δ-time-concentration curve after;

Figure 17 has illustrated Orally administered T3 sodium or P2-T3 (12mg/kg T3 content; HED～120mgT3 sodium) the total T3-time-concentration curve after;

Figure 18 has illustrated Orally administered T3 sodium or P2-T3 (12mg/kg T3 content; HED～120mgT3 sodium) the total T3 Δ-time-concentration curve after;

Figure 19 has illustrated Orally administered T3 sodium or F2-T3 (12mg/kg T3 content; HED～120mgT3 sodium) the total T3-time-concentration curve after;

Figure 20 has illustrated Orally administered T3 sodium or F2-T3 (12mg/kg T3 content; HED～120mgT3 sodium) the total T3 Δ-time-concentration curve after;

Figure 21 has illustrated Orally administered T3 sodium, G-T3, V-T3, I-T3, Y-T3, A2-T3, P2-T3 or F2-T3 (12mg/kg T3 content; HED～120mg T3 sodium) the total T3-time-concentration curve separately after;

Figure 22 has illustrated Orally administered T3 sodium, G-T3, V-T3, I-T3, Y-T3, A2-T3, P2-T3 or F2-T3 (12mg/kg T3 content; HED～120mg T3 sodium) the total T3 Δ-time-concentration curve separately after;

Figure 23 has illustrated Orally administered T3 sodium or V-T3 (12mg/kg T3 content; HED～120mg T3 sodium) the TSH-time-concentration curve after;

Figure 24 has illustrated Orally administered T3 sodium or I-T3 (12mg/kg T3 content; HED～120mg T3 sodium) the TSH-time-concentration curve after;

Figure 25 has illustrated Orally administered T3 sodium or Y-T3 (12mg/kg T3 content; HED～120mg T3 sodium) the TSH-time-concentration curve after;

Figure 26 has illustrated Orally administered T3 sodium or A2-T3 (12mg/kg T3 content; HED～120mgT3 sodium) the TSH-time-concentration curve after;

Figure 27 has illustrated Orally administered T3 sodium or P2-T3 (12mg/kg T3 content; HED～120mgT3 sodium) the TSH-time-concentration curve after;

Figure 28 has illustrated Orally administered T3 sodium or F2-T3 (12mg/kg T3 content; HED～120mgT3 sodium) the TSH-time-concentration curve after;

Figure 29 has illustrated Orally administered T3 sodium, G-T3, V-T3, I-T3, Y-T3, A2-T3, P2-T3 or F2-T3 (12mg/kg T3 content; HED～120mg T3 sodium) the total TSH-time-concentration curve after.

Detailed Description Of The Invention

The present invention relates to change the pharmacokinetics and the pharmacological property of iodine thyronine by covalent modification.Covalently bound one or more following character that can change the iodine thyronine of chemical part and iodine thyronine: uptake rate, degree of absorption, metabolism, distribution and elimination (ADME pharmacokinetic property).Therefore, can design one or more these characteristics of change provides quick or slowly release.In addition, change one or more these characteristics and can also reduce the side effect relevant with using the iodine thyronine.

An aspect of of the present present invention comprises iodine thyronine binding substances, and when it was used with normal therapeutic dosage, (time was to area under the concentration curve for the bioavailability of iodine thyronine; AUC) can provide the iodine thyronine of medicine effective quantity.But when dosage increased, for parent iodine thyronine, the bioavailability of the iodine thyronine of covalent modification began to descend, and is particularly like this for oral dosage form.When super pharmacological dose, to compare with parent iodine thyronine, the bioavailability of iodine thyronine binding substances significantly reduces.The risk that the relative reduction of bioavailability can reduce or minimizing is relevant with iodine thyronine dosage when higher dosage also helps to reduce the fluctuation of bioavailability.

The invention provides the iodine thyronine prodrug that comprises with the covalently bound iodine thyronine of chemical part.Iodine thyronine prodrug can also be described as binding substances, covalently bound because they have.They can also be described as the bioreversible derivative of conditionality (" CBD ").

In an embodiment, to compare with the free-iodine thyronine, iodine thyronine prodrug (compound with one of structural formula as herein described) can demonstrate one or more following advantages.Iodine thyronine prodrug can stop or reduce side effect.Preferred iodine thyronine prodrug provides the serum release profiles that does not increase the toxic level of above iodine thyronine when using with the dosage that is higher than therapeutic dose.Compare with the free-iodine thyronine, the uptake rate that iodine thyronine prodrug can demonstrate the iodine thyronine reduces and/or the clearance rate increase.Iodine thyronine prodrug can also demonstrate stable state serum release profiles.Preferred iodine thyronine prodrug provides bioavailability but has stoped and the relevant C of existing controlled release iodine thyronine product _MaxSpike forms, serum-concentration raises or releasing properties is not steady.Preferred prodrug was metabolized to independent amino acid effectively by digestive enzyme before arriving the body circulation.

The invention provides the covalently bound of triiodothyronine (T3) or thyroxine (T4) and carrier peptides, also be called peptide iodine thyronine (common name), peptide triiodothyronine (T3) or peptide thyroxine (T4) mixture.The present invention is covalently bound on carrier peptides with T3 or T4 with the peptide ways of connecting, is connected to N-end, C-end or the amino acid side chain of carrier peptides.In a more preferred embodiment, described connection is not used and is connected base.

Carrier peptides itself can also be used as adjuvant.In preferred embodiments, T3 or T4 and carrier peptides or amino acid whose N-end or C-end are covalently bound, also are called attach the names of pre-determined candidates T3 and T4 mixture.In another embodiment preferred, T3 or T4 directly and carrier peptides or amino acid whose amino acid side chain covalently bound, also be called side chain T3 or T4 mixture.

The iodine thyronine can combine with the chemical part of one or more called after X and Z.Chemical part can be Comparatively speaking to reduce arbitrary portion with the pharmacological activity of chemical part bonded iodine thyronine with the iodine thyronine that does not combine (dissociating).The chemical part that is connected can be naturally occurring or synthetic.In an embodiment, the invention provides the iodine thyronine prodrug of formula I:

I-X _n-Z _m (I)

Wherein I is the iodine thyronine; X is chemical part independently of one another; Z is the chemical part that is used as adjuvant and is different from least one X independently of one another; N is 1 to 50, preferred 1 to 10 increment; And m is 0 to 50, preferred 0 increment.When m was 0, iodine thyronine prodrug was formula (II) compound:

I-X _n (II)

Wherein X is chemical part independently of one another.

Formula (II) can also be write the chemical part that is connected physically with the iodine thyronine to indicate:

I-X ₁-(X) _n-1 (III)

Wherein I is the iodine thyronine; X ₁Be chemical part, preferred single amino acids; X is and X independently of one another ₁Identical or different chemical part; And n is 1 to 50 increment.

Compound of the present invention, composition and method provide the excessive possibility of the dosage of reduction and/or have improved the characteristic of relevant high toxicity of iodine thyronine or suboptimum releasing properties.

Term iodine thyronine compound refers to formula IV compound as used herein,

Wherein A is that iodine and B, C and D are hydrogen or iodine independently, in these compounds are intended to be included in separately as the possible compound that can be used as the precursor compound of setting up prodrug of the present invention.In particular, thyroxine or T4 are commonly referred to as 3: 5,3 ': 5 ' T4, and T3 is commonly referred to as 3: 5,3 ' triiodothyronine.In formula IV, NH-is connected with hydrogen and the CO-of formula IV is connected with hydroxyl; Promptly be respectively NH ₂And COOH.

Preferred prodrug of the present invention be glycine-3,3 ', 5-three iodo-L-thyronine hydrochlorides.Its molecular weight is 744.5.Its structure delineation is as follows:

Another kind of preferred prodrug is glycine-T4, and it has similar structure but comprises other I.

In the normal or standard state, Tiroidina secretion T4 and T3 are in blood flow in thyroid function; For optimum health and Ankang, two kinds of hormones with surpass by T4 periphery only take off iodine the level of issuable those levels be essential to the continuous attainability of target tissue.Therefore, the present invention allows to simulate some activity of normal thyroid, the promptly synthetic carrier peptides that contains hormone.Carrier peptides by proteolysis after, hormone can with approximately with by the secreted identical T4 of healthy Tiroidina: the T3 ratio is released in the blood flow.

Link position depends on covalently bound selected functional group.For example, the carboxylic acid of iodine thyronine is connected with the N-of carrier peptides is terminal, as shown in fig. 1.Perhaps, hydroxy-acid group can be connected with the side chain of substituted amino acid such as Methionin aptly.The amine functional group of T3 or T4 is connected with the C-of carrier peptides is terminal, as shown in Figure 2.In C-and the terminal two kinds of examples of N-, a monomeric unit that forms new peptide bond has in fact prolonged the carrier peptide chain.If the amine of T3 or T4 all is used for being connected with carrier peptides with carboxylic acid, then can prepare T3 that is dispersed in or T4 mixture that peptide connects.If the alcohol of T3 or T4 is used for being connected with carrier peptides, then side chain, C-end or N-end are tie points obtaining stabilized complex, though carbonyl or its equivalent may need to be inserted between the pure and mild peptide functional group.

In another embodiment of the present invention, iodine thyronine-binding substances, be T3-binding substances or T4-binding substances, with following material covalent attachment: Ala, Arg, Asn, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Glu, Val, Ala-Ala, Arg-Arg, Asn-Asn, Gln-Gln, Gly-Gly, His-His, Ile-Ile, Leu-Leu, Lys-Lys, Met-Met, Glu-Glu, Phe-Phe, Pro-Pro, Ser-Ser, Thr-Thr, Trp-Trp, Tyr-Tyr, Val-Val, Ala-Ala-Ala, Arg-Arg-Arg, Asn-Asn-Asn, Gln-Gln-Gln, Gly-Gly-Gly, Glu-Glu-Glu, His-His-His, Ile-Ile-Ile, Leu-Leu-Leu, Lys-Lys-Lys, Met-Met-Met, Phe-Phe-Phe, Pro-Pro-Pro, Ser-Ser-Ser, Thr-Thr-Tlir, Trp-Trp-Trp, Tyr-Tyr-Tyr or Val-Val-Val.In another embodiment preferred, compound is Gly-T3, Gly-T4, Gly-T3, Ile-T3, Tyr-T3, Ala-Ala-T3, Val-T3, Pro-Pro-T3, Phe-Phe-T3, Glu-Glu-T3, Gly-T4, Ile-T4, Tyr-T4, Ala-Ala-T4, Val-T4, Pro-Pro-T4, Phe-Phe-T4, T4-Glu, T4-Glu-Glu, T4-Lys, Glu-T4, Glu-Glu-T4 or Lys-T4.Will be appreciated that described embodiment location separately can be C-end, N-end or side chain (wherein amino acid provides the side chain connection).But, should be appreciated that institute's bonded form relates in covalent attachment and salt form be included in.In addition, these compounds can also be that its salt form is to be easy to storage or to use in preparation.

The invention provides the method that T3 or T4 is delivered to the patient, this patient is people or non-human animal, and described method comprises composition of the present invention is applied to the patient.

Peptide iodine thyronine composition of the present invention has the advantage that is better than independent T4 and T3, because iodine thyronine prodrug (binding substances) composition is the functional surrogate of naturally occurring thyroglobulin.Method of the present invention, compound and composition provide number of important advantages and progress.Composition of the present invention can prepare to reduce purity and the Efficacy Problem relevant with other T3 or T4 treatment, compound and composition with synthesis mode.Method and composition of the present invention stops and/or has avoided excessive dosage (for example " spike ").By guaranteeing the utilizability of dosage circulation ratio and/or minimizing dosage, the invention provides the additional advantage that improves patient's conformability.The present invention regularly discharges (time-release) character for T3 and/or T4 provide.Provide regularly releasing properties also to guarantee the dosage circulation ratio and/or reduced required dosage number.

In preferred embodiments, do not rely in preparation process other delay commonly used by timing releasing properties provided by the invention and discharge or regularly discharge formulation, for example microencapsulation matrix.This provides additional advantage: reliably quantitatively and batch between circulation ratio.This embodiment provides the regularly other advantage of releasing properties, and does not increase the water miscible dependence to T3 or T4.Therefore, regularly releasing properties does not need other preparation, for example by related process in leaching in the enteric coated promoting agent of pH control.

By another advantage of preferably executing scheme and providing of the present invention be aspect molecular weight, molecular size, granularity or its combination to the control of T3 or T4 transfer system.Make that by the control that this embodiment provided rate of diffusion and pharmacokinetics can be predicted to these physical propertys.

In a preferred embodiment of the invention, one or more iodine thyronine prodrugs are transmitted synergistically.In another embodiment, composition of the present invention is protection T3 and T4 in storage process and/or in passing through the stomach process.In a more preferred embodiment, the invention provides protection iodine thyronine compound, control its transmission or control its release or the method for their combination.

In preferred embodiments, with T3-peptide binding substances, T4-peptide binding substances, its combination is used for and uncombined iodine thyronine is used in combination.These combinations can be applied to the patient who suffers from the illness relevant with Tiroidina, comprise compound as herein described or composition are applied to the patient who needs it.In preferred embodiments, illness is hypothyroidism or dysthymia disorders.In another embodiment preferred, the illness relevant with Tiroidina comprises the normal thyrocele of thyroid function, the normal ill syndrome of thyroid function, hyperthyroidism, hypothyroidism, thyroiditis and thyroid carcinoma.The present invention can be used for the treatment of, stops or prevent hypothyroidism.

The present invention provides the amount of biologically available T3 and/or T4 in the mode of regulating, and therefore, can stop the known side effect that is produced by the T3 of using too high dose (T3) and/or thyroxine (T4).The amount of free T3 or free T4 is regulated by cracking amido linkage and the mechanism that discharges active medicine, makes minimum by the possibility of the adverse side effect that high dosage produced thus.In addition, can also improve the absorption of T3 or T4.

The present invention provides several advantages for using of T3 and T4, such as but not limited to: prolong storage period and prevent to digest under one's belt; With T3 and T4 targeted delivery to specific site of action, particularly specific organ; Delay by T3 and T4 discharges the prolonged pharmacological effect; Can with T3 and T4 combines or with adjuvant combination to produce synergy; Promote T3 or T4 in enteron aisle, to absorb; And preparation is used for by the targeted delivery of intestines enzyme, desmo enzyme or seroenzyme digestion.

In preferred embodiments, the hydroxy-acid group of T3 or T4 and amine groups participation are covalently bound with carrier peptides, make promoting agent be dispersed in the peptide ways of connecting in carrier peptides thus.In another embodiment preferred, the carboxylic acid of T3 or T4 and the N-of carrier peptides are terminal covalently bound to produce acid amides, and this paper is called " N-attaches the names of pre-determined candidates ".In another embodiment preferred, the amine of T3 or T4 and the C-of carrier peptides are terminal covalently bound to produce acid amides, and this paper is called " C-attaches the names of pre-determined candidates ".

The invention provides preparation comprise carrier peptides and with covalently bound T3 of carrier peptides or the method for compositions of T4.For example, can T4 be connected with amino acid whose side chain to form promoting agent/amino acid conjugates according to following explanation.

It below is the terminal example that is connected with T3 of amino acid whose C-.

The DCC=dicyclohexylcarbodiimide

The NHS=N-N-Hydroxysuccinimide

The NMM=4-methylmorpholine

The DMF=dimethyl formamide

It below is the terminal example that is connected with T4 of amino acid whose C-.

The DCC=dicyclohexylcarbodiimide

The NHS=N-N-Hydroxysuccinimide

The NMM=4-methylmorpholine

The DMF=dimethyl formamide

It below is the terminal example that is connected with T3 of amino acid whose N-.

The NMM=4-methylmorpholine

The DMF=dimethyl formamide

It below is the terminal example that is connected with T4 of amino acid whose N-.

The NMM=4-methylmorpholine

The DMF=dimethyl formamide

It is as follows that Gly-T4 (HCL salt) synthetic described.

Gly-T4.HCl with ¹H NMR characterizes; Purity～94%.

It is as follows that Gly-T3 (HCl salt) synthetic described.The raw material of preparation among the NRP409 be 3,3 ', 5-three iodo-L-thyronine (T3) and Boc-Gly-OSu.3,3 ', 5-three iodo-L-thyronine are obtained by Sigma-Aldrich company (Sigma-Aldrich), and Boc-Gly-OSu is obtained by Ba Heng company (BaChem).

Can use routine techniques to prepare carrier peptides.Particular sequence then can use the automatic peptide synthesizer if desired.

Mixture of the present invention can comprise by acid and amine and forms acid amides, and can prepare by the embodiment of this paper.In the application's full text, figure is used to describe the generalized flowsheet that promoting agent is connected with multiple peptide binding substances by different functional groups, thereby has produced different embodiment of the present invention.One skilled in the art will know that to make other promoting agent combine necessary other reagent, condition and character with other polypeptide from flow process, it is nonrestrictive example that these flow processs are intended to.These figure also represent the different embodiments of the present invention about active agent combinations length.

The present invention has broadly instructed T3-prodrug and/or the T4-prodrug with unconjugated T3 and/or unconjugated T4 combination, to form the compositions and methods of the invention, for example: T3-prodrug and unconjugated T4; T4 prodrug and unconjugated T3; T3 prodrug, T4 prodrug and unconjugated T4 etc.

This T3 and/the T4 binding substances can be co-administered with known thyroid drug, described known thyroid drug is such as but not limited to being made up

Levothyroxine/Levothyroxinnatrium, T3, liotrix (Liotrix), Thiamazole, propylthiouracil/PTU, natural thyroid, thyrotropic hormone α and the T3 that regularly discharges.

These products will be similar to existing therapy as Wait and treat among the hypothyroidism patient level of used those and use.Can use the well-known method of those skilled in the art to measure the accurate level that is used for particular patient, comprise and use known technology to monitor the blood levels of Triiodothyronine and regulate dosage in view of the above to obtain in the blood levels that can accept in the limit.Composition can be used in particular for providing the oral dosage preparation for Triiodothyronine.Although the oral dosage preparation is an embodiment preferred for transmission, also can adopt the method for transmitting known iodine thyronine compound.

The iodine thyronine can be connected with carrier peptides by C-end, N-end or the side chain of carrier peptides.Preferred iodine thyronine is connected with the C-of carrier peptides is terminal.Preferably except being connected of carrier peptides and iodine thyronine, both are not all further replaced or are protected.In an embodiment, except with the tie point of iodine thyronine, chemical part has one or more free carboxies and/or amine end and/or side-chain radical.Chemical part can be such free state or its ester or salt.

Another embodiment of the present invention is composition or the method that is used for safe transfer iodine thyronine, comprise provide the treatment significant quantity, with the covalently bound iodine thyronine of chemical part, wherein, compare with transmitting unconjugated iodine thyronine, described chemical part has changed the uptake rate of iodine thyronine.Another embodiment can also provide the method that reduces drug toxicity by the clearance rate that changes the iodine thyronine.

Another embodiment of the present invention is the composition or the method for slowly-releasing iodine thyronine mixture, comprise and providing and the covalently bound iodine thyronine of chemical part, wherein said chemical part provides the release of iodine thyronine with such speed: time period, for example 8-24 hour or the longer time of going through prolongation, the level of iodine thyronine still is lower than toxic level in therapeutic domain.

Another embodiment of the present invention is composition or the method that reduces bioavailability or stop iodine thyronine toxicity releasing properties, comprise and the covalently bound iodine thyronine of chemical part, wherein, compare with unconjugated iodine thyronine, described bonded iodine thyronine has kept stable state serum release profiles, and it can provide the effective bioavailability of treatment but stop the formation spike or increased serum-concentration.

Another embodiment of the present invention is to stop C _MaxSpike and/or for the iodine thyronine provides constant release profiles more, the composition or the method for the effective bioavailability curve of treatment still can be provided simultaneously comprises and the covalently bound iodine thyronine of chemical part.

Another embodiment of the present invention is to reduce or prevent the toxicity of pharmaceutical composition and/or improve its release and/or provide the method for steady state release for it, this method comprises and described composition is offered, is applied to or leave the people that prescription is given needs it that wherein said composition comprises the chemical part covalently bound with the iodine thyronine.

For various described methods of the present invention, can obtain following character by the iodine thyronine is combined with chemical part.In an embodiment, the toxicity of compound can significantly be lower than the iodine thyronine when with its not combined or the toxicity when transmitting as its salt.In another embodiment, by Orally administered dosage excessive/toxic possibility is lowered or eliminated.

The compositions and methods of the invention provide the iodine thyronine, the iodine thyronine when combining with chemical part by improving bioavailability curve and/or safer C _MaxFor the iodine thyronine provides safer and/or more effective dosage and/or has reduced the area under curve that is used for bioavailability.

Compare with unconjugated iodine thyronine, the oral administration biaavailability of the iodine thyronine that preferred iodine thyronine prodrug shows is at least about 60%AUC (area under curve), more preferably at least about 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%.

In an embodiment, iodine thyronine prodrug provide 80% to 125%, 80% to 120%, 85% to 125%, 90% to 110% or wherein the unconjugated iodine thyronine within the increment or the existing goods that is used for the treatment of as

Pharmacological parameters (AUC, C _Max, T _Max, C _MinAnd/or t _1/2).Should be known in these scopes can but need not to be symmetric, for example 85% to 105%.

In another embodiment, the toxicity of iodine thyronine prodrug significantly is lower than the toxicity of unconjugated iodine thyronine.For example, in preferred embodiments, the lethality of acute toxicity is than Orally administered unconjugated iodine thyronine little 1,2,3,4,5,6,7,8,9,10 times or wherein increment.

According to the present invention and following as used herein term be defined as having following implication, except other offers some clarification on.

Compound of the present invention, composition and method adopt " iodine thyronine binding substances ", and it also is called iodine thyronine prodrug.

" iodine thyronine " broadly refers to triiodothyronine (T3), T3,3,5-diiodothyronine (3,5-T2), 3,3 '-diiodothyronine (3,3 '-T2), rT3 (3,3 ', 5 '-triiodothyronine, rT3) and the single iodine thyronine (3-T1) of 3-, thyronine (T4), diiodotyrosine and iodotyrosine.

In whole the application, " chemical part "-be sometimes referred to as " binding substances " or " carrier "-use be intended to comprise and reduce pharmacological activity until the d/d any chemical substance of iodine thyronine, these chemical substances can be naturally occurring or synthetic, comprise carrier peptides, glycopeptide, carbohydrate, lipid, nucleic acid, nucleosides or VITAMIN at least.Preferred chemical part is considered to safe (" GRAS ") usually.

In whole the application, the use of " carrier peptides " is intended to comprise naturally occurring amino acid, synthetic amino acid and combination thereof.Particularly carrier peptides is intended to comprise at least single amino acid, dipeptides, tripeptides, oligopeptides, polypeptide or nucleic acid-amino acid peptide.Carrier peptides can comprise natural existence or amino acid whose homopolymer of synthetic or heteropolymer.

The use of term " straight chain carrier peptides " be intended to comprise connect by-C (O)-NH-key (this paper also is called " peptide bond ") but can be along the substituted amino acid of the side chain of carrier peptides.The amino acid that does not link together by peptide bond or not only connect by peptide bond is not intended to be included in the definition of straight chain carrier peptides.

The use of term " unsubstituted carrier peptides " is intended to comprise by-C (O)-NH-key and connects and along the not other substituted amino acid of the side chain of carrier peptides.The amino acid that does not link together by peptide bond or not only connect by peptide bond is not intended to be included in the definition of unsubstituted carrier peptides.

" oligopeptides " is intended to comprise 2 amino acid to 10 amino acid." polypeptide " is intended to comprise 2 to 50 amino acid.

" carbohydrate " comprises sugar, starch, Mierocrystalline cellulose and allied compound, for example (CH ₂O) _n(wherein n is the integer greater than 2) or C _n(H ₂O) _N-1(wherein n is greater than 5).Example for example comprises fructose, glucose, lactose, maltose, sucrose, Glycerose, otan, erythrose, ribose, ribulose, xylulose, semi-lactosi, seminose, sedoheptulose, neuraminic acid, dextrin and glycogen more specifically.

" glycoprotein " is the compound that contains the carbohydrate covalently bound with protein (or glycan).Carbohydrate can be the form of monose, disaccharides, oligose, polysaccharide or derivatives thereof (for example sulfo group-or phosphate-replacement).

" glycopeptide " is the compound that comprises the carbohydrate that is connected with oligopeptides, and described oligopeptides is made up of L-and/or D-amino acid.Glycoprotein amino acid is the sugar that the covalent linkage by any kind is connected with single amino acid.Glycosyl amino acid is the compound that comprises the sugar that is connected with amino acid by glycosyl bond (O-, N-or S-).

" carrier scope " or " carrier size " determined according to required being used for.Preferred 1 to 12 chemical part, preferred 1 to 8 part.In another embodiment, the number of the chemical part that is connected is concrete number, for example 1,2,3,4,5,6,7,8,9 or 10 etc.Perhaps, chemical part can be described according to its molecular weight.It is about 2 that the preferred combination thing weighs less than, 500kD, and more preferably less than about 1,000kD most preferably is lower than about 500kD.

" composition " broadly refers to contain the arbitrary composition of iodine thyronine binding substances as used herein." pharmaceutical composition " refers to contain the arbitrary composition of iodine thyronine binding substances, and it only comprises medicinal acceptable component, for example got rid of the iodine thyronine binding substances that is used for immune purpose.

Phrase comprises that as the use of " minimizing " or " reduction " pharmacological activity is at least a ADME characteristic or AUC, C _Max, T _Max, C _MinAnd t _1/2In at least one aspect at least 10% variation is arranged.For example, changing also can be greater than 25%, 35%, 45%, 55%, 65%, 75%, 85%, 95%, 96%, 97%, 98%, 99% or other increment.

The use of phrase " similarly pharmacological activity " represents that two kinds of compound exhibits go out to have substantially the same AUC, C _Max, T _Max, C _MinAnd/or t _1/2The curve of parameter, preferably mutually within about 30%, more preferably about 25%, 20%, 10%, 5%, 2%, 1% or other increment within.

" C _Max" be defined in the peak concentration of free-iodine thyronine in the body that obtains during the dosing interval.

" T _Max" be defined as reaching time of peak concentration.

" C _Min" be defined as after the administration Cmin of iodine thyronine in the body.

" t _1/2" be defined as in the body amount of iodine thyronine and be reduced to it and be worth half needed time.

In whole the application, term " increment " is used to define the numerical value of different precision, and for example immediate 10,1,0.1,0.01 etc.Increment can be rounded to the precision that can survey arbitrarily.For example, scope 1 to 100 or increment wherein comprise that scope is as 20 to 80,5 to 50,0.4 to 98 and 0.04 to 98.05.

" hypothyroidism " refers to that broadly Tiroidina wherein can not produce the illness of enough Triiodothyronines as used herein.It also is called " myxedema " and " adult's hypothyroidism ".

" Tiroidina " broadly refers to be positioned at throat portion and the body of gland under larynx just in time as used herein, and this body of gland can be secreted the metabolic hormone of control, be thyroxine (T4) and triiodothyronine (T3).

" patient " broadly refers to any animal of needs treatments as used herein, most preferably suffers from the animal of thyroid disease, disorder of thyroid gland or the illness relevant with Tiroidina.The patient can be a clinical patients, for example people or beasts patient such as companion animals, performing animal, domestic animal, external animal or zoo animal.Animal can be Mammals, Reptilia, bird, Amphibians or invertebrates.

" Mammals " broadly refers to arbitrarily and all Mammalia warm-blooded vertebrates as used herein, comprises people, non-human primates, cat family, Canidae, rat, pig, horse, sheep etc.

As used herein " pretreat " broadly refer to before accepting iodine thyronine compound of the present invention or composition, to take place arbitrarily and all preparation, treatment or schemes.

As used herein " treatment " broadly refer to preventing disease, that is, the clinical symptom of disease is not developed may suffering from or be easy to suffer from disease but also do not experience or demonstrate among the patient of disease symptoms; Suppress disease, that is, and the development of containment or reduction disease or its clinical symptom; And/or palliate a disease, that is, disease or its clinical symptom are disappeared.Treatment includes also that ameliorate body is levied and/or symptom.

" treatment significant quantity " broadly refers to the amount that is enough to when the patient treats disorder of thyroid gland to realize to the compound of the treatment of disorder of thyroid gland when being applied to as used herein." treatment significant quantity " will change according to compound, disease and seriousness thereof and the patient's age for the treatment of, body weight etc.

" effective dose " of iodine thyronine prodrug or composition or " significant quantity " are essential for the treatment disorder of thyroid gland or for disorder of thyroid gland provides prevention.

As used herein " patient's selection " and " patient's screening " broadly refer to select the patient that suits to accept the practice of treatment as herein described.Multiple factor includes but not limited to age, body weight, health history, medicine, operation, damage, illness, sufferer, disease, infection, sex, race's property, genetic marker, polymorphism, the colour of skin and to the susceptibility of T3 or T4 treatment.Other factors also comprises being made by the doctor and is used for determining whether the patient is suitable for accepting those of treatment as herein described.

As used herein " diagnosis " broadly refer to check, estimate, measure and whether definite patient suffers from the practice of thyroid disease.

" thyroid disease " broadly comprises the normal thyrocele of thyroid function, the normal ill syndrome of thyroid function, hyperthyroidism, hypothyroidism, depression, thyroiditis and thyroid carcinoma etc. as used herein.

" illness relevant with Tiroidina " broadly comprises the normal thyrocele of thyroid function, the normal ill syndrome of thyroid function, hyperthyroidism, hypothyroidism, depression, thyroiditis and thyroid carcinoma etc. as used herein.

About stereochemistry, this patent is intended to comprise the compound of all discussion, regardless of its absolute configuration.Therefore, natural L-amino acid has been discussed, but has also been comprised the amino acid whose use of D-.

For each embodiment as herein described, carrier peptides can comprise one or more naturally occurring (L-) amino acid: L-Ala, arginine, l-asparagine, aspartic acid, halfcystine, glycine, L-glutamic acid, glutamine, Histidine, Isoleucine, leucine, Methionin, methionine(Met), proline(Pro), phenylalanine, Serine, tryptophane, Threonine, tyrosine and Xie Ansuan.Another kind of preferred amino acids is a Beta-alanine.In another embodiment, amino acid or peptide comprise the naturally occurring amino acid of one or more D-forms.In another embodiment, amino acid or peptide comprise that one or more are non-natural, off-gauge or synthetic amino acid, hexosamine for example, biphenyl alanine, Cyclohexylalanine, Cyclohexylglycine, diethyl glycine, the dipropyl glycine, 2, the 3-diaminopropionic acid, hyperphenylalaninemia (homophenylalanine), homoserine, high tyrosine, the naphthyl L-Ala, nor-leucine, ornithine, phenylalanine (4-fluorine), phenylalanine (2,3,4,5,6 five fluorine), phenylalanine (4-nitro), phenylglycocoll, pipecolic acid, sarkosine, tetrahydroisoquinoline-3-formic acid and Terleu.In another embodiment, amino acid or peptide comprise one or more amino acid alcohols.In another embodiment, amino acid or peptide comprise one or more N-methylamino acids.

In another embodiment, listed specific carrier can have one or more by the monobasic amino acid of 20 kinds of natural amino acids in the table.Preferred replace by on structure or electric charge with sequence in amino acids like aminoacid replacement.For example, Isoleucine (Ile) [I] is structurally very similar with leucine (Leu) [L], tyrosine (Tyr) [Y] is similar with phenylalanine (Phe) [F], Serine (Ser) [S] is similar with Threonine (Thr) [T], halfcystine (Cys) [C] is similar with methionine(Met) (Met) [M], L-Ala (Ala) [A] is similar with Xie Ansuan (Val) [V], Methionin (Lys) [K] is similar with arginine (Arg) [R], l-asparagine (Asn) [N] is similar with glutamine (Gln) [Q], aspartic acid (Asp) [D] is similar with L-glutamic acid (Glu) [E], Histidine (His) [H] is similar with proline(Pro) (Pro) [P], and glycine (Gly) [G] is similar with tryptophane (Trp) [W].Perhaps, can select preferred amino acids to replace situation according to hydrophilic nmature (being polarity) or other general characteristic relevant with 20 kinds of indispensable amino acids.Although embodiment preferred can know because 20 kinds of natural amino acids have the GRAS characteristic and use them, also can consider not influence amino fundamental characteristics, along the little replacement of amino acid chain.

Be according to the list of side chain characteristic with the amino acid classification herein:

Aliphatic category: L-Ala, glycine, Isoleucine, leucine, proline(Pro), Xie Ansuan

The fragrance same clan: phenylalanine, tryptophane, tyrosine

Acid class: aspartic acid, L-glutamic acid

Alkaline species: arginine, Histidine, Methionin

Hydroxyl acids (hydroxylic): Serine, Threonine

Sulfur-bearing class: halfcystine, methionine(Met)

Amino acid class (amidic) (containing amide group): l-asparagine, glutamine.

Iodine thyronine binding substances can also be the form of salt.Pharmacologically acceptable salt, for example nontoxic inorganic and organic acid addition salt are known in the art.Exemplary salt includes but not limited to the 2-isethionate, the 2-naphthalenesulfonate, 3-hydroxyl-2-naphthoate, 3-phenylpropionic acid salt, acetate, adipate, alginates, amsonate, aspartate, phenylbenzimidazole sulfonic acid salt, benzoate, benzene sulfonate, supercarbonate, hydrosulfate, bitartrate, borate, butyrates, Ca-EDTA, camphorate, camsilate, camsilate, carbonate, citrate, clavulariate (Clavulanate), cyclopentane propionate, digluconate, dodecyl sulfate, edetate, ethanedisulphonate, estolate, esilate, ethane sulfonate, finnarate (non-that hydrochlorate), glucoheptose salt, gluceptate, gluconate, glutaminate, phospho-glycerol, ethylene glycol arsanilate (glycollylarsanilate), Hemisulphate, enanthate, hexafluorophosphate, hexanoate, hexyl Resorcino salt, breathe out amine (hydrabamine), hydrobromate, hydrochloride, hydriodate, Hydroxynaphthoate, different thiosulphate, lactic acid salt, Lactobionate, lauroleate, lauryl sulfonate, malate, maleate, mandelate, mesylate, methane sulfonates, Methylsulfate, mucate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, N-methylglucosamine ammonium salt, oleate, oxalate, palmitate, pamoate, pantothenate, pectate, phosphoric acid salt, phosphateldiphosphate (phosphoric acid salt diphosphate), picrate, Pivalate, Polygalacturonate, propionic salt, tosilate, saccharate, salicylate, stearate, subacetate, succinate, vitriol, sulfosaliculate (sulfosalicylate), suramate (shura hydrochlorate), tannate, tartrate, the teoclate, thiocyanate-, tosylate, triethiodide, undecane hydrochlorate and valerate etc.

In the present invention, the iodine thyronine can by ketone group be connected the base with peptide covalently bound.This connection base can be little line style or the ring molecule that contains 2-6 atom (having one or more heteroatomss such as O, S, N) and one or more functional group (for example amine, acid amides, alcohol or acid), perhaps can be made up of the short chain of amino acid or carbohydrate.For example, glucose will suit as connecting base.

In another embodiment of the present invention, connect base and can be selected from the compound of all chemical classes so that any side chain that in fact can connection peptides.Connect base and should have functional side group such as carboxylic acid group, alcohol radical, thiol, oximido, hydrazone group (hydraxone), hydrazide group or amido with covalently bound with carrier peptides.In an embodiment preferred, the alcohol radical of iodine thyronine is covalently bound with the N-end of peptide by connecting base.In another embodiment preferred, the ketone group of iodine thyronine by forming ketone acetal with is connected base and connects, and connect the basic side group that is connected with carrier peptides that has.The example that the terminal type of the N-of organic compound and peptide is connected includes but not limited to being connected of being connected of naphthyl acetic acid and LH-RH, coumaric acid and opioid peptides and 1, and 3-dialkyl group-3-acyl group triazene is connected with tetra gastrin and pentagastrin.As another example, the acridine that the vitamin H that exists known technology to be used to form the peptide connection is connected with peptide.

Except iodine thyronine prodrug, pharmaceutical composition of the present invention can also comprise one or more auxiliary pharmaceutical adjuvants.Auxiliary pharmaceutical adjuvant comprises large-scale material, includes but not limited to thinner and filler, tackiness agent and tackiness agent, lubricant, glidant, softening agent, disintegrating agent, carrier solvent, buffer reagent, tinting material, correctives, sweeting agent, sanitas and stablizer, sorbent material and other auxiliary pharmaceutical adjuvant known in the art.

Lubricant includes but not limited to Magnesium Stearate, calcium stearate, Zinic stearas, powder stearic acid, glyceryl monostearate, glyceryl palmitostearate, glyceryl behenate, silicon-dioxide, Magnesium Silicate q-agent, colloid silica, titanium dioxide, Sodium Benzoate, Sulfuric acid,monododecyl ester, sodium salt, sodium stearyl fumarate, hydrogenated vegetable oil, talcum powder, polyoxyethylene glycol and mineral oil.

The tensio-active agent that is used for preparation comprises but is not limited to Sulfuric acid,monododecyl ester, sodium salt, Sodium docusate, trolamine, polyoxyethylene sorbitan, poly-third ethylene copolymer of polyoxyethylene and quaternary ammonium salt; Vehicle, for example hydrochloride of lactose, N.F,USP MANNITOL, glucose, fructose, wood sugar, semi-lactosi, sucrose, maltose, Xylitol, sorbyl alcohol, potassium, sodium and magnesium, vitriol and phosphoric acid salt; Jelling agent, for example Colloidal Clay; Thickening material, for example tragakanta or sodium alginate; Effervescent mixture; And wetting agent, for example Yelkin TTS, polysorbate or lauryl sulfate.

Tinting material can be used to improve outward appearance or help the identification pharmaceutical composition.Referring to: 21 C.F.R., the 74th part.Exemplary tinting material comprises D﹠amp; C red No. 28, D﹠amp; C yellow No. 10, FD﹠amp; C blue No. 1, FD﹠amp; C red No. 40, FD﹠amp; C green No. 3, FD﹠amp; C yellow No. 6 and edible China ink.

Pharmaceutical composition is pressed in the embodiment of solid dosage such as tablet therein, and tackiness agent can help composition to keep together.Tackiness agent includes but not limited to: sugar, for example sucrose, lactose and glucose; Maize treacle; Soybean polysaccharide, gelatin; Polyvidone (for example

); Propiram; Derivatived cellulose, for example Microcrystalline Cellulose, Vltra tears are (for example ), hydroxypropylcellulose (for example ), ethyl cellulose, Natvosol, Xylo-Mucine and methylcellulose gum; Vinylformic acid and Sipacril 2739OF; Carbomer (for example

); Polyvinylpolypyrrolidone, polyoxyethylene glycol (

); Pharmaceutical glaze; Marine alga acids, for example Lalgine and sodium alginate; Natural gum, for example gum arabic, guar gum and gum arabic; Tragakanta; Dextrin and maltodextrin; Breast derivative, for example whey; Starch, for example pregelatinized Starch and starch paste; Hydrogenated vegetable oil and neusilin, and other conventional tackiness agent well known by persons skilled in the art.Exemplary non-limiting filler comprises sugar, lactose, gelatin, starch and silicon-dioxide.

Glidant can improve the mobile of incompressibility solid dosage and can improve the accuracy of administration.Glidant includes but not limited to colloid silica, vaporific silicon-dioxide, silica gel, talcum powder, Magnesium Trisilicate, Magnesium Stearate or calcium stearate, Solka-floc, starch and calcium phosphate.

Softening agent includes but not limited to hydrophobic and/or hydrophilic softening agent, for example Unimoll DA, Butyl Phthalate, ethyl sebacate, Uniflex DBS, citric acid triethyl ester, CitroflexA-2, Tributyl O-acetylcitrate, cronotic acid (Ba Dousuan), propylene glycol, Viscotrol C, triacetin, polyoxyethylene glycol, propylene glycol, glycerine and sorbyl alcohol.Softening agent can be used in particular for containing the pharmaceutical composition of polymkeric substance and be used for soft capsule and film coated tablet.

Correctives can improve palatability and can be used in particular for chewable tablets or liquid dosage form.Correctives includes but not limited to voitol, Vanillin, vanillal, mentha camphor, Citric Acid, fumaric acid, veltol plus and tartrate.Sweeting agent comprises but is not limited to sorbyl alcohol, asccharin, soluble saccharin, sucrose, aspartame, fructose, N.F,USP MANNITOL and Nulomoline.

The sanitas of improvement storage property and/or stablizer comprise but are not limited to alcohols, Sodium Benzoate, Butylated Hydroxytoluene, Butylated Hydroxyanisole and ethylenediamine tetraacetic acid (EDTA).

Disintegrating agent can increase the dissolution rate of pharmaceutical composition.Disintegrating agent includes but not limited to marine alga acids such as Lalgine and sodium alginate, calcium carboxymethylcellulose, Xylo-Mucine (Ac-Di-for example

), colloid silica, croscarmellose sodium, Crospovidone (for example

), polyvinylpolypyrrolidone (Plasone-

), guar gum, neusilin, methylcellulose gum, Microcrystalline Cellulose, polacrilin potassium, Solka-floc, starch, pregelatinized Starch, primojel (for example

).

Thinner can increase the volume of formulation and can make formulation be easier to operation.Exemplary thinner includes but not limited to: the lactose, glucose, sucrose, Mierocrystalline cellulose, starch and the calcium phosphate that are used for solid dosage such as tablet and capsule; The sweet oil and the ethyl oleate that are used for soft capsule; The water and the vegetables oil that are used for liquid dosage form such as suspensoid and emulsion.Suitable thinner in addition (for example includes but not limited to sucrose, dextrates, dextrin, maltodextrin, Microcrystalline Cellulose

), fine cellulose (microfine cellulose), Solka-floc, pregelatinized Starch (starch for example

), calcium phosphate dihydrate, soybean polysaccharide (for example

), gelatin, silicon-dioxide, calcium sulfate, lime carbonate, magnesiumcarbonate, magnesium oxide, sorbyl alcohol, N.F,USP MANNITOL, kaolin, polymethacrylate (for example

), Repone K, sodium-chlor and talcum powder.

Pharmaceutical composition is used for the embodiment of liquid dosage form by preparation therein, and pharmaceutical composition can comprise one or more solvents.The suitable solvent includes but not limited to that water, alcohol are as ethanol and Virahol, methylene dichloride, vegetables oil, polyoxyethylene glycol, propylene glycol and glycerine or its mixture and combination.

Pharmaceutical composition can comprise buffer reagent.Buffer reagent includes but not limited to lactic acid, Citric Acid, acetate, Sodium.alpha.-hydroxypropionate, Sodium Citrate and sodium acetate.

The hydrophilic polymer that is applicable to sustained release preparation comprises: one or more natural or part or all of synthetic wetting ability natural gum, for example gum arabic, tragakanta, locust bean gum, guar gum or kuteera gums; Modified-cellulose material, for example methylcellulose gum, Walocel MT 20.000PV (hydroxomethylcellulose), Vltra tears, hydroxypropylcellulose, Natvosol, carboxymethyl cellulose; Protein substance, for example agar, pectin, carrageen (glue) and marine alga acids; With other hydrophilic polymer, for example carboxypolymethylene, gelatin, casein, zein, swelling soil, neusilin, polysaccharide, modified starch derivative, and the combination of other hydrophilic polymer well known by persons skilled in the art or this base polymer.

Those of ordinary skill in the art will recognize that the multiple structure such as pearl structure and the dressing that can be used for obtaining specific releasing properties.For formulation, also the release of the known arbitrary form of those of ordinary skills may be made up.These releasing patterns comprise immediately discharge, prolong release, pulse release, variable release, sustained release, regularly discharge, slowly discharge, postpone to discharge, long-acting and combination.The ability that acquisition discharges, prolongs release, pulse release, variable release, sustained release, timing release, slowly release, delay release, long-acting characteristic and combination thereof immediately is known in the art.For example referring to U.S.6,913,768.

But, should be pointed out that the time that iodine thyronine binding substances may command iodine thyronine is gone through prolongation is discharged in the digestive tube when comparing with release combination immediately, thereby character is improved, and can under the situation that does not add above additive, reduces and/or prevent toxicity.In preferred embodiments, do not need to use other slow release additives to discharge with the iodine thyronine that obtains pharmacokinetics curve rust or that reduce and acquisition treatment significant quantity.

The dosage range that is used to be grown up will depend on multiple factor, comprise patient's age, body weight and illness and route of administration.Tablet and contain the iodine thyronine binding substances of per daily dose or its appropriate fraction with other appearance form that separation unit provides easily.The dosage that formulation can contain for about 2.5mg to about 500mg, about 10mg about 300mg, about 10mg extremely about 75mg or increment wherein of about 100mg, about 25mg extremely extremely.In preferred embodiments, formulation contains the iodine thyronine prodrug of 5mg, 10mg, 25mg, 50mg or 100mg.

Tablet and can contain one or more iodine thyronine prodrugs of per daily dose or its appropriate fraction with other appearance form that separation unit provides.

Composition of the present invention can during 24 hours with part dosage, be that fractionated dose is used one or many, used with single dose during 24 hours, using with dose double during 24 hours or using with the dosage more than the dose double during 24 hours.Fractionated dose, dose double or other multiple doses can be used during 24 hours simultaneously or at different time.These dosage can be uneven dosage mutually, perhaps for being uneven dosage for each component of different administration time.Use one time single dose preferred every day.

Equally, composition of the present invention can provide with Blister Package or other this class drug packages.In addition, the composition of theme of the present invention can also comprise or with the permission individuality composition is identified as the mark of the product that is used for the defined treatment.In addition, mark can also comprise above specified explanation of using the time bar of composition.For example, mark can be the time mark that shows in the date of using composition concrete or approximate time, and perhaps mark can be the target note that shows the date in the week of using composition.Blister Package or other combination packaging can also comprise second kind of medicament production.

Compound of the present invention can be used by multiple formulation.Known acceptable forms and the combination thereof biologically arbitrarily of those of ordinary skills all can be considered.The example of this class formulation includes, without being limited to chewable tablets, dissolving tablet, effervescent tablet, the restructural powder, elixir, liquid, solution, suspensoid in waterborne liquid or non-aqueous liquid, emulsion, tablet, syringe, multilayer tablet, bilayer tablet, capsule, Gelseal, hard-gelatin capsules, Caplet, lozenge, can chew lozenge, the pearl agent, powder, granule, granula subtilis (particles), microgranules, but dispersible granule, cachet, suppository, ointment, topical formulations, inhalation, the aerosol inhalation, patch, the particulate inhalation, implant, storage storehouse implant, can swallow agent (ingestibles), injection (comprises subcutaneous, intramuscular, intravenously and intracutaneous), infusion solution, emulsion, health stylus (health bars), confection (confections), animal-feed, cereal, yogourt, the cereal coating, food, nutritive foodstuff, functional food and combination thereof.Preferred described composition can be arbitrarily known various tablets (for example chewable tablets, conventional tablet, film coated tablet, compressed tablets), capsule, be used for the form of Orally administered liquid dispersion (for example syrup, emulsion, solution or suspensoid).

But, the most effectual way of transmitting the iodine thyronine compound of anti-abuse of the present invention (abuse-resistant) is an oral administration, to allow maximum ground release iodine thyronine that treatment validity is provided and/or slowly to discharge and the anti-abuse property of maintenance simultaneously.When by oral route is transmitted, to compare with independent iodine thyronine, the time that the iodine thyronine is preferably gone through prolongation is released in the circulation.

Preferred iodine thyronine binding substances is enough tight so that always use size and reduce.Pharmaceutically dosage form can promote to swallow easiness before the iodine thyronine of reduced size.

For Orally administered, containing the fine powder of thinner, dispersion agent and/or tensio-active agent or particle can be with a clothes form, in water or syrup, in the capsule or sachet of drying regime, can comprise in the non-aqueous suspensoid of suspending agent therein or present in the suspensoid in water or syrup.When expecting or needing, can comprise correctives, sanitas, suspension agent, thickening material or emulsifying agent.

Preferred composition of the present invention is to be suitable for Orally administered form.Usually the oral preparations of using further describes in US2003/0050344, and document integral body is incorporated herein by reference.Other oral preparations has description in American Pharmacopeia the 28th volume (2005), and can find in http://www.fda.gov/cder/dsm/DRG/drg00201.htm.

Therefore, the present invention also provides and has comprised the method that provides, uses, leaves prescription or use iodine thyronine prodrug.The present invention also provides the pharmaceutical composition that comprises iodine thyronine prodrug.The preparation of this pharmaceutical composition can randomly improve or obtain required releasing properties.

The exemplary purposes of prodrug and composition is listed in the table below among the A.

Table A

Application that prodrug is considered and combination thereof
	In the drug abuser who tricyclics is not had response, treat dysthymia disorders
The treatment raynaud's disease
	Treatment vasospasm outbreak
Strengthen the treatment of tricyclics to panic disorder
	Treat high-level astrocytoma
Treat glioblastoma multiforme with the radiation combination
	The colon Pseudo-Obstruction that treatment is caused by myxedema
The treatment septic shock
	Treatment of obesity
Auricular fibrillation behind the minimizing coronary artery bypass surgery
	Reduce behind the coronary artery bypass surgery needs to cardioversion
Reduce behind the coronary artery bypass surgery needs to anti-freezing
	Can be used as vasodilator
Can be used as the material that influences convergent force
	Strengthening selective serotonin reuptake inhibitor recovers to improve in suffering from the patient of post-traumatic stress disorder
The treatment anxious depression
	The treatment chronic schizophrenia

Treatment Kashin-Beck (the disease of Ka-Bei)
	Be used to increase the level of active and/or the TGF-β that hides
Treatment Dopamine HCL dependency shock
	Treatment mammary cancer
Increase the patient to response with the refractory dysthymia disorders of tricyclics therapy for treating
	In the patient of experience coronary artery bypass surgery, increase cardiac output
In the patient of experience coronary artery bypass surgery, reduce systemic vascular resistance
	The psychosis children of treatment below 6 years old
In suffering from the patient of acute injury, prevent central nervous system (CNS) ischemic
	Promote natural on-off cycles of hair growth
Component as the composition that can be used for the immunity system stimulation
	Improvement is by using the skin injury that radiation causes
Induce liver proliferative microenvironment in the body that helps the foreign gene transfection
	As sensitizing agent so that cancerous cells pair cell toxicant sensitivity
Use half-synchronous waves jointly with KGF with co-induction hepatocyte growth in vivo
	The directed differentiation that is used for the vitro culture thing of mammalian central nervous system stem cell
Treatment is owing to hypothyroid hyponatremia
	In showing antigenic patient, increase the lymphocyte response
Promote the maturation of kidney
	Use jointly with lithium and to eliminate Rapid Cycle type bipolar disorder
Be used for the treatment of 1 type Feng willebrand's syndrome
	The treatment myxedema coma
In suffering from the autoimmune patient of Tiroidina, treat chronic urticaria
	Treatment suffers from the patient of chronic depression
Treatment suffers from chronic dysthymic patient
	Treat the patient who suffers from dilated cardiomyopathy by increasing cardiac output
Treat the patient who suffers from dilated cardiomyopathy by increasing heart rate
	With 131The I therapy is used jointly and is treated graves' ophthalmopathy

Treatment suffers from the patient of the non-Rapid Cycle type two-phase disposition sense disease of severe form
	Treatment suffers from the patient of congenital hypothyroidism
Treatment suffers from the patient of necrotizing enterocolitis
	The treatment benign goiter
Raising is from the cardiac transplantation survival rate of donor stable on the haemodynamics
	In the antithyroid drug therapeutic process, use to reduce the body of gland quality
The treatment sporadic goiter
	The treatment headache
Be used to prevent the recurrent nodular goiter
	Use the D-Tiroidina usually to treat VI and VIa type glycogenosis
Use and be used to reduce total plasma cholesterol
	Use and be used to reduce the blood plasma low density lipoprotein cholesterol
Use and be used to reduce plasma hdl cholesterol
	The treatment Hashimoto thyroiditis
Use the D-Tiroidina and usually treat endocrine exophthalmos
	Treatment seasonal affective disorder (SAD)
In children, use and treat cretinism
	In children, use to resist hypothyroid influence
Be used to improve stenocardia
	The treatment FBD
Treat high halfcystine mass formed by blood stasis of the same race (hyperhomocysteinemia)
	The treatment hirsutism
The treatment acanthosis nigricans
	The treatment angioedema
The treatment NIHF
	Treatment distally renal tubular acidosis
Use the hyperglycemia susceptibility that increases Regular Insulin jointly with dopamine agonist and prolactin stimulator agent

Use jointly with dopamine agonist and prolactin stimulator agent and to reduce body fat storage
	Use jointly with dopamine agonist and prolactin stimulator agent and to suppress hyperinsulinemia
Use jointly with dopamine agonist and prolactin stimulator agent and to reduce hyperglycemia
	Increase potassium content in the lymphocytic cell of Mammals
Use jointly with tocotrienols and to treat diabetes
	Use jointly with tocotrienols and to treat heating
Use jointly with tocotrienols and to treat pain
	Use jointly with tocotrienols and to treat chronic fatigue syndrome
Use jointly with tocotrienols and to treat defunctionalization
	Use and be used to recover neural plasticity (neuronal plasticity) (promptly treating the sex change symptom, for example senile dementia such as alzheimer's disease, parkinson's syndrome etc.)
Active ingredient as the composition of inducing hibernation
	Be used for the treatment of mastopathy
Treat the bad inflammatory effects of some autoimmunization response
	In the baby, treat coeliac disease
Treat subacute (De Kuierwanshi) thyroiditis
	The treatment multiple organ dysfunction syndrome
Treat the cataract illness, comprise cortical cataract
	The treatment osteoporosis
The speed that can be used for accelerated wound healing
	The treatment hyperkeratosis

Should be appreciated that and to use standard pharmacology model known in the art to prove the pharmacological activity of composition of the present invention.For described each embodiment, can realize as described in the whole text one or more characteristics of this specification sheets.It should also be appreciated that described compound of this specification sheets and composition can be used for multiple new methods of treatment, reduce toxicity, improve releasing properties etc. in the whole text.Embodiment can obtain one or more binding substancess, and the iodine thyronine toxicity that it had significantly is lower than the toxicity of unconjugated iodine thyronine.

Embodiment

The arbitrary characteristics of above-mentioned embodiment can be used in combination with any further feature of above-mentioned embodiment.Can use following analytical procedure to verify the synthetic of amino acid and peptide binding substances: nucleus magnetic resonance, high resolution mass spec method or ultimate analysis and fusing point or dsc (DSC).

In order to help to understand more up hill and dale the present invention, hereinafter provide embodiment.But scope of the present invention is not restricted to disclosed in these embodiments specific embodiments, and these specific embodiments only are for illustrative purposes.For example, when embodiment relates to T3 compound and composition, should consider that the T4 compound can be produced and will provide and following T3 compound and the similar characteristic of composition.

Below be the limiting examples that can prepare according to the present invention with the preferred carrier peptides that is connected: Ala, Arg, Ash, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Ala ₂, Gly ₂, Ile ₂, Leu ₂, Lys ₂, Phe ₂, Pro ₂, Ser ₂, Thr ₂, Tyr ₂, Val ₂, Ala ₃, Gly ₃, Ile ₃, Leu ₃, Phe ₃, Tyr ₃And Val ₃

In an embodiment and in whole this patent, used following abbreviation:

G-T3=glycine-T3 binding substances

Gly-T3=glycine-T3 binding substances

Gly-T3=2-(2-glycyl amino)-3-(4-(4-hydroxyl-3-iodine phenoxy group)-3,5-diiodo-phenyl) propionic salt hydrochlorate

N=animal number

N/A=can not use

NS=does not have sample

The PO=oral route

T3=3,3,4-three iodo-Levothyroxinnatriums

The TSH=thyrotropic hormone

Embodiment 1: the preparation of amino acid succinate

Amino acid to N-protected (adds N-methylmorpholine (1.1 equivalent) and 1,3-dicyclohexylcarbodiimide (1.1 equivalent) in the solution in the 1.0 equivalent) Zai dioxs (22ml/ restrains amino acid).Under argon gas, this solution stirring is spent the night in envrionment temperature.The filtering dicyclohexylurea under reduced pressure concentrates filtrate then.In 0 ℃ with product recrystallization in acetone/hexane, drying obtains the amino acid succinate of corresponding N-protection.

Embodiment 2: the preparation of dipeptides and tripeptides succinate

Suitable amino acid (1.5 equivalent) is dissolved in N, dinethylformamide/diox/H ₂Among the O (2: 2: 1).Add the amino acid succinate (1.0 equivalent) of N-methylmorpholine (3.0 equivalent) and N-protected, under argon gas, this solution stirring is spent the night in envrionment temperature.Add ethyl acetate then, organic layer with 2% acetate, water, salt water washing, is passed through dried over sodium sulfate.Organic extract liquid is concentrated, and vacuum-drying obtains dipeptides.The synthetic method of dipeptides succinate is identical with the synthetic method of amino acid succinate.Use the method identical with synthetic dipeptides succinate to prepare the tripeptides succinate, different is makes the dipeptides succinate of suitable N-protected and amino acid reaction to form tripeptides, to be converted into succinate then.

Embodiment 3: the preparation of protected amino acid T3

In the mixture of T3 (1.0 equivalent) in dimethyl formamide (10ml), add N-methylmorpholine (2.5 equivalent) and protected amino acid succinate (1.1 equivalent).Under argon gas, this solution stirring is spent the night, under reduced pressure remove then and desolvate in envrionment temperature.Add entry, mixture was stirred 15 minutes, under reduced pressure remove then and desolvate.Crude mixture is dissolved in the ethyl acetate, with 2 ¹/ ₂Dried over sodium sulfate is passed through in % acetate (aqueous solution), salt brine solution washing.Under reduced pressure remove the solvent in the organic extract liquid, carry out purifying, obtain required product by preparation HPLC.As shown in Figure 3.

Embodiment 4: the deprotection of protected amino acid T3

Protected amino acid amphetamine binding substances is dissolved in the solution (25ml) in the 4N HCl Zai diox, under argon gas, stirs and spend the night in envrionment temperature.Under reduced pressure remove then and desolvate, obtain amino acid conjugates.

Embodiment 5: the method for preparing Gly-T3 (HCl salt)

In the reactor of 20 gallons of glass lined with single pot process reaction the having carried out preparation of medicine Gly-T3HCl.For the restraint of labour personnel contact with effective material, in shield retaining, initial reagent T3 is prepared into slurries in THF.By polyfluortetraethylene pipe the gained slurries are transferred in 20 gal reactor then.Subsequently, Boc-Gly-OSu is dissolved among the THF, transfers in 20 gal reactor, then DIEA is dissolved among the THF, also transfer in the 20-gal reactor.In envrionment temperature this suspension was stirred 15 hours, this suspension becomes settled solution.By the sample of HPLC (%AUC) mensuration collection after 15 hours, the purity that shows required compound Boc-Gly-T3 is 98.5% during the course.By adding entry, remove THF then by distillation with the reactant cancellation.Add solvent TBME then, in 5 to 10 ℃ are stirred batch of material and spend the night.With solution 20%Na ₂SO ₄/ NaHSO ₄The aqueous buffer solution acidifying.Product is extracted in TBME, at 60L Pope ^TMMerge organic layer in the bucket, use Na ₂SO ₄Dry.By 0.22 μ m strainer exsiccant solution is filtered then, join in 20 gal reactor, spend the night in 15 ℃ of stirrings.Remove TBME by distillation, carry out IPAc then and follow the trail of (adding continuously), in 15 ℃ the batch of material stirring is spent the night simultaneously.By 20 gal reactor headspaces pressurization 3 hours 30 minutes being carried out the Boc deprotection with intermediate with 30psi HCl gas.With the gained throw out at the shield retaining inner filtration, with IPAc washing, in vacuum drying oven in 35 ℃ of dryings 110 hours.Measure by GC during the course, show the IPAc that has 6.13% remnants.Therefore, with about 24 hours of metaborate monohydrate (water displacement), in vacuum drying oven in 35 ℃ of dryings 50 hours to constant weight.Material is packaged in the amber glass bottle, is placed in the polyethylene bag, store with siccative in-20 ℃.

Embodiment 6: the preparation of dipeptides T3

The synthetic method of peptide binding substances is identical with the synthetic method of amino acid conjugates, and the different suitable dipeptides succinates that are to use replace the amino acid succinate.

Embodiment 7: the preparation of tripeptides T3

The synthetic method of tripeptides binding substances is identical with the synthetic method of amino acid conjugates, makes the reaction of suitable dipeptides succinate and amino acid conjugates then, forms tripeptides.

All reagent all form when obtaining use.On Bruker 300MHz (300) or JEOL500MHz (500) NMR spectrophotometer, use tetramethylsilane to carry out as interior mark ¹HNMR.

Embodiment 8: performance study in the body

The material and the method for performance study in the body

The solid dosage oral delivery

The Sprague-dawley rat (～measured compound in 250g).Transmitted defined dosage as the capsule content.After the capsule transmission, from rat, gathered serum in 2,4,6,9,12 and 24 hours.By ELISA use the commercial reagent box (total triiodothyronine (total T3) ELISA test kit, product #1700, alpha's diagnostic companies (ALPHA DIAGNOSTIC), San Antonio TX) has measured total serum T3 concentration.By ELISA use the commercial reagent box (total thyronine (total T4) ELISA test kit, product #1100, alpha's diagnostic companies (ALPHA DIAGNOSTIC), San Antonio TX) has measured total serum T4 concentration.

Solution dosage oral delivery

The Sprague-dawley rat (～measured compound in 250g).Transmitted the defined dosage as the oral liquid in 0.5% sodium bicarbonate buffer liquid, this oral liquid has T3 sodium salt that contains 12mcgT3/kg or the triiodothyronine composition that contains equivalent T3.Behind 0 hour serum of collection, immediately rat is carried out administration.After the capsule transmission, from rat, gathered serum in 2,4,6,9,12 and 24 hours.By ELISA use the commercial reagent box (total triiodothyronine (total T3) ELISA test kit, product #1700, alpha's diagnostic companies (ALPHA DIAGNOSTIC), San Antonio TX) has measured total serum T3 concentration.By ELISA use the commercial reagent box (total thyronine (total T4) ELISA test kit, product #1100, alpha's diagnostic companies (ALPHA DIAGNOSTIC), San Antonio TX) has measured total serum T4 concentration.

Use above-mentioned universal method and obtain following experimental data.These methods can be through too small change at aspects such as timing and rat body weights.

Performance study result in the body

The amino acid of preferred T3 and the AUC and the dAUC (delta-AUC) of peptide binding substances

	T3	G-T3	V-T3	I-T3	Y-T3	A 2-T3	P 2-T3	F 2-T3
									AUC
	100	88	95	97	96	104	92	88
									dAUC	100	91	99	101	100	113	98	95

The pharmacokinetics evaluation of Orally administered T3 sodium or amino acid conjugates glycine in hypothyroid rat-total T3 in T3 HCl (G-T3) back and TSH

With T3 sodium, G-T3, V-T3, I-T3, Y-T3, A2-T3, P2-T3 or F2-T3 with etc. molar dose be applied to owing to excised the hypothyroid Sprague-Dawley rat that Tiroidina causes (12 μ g/kg T3 in one week of precontract estimating; HED～120 μ g T3 sodium; Every group of n=6).After 0 hour (before the administration), administration, gathered serum in 1,2,4,6,8 and 12 hour, by chemiluminescence immunoassay (Immulite CIA) analyzing total T3 and TSH.The pharmacokinetic parameter of total T3 and total T3 Δ (increase that 0 little base line is above) is summarised in the table 1.With compare with the animal of T3 sodium administration, in rat, observed total T3 (Fig. 4,9,11,13,17 and 19) and total T3 Δ (Fig. 5,10,12,14,18 and 20) has increase more progressively, with the slow releasing pharmaceutical kinetic property with G-T3, V-T3, I-T3, Y-T3, P2-T3 or F2-T3 administration.After administration 1 hour, mean level (ML) with total T3 of the animal of T3 sodium administration is 577ng/ml, in contrast to this, be respectively 327.3,429.5,432.7,403.3,431 and 433.1ng/ml with the mean level (ML) of total T3 of the animal of G-T3, V-T3, I-T3, Y-T3, P2-T3 and F2-T3 administration.The applicant notices that for A2-T3, can there be some changes (Figure 15 and 16) in these values.The C of total T3 of T3 sodium _MaxBe 685.5ng/dL, in contrast to this, the C of total T3 of G-T3 _MaxBe 539ng/dL.AUC with the animal of T3 sodium administration _{The most last}Value is 5230ng.h/dL, in contrast to this, uses the AUC of the animal of G-T3 administration _{The most last}Value is 4555ng.h/dL, and the bioavailability of total T3 of each compound approximately equates.Total T3 Δ parameter shows and total similar character of T3 parameter.The T of total T3 of T3 sodium _MaxBe 3.2 hours, in contrast to this, the T of total T3 of G-T3 _Max4 hours have been increased to.

Compare with T3 sodium, G-T3 is observed the AUC of total T3 and total T3 Δ _{The most last}And C _MaxVariability (CV%) reduced (table 1).It should be noted that the C of total T3 Δ of G-T3 _MaxVariability (14%) be about half of after using T3 sodium observed variability (27.9%).Draw the total T3 (Fig. 6) of each animal and the concentration curve of total T3 Δ (Fig. 7), illustrate: compare with T3 sodium, reduced from the variability of the T3 absorption of G-T3.Draw the total T3 (Figure 21) of each animal and the binding substances concentration curve of total T3 Δ (Figure 22), illustrate: compare with T3 sodium, reduced from the variability of the T3 absorption of G-T3, V-T3, I-T3, Y-T3, P2-T3 and F2-T3.

The TSH horizontal respone reduces rapidly in G-T3, V-T3, I-T3, Y-T3, P2-T3, A2T3, F2-T3 or using of T3 sodium, and demonstrates similar pharmacokinetic property (Fig. 8 and 23-29).Level reduces rapidly after after the administration 1 hour, and continues to descend until 6 hours.The TSH of each compound little increase occurred from 8 hours level to 12 hour levels.

When comparing with T3 sodium, G-T3 provides the delay of T3 to discharge, and with total T3C _MaxReduction, T _MaxThe bioavailability that increases and approximately equate.G-T3 has reduced the C of total T3 and total T3 Δ _MaxAnd AUC _{The most last}Variability.In response to using of G-T3 or T3 sodium, having observed the TSH level has similar reduction.

Prodrug of the present invention can be used as hypothyroid Hormone Replacement Therapy.For example, prodrug such as Gly-T3 will preferably provide the bioavailability suitable with T3 sodium, still, for the release immediately of T3 sodium, have the T3 peak level of slower uptake rate and reduction.Preclinical study is verified: prodrug of the present invention has the absorption of delay, the C of reduction when comparing with T3 sodium in rat _MaxWith the bioavailability that approximately equates.

The total T3 of table 1. and total T3 Δ pharmacokinetic parameter

Parameter	T3 sodium	G-T3
			C max(ng/dL)	685.5+/-178.6	539+/-63.9
CV％	26.1	11.9
			％T3	100	79
Low-Gao	484-915	459-625
			Scope	431	166
C maxΔ(ng/dL)	629.8+/-178.6	490.4+/-68.6
			CV％	27.9	14
％T3	100	78
			Low-Gao	444-875	403-534
Scope	431	131
			AUC The most last(ng.h/dL)	5230+/-821	4555+/-450
CV％	16	9.9
			％T3	100	89
Low-Gao	4292-6421	3766-5072
			Scope	2129	1306
AUC The most lastΔ(ng.h/dL)	4461+/-808	3971+/-481
			CV％	18.1	12.1
％T3	100	89
			Low-Gao	3688-5526	3088-4454
Scope	1838	1366
			T max	3.2+/～1.8(1-6)	4.0+/-2.2(2-6)
CV％	56	55
			％T3	100	125
Low-Gao	1-6	2-6
			Scope	5	4

Total T3 (ng/dL) of solitary animal behind the Orally administered T3 sodium of table 2.

Time (h)	1	2	3	4	5	6	On average	SD	CV％
											0	0.0	0.0	89.4	0.0	50.3	74.6	35.7	41.1	115.0
1	523.0	432.0	650.0	605.0	517.0	735.0	577.0	108.3	18.8
										2	585.0	452.0	595.0	915.0	377.5	890.0	635.8	222.4	35.0
4	630.0	426.5	530.0	600.0	544.0	610.0	556.8	74.7	13.4
										6	550.0	484.0	292.0	259.0	343.0	346.0	379.0	113.7	30.0
8	391.0	390.0	276.5	225.0	316.0	550.0	358.1	114.1	31.9
										12	442.0	245.0	353.0	NS	231.0	376.0	329.4	89.7	27.2
AUC The most last (ng.h/dL)	5817.5	4591.0	4766.7	3920.5	4292.4	6421.3	4968.2	956.0	19.2
										C max (ng/dL)	630	484	650	915	544	890	685.5	178.6	26.1
T max(h)	4	6	1	2	4	2	3.2	1.8	56.3

Total T3 (ng/dL) of solitary animal behind the Orally administered G-T3 of table 3.

Time (h)	1	2	3	4	5	6	On average	SD	CV％
											0	56.5	0.0	0.0	51.1	51.5	52.7	35.3	27.4	77.6
1	309.5	314.0	310.0	308.5	351.5	370.0	327.3	26.7	8.1
										2	390.5	625.0	520.0	585.0	555.0	361.5	506.2	107.0	21.1
4	269.5	410.5	499.0	401.5	476.5	358.0	402.5	83.1	20.6
										6	459.0	497.0	536.0	533.0	354.0	474.0	475.5	67.0	14.1
8	377.0	360.0	328.0	452.0	553.0	454.0	420.7	82.2	19.5
										12	127.0	231.0	175.0	222.0	271.0	252.0	213.0	53.2	25.0
AUC The most last (ng.h/dL)	3765.5	4608.5	4494.0	4880.6	5071.8	4468.6	4548.2	449.5	9.9
										C max (ng/dL)	459	625	536	585	555	474	539.0	63.9	11.9
T max(h)	6	2	6	2	2	6	4.0	2.2	54.8

Total T3 Δ (ng/dL) of solitary animal behind the Orally administered T3 sodium of table 4.

Time (h)	1	2	3	4	5	6	On average	SD	CV％
											0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0
1	483.0	392.0	560.6	565.0	466.7	660.4	521.3	93.8	18.0
										2	545.0	412.0	505.6	875.0	327.2	815.4	580.0	219.7	37.9
4	590.0	386.5	440.6	560.0	493.7	535.4	501.0	76.7	15.3
										6	510.0	444.0	202.6	219.0	292.7	271.4	323.3	125.3	38.8
8	351.0	350.0	187.1	185.0	265.7	475.4	302.4	112.2	37.1
										12	402.0	205.0	263.6		180.7	301.4	270.5	87.5	32.3
ΔAUC The most last (ng.h/dL)	5367.5	4131	3693.9	4360.5	3688.8	5526.1	4461.3	807.5	18.1
										ΔC max (ng/dL)	590	444	560.6	875	493.7	815.4	629.8	175.5	27.9
T max(h)	4	6	1	2	4	2	3.2	1.8	56.3

Total T3 Δ (ng/dL) of solitary animal behind the Orally administered G-T3 of table 5.

Time (h)	1	2	3	4	5	6	On average	SD	CV％
											0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0
1	253.0	274.0	270.0	257.4	300.0	317.3	278.6	25.1	9.0
										2	334.0	585.0	480.0	533.9	503.5	308.8	457.5	111.4	24.3
4	213.0	370.5	189.0	350.4	425.0	305.3	308.9	92.3	29.9
										6	402.5	457.0	496.0	481.9	302.5	421.3	426.9	70.4	16.5
8	320.5	320.0	288.0	400.9	501.5	401.3	372.0	78.6	21.1
										12	70.5	191.0	135.0	170.9	219.5	199.3	164.4	54.2	33.0
ΔAUC The most last (ng.h/dL)	3087.5	4148.5	4034	4267.4	4453.8	3836.2	3971.2	480.7	12.1
										ΔC max (ng/dL)	402.5	585	496	533.9	503.5	421.3	490.4	68.6	14.0
T max(h)	6	2	6	2	2	6	4.0	2.2	55.0

The TSH (μ IU) of solitary animal behind the Orally administered T3 sodium of table 6.

Time (h)	1	2	3	4	5	6	On average	SD	CV％
											0	1.840	2.296	2.088	2.480	1.884	2.572	2.193	0.306	14.0
1	1.680	1.796	1.924	2.580	1.868	2.344	2.032	0.351	17.3
										2	1.264	1.284	0.920	1.116	1.080	1.180	1.141	0.134	11.7
4	0.240	0.252	0.252	0.204	0.200	0.312	0.243	0.041	16.9
										6	0.116	0.140	0.136	0.120	0.120	0.160	0.132	0.017	12.9
8	0.080	0.156	0.152	0.132	0.108	0.188	0.136	0.038	27.9
										12	0.120	0.260	0.256	NS	0.416	0.300	0.270	0.106	39.3

The TSH of solitary animal (μ IU) behind the Orally administered G-T3 of table 7.

Time (h)	1	2	3	4	5	6	On average	SD	CV％
											0	1.680	2.584	2.304	1.956	1.860	1.740	2.021	0.353	17.5
1	2.660	2.564	2.392	1.960	1.612	1.400	2.098	0.522	24.9
										2	1.340	1.472	1.648	1.160	1.104	1.008	1.289	0.243	18.9
4	0.364	0.352	0.296	0.216	0.276	0.248	0.292	0.058	19.9
										6	0.232	0.172	0.152	0.112	0.205	0.100	0.162	0.052	32.1
8	0.232	0.172	0.136	0.124	0.168	0.076	0.151	0.053	35.1
										12	0.540	0.612	0.224	0.548	0.268	0.372	0.427	0.162	37.9

Table 8.T3 in contrast to T3 binding substances-total T3 (ng/dL) and in contrast to the time

Time (h)	T3	G-T3	V-T3	I-T3	Y-T3	A2-T3	P2-T3	F2-T3
									0	71.4	53	54.1	54	50.7	42.2	45.7	40
1	577	327.3	429.5	432.7	403.3	609.3	431	433.1
									2	635.8	506.2	532.8	531.8	493.5	611.3	592.1	480.8
4	556.8	402.5	466.5	551.9	568.8	525.1	515.5	467.7
									6	379	475.5	415.6	378.3	467.8	468.6	501	438.2
8	358.1	420.7	461.5	385.6	378.5	414	314.3	367.5
									12	329.4	213	250.3	361	280.8	310.8	226.6	238.2
AUC	5171	4557	4905	4997	4939	5398	4771	4565
									％	100	88.1	94.9	96.6	95.5	104.4	92.3	88.3

Table 9.T3 in contrast to T3 binding substances-total T3 Δ (ng/dL) and in contrast to the time

Time (h)	T3	G-T3	V-T3	I-T3	Y-T3	A2-T3	P2-T3	F2-T3
									0	0	0	0	0	0	0	0	0
1	505.6	274.3	375.4	378.7	352.6	567.1	385.3	393.1
									2	564.4	453.2	478.7	477.8	442.8	569.1	546.4	440.8
4	485.4	349.5	412.4	497.9	518.1	482.9	469.8	427.7
									6	307.6	422.5	361.5	324.3	417.1	426.4	455.3	398.2
8	286.7	367.7	407.4	331.6	327.8	371.8	268.6	327.5
									12	258	160	196.2	307	230.1	268.6	180.9	198.2
dAUC	4314.3	3,921.20	4255.9	4348.6	4330.8	4892	4222.7	4085
									％	100	90.9	98.6	100.8	100.4	113.4	97.9	94.7

Table 10.T3 in contrast to T3 binding substances-TSH (μ IU) and in contrast to the time

Time (h)	T3	G-T3	V-T3	I-T3	Y-T3	A2-T3	P2-T3	F2-T3
									0	2.193	2.021	2.309	2.331	2.595	2.459	2.988	3.035
1	2.032	2.098	2.212	2.218	2.648	2.11	2.438	2.192
									2	1.141	1.289	1.123	1.203	1.601	0.889	1.363	1.364
4	0.243	0.292	0.282	0.351	0.471	0.292	0.346	0.405
									6	0.132	0.162	0.174	0.169	0.27	0.174	0.21	0.246
8	0.136	0.151	0.175	0.131	0.221	0.182	0.189	0.242
									12	0.27	0.427	0.54	0.271	0.651	0.381	0.735	0.757

Claims (35)

1. the composition that comprises at least a peptide iodine thyronine or its salt and at least a non-peptide iodine thyronine or its salt.

2. the composition of claim 1 comprises Gly-T3 or its salt and T4 or its salt.

3. the composition of claim 1 comprises Gly-T4 or its salt and T3 or its salt.

4. composition comprises Gly-T3 or its salt and Gly-T4 or its salt.

5. treat the method for thyroid disease, this method comprises to people patient's Orally administered iodine thyronine prodrug or its salt, wherein said prodrug comprises the terminal covalently bound independent iodine thyronine with the C-of peptide carrier, and wherein carrier peptides is less than 5 amino acid.

6. the method for claim 5, wherein said iodine thyronine is T3.

7. the method for claim 5, wherein said iodine thyronine is T4.

8. the method for claim 6, wherein said carrier peptides is independent amino acid.

9. the method for claim 6, wherein said carrier peptides is Gly, Lys, Glu, Ile, Tyr, Val, Ala-Ala, Pro-Pro, Glu-Glu or Phe-Phe.

10. the method for claim 8, wherein said prodrug is a salt form.

11. the method for claim 8, wherein said salt form are HCl salt, acetate, vitriol, mesylate, citrate, phosphoric acid salt or tartrate.

12. the method for claim 8, wherein said salt form are HCl salt.

13. the method for claim 8, wherein said prodrug are Gly-T3 or its salt.

14. the method for claim 8 or 13, wherein said illness is a hypothyroidism.

15. the method for claim 8 or 13, wherein said illness is a dysthymia disorders.

16.Gly-T3。

17.Ile-T3。

18.Tyr-T3。

19.Ala-Ala-T3。

20.Val-T3。

21.Pro-Pro-T3。

22.Phe-Phe-T3。

23.Gly-T4。

24.Ile-T4。

25.Tyr-T4。

26.Ala-Ala-T4。

27.Val-T4。

28.Pro-Pro-T4。

29.Phe-Phe-T4。

30.T4-Glu。

31.T4-Glu-Glu。

32.T4-Lys。

33.Glu-T4。

34.Glu-Glu-T4。

35.Lys-T4。

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