CN1946401A - Alkaloid formulations - Google Patents

Abstract

There is provided an alkaloid formulation comprising the reaction product of one or more alkaloids with one or more phosphate derivatives of one or more electron transfer agents.

Description

Alkaloid formulations

Technical field

The present invention directly relates to and comprises one or more alkaloidal preparations.Be particularly related to (but being not limited to) and contain the preparation of one or more alkaloids and one or more phosphate derivatives of electron transfer agents.

Background technology

In this description for document, behavior or knowledge to quote or discuss not be to admit that the document, behavior or knowledge or its combination in any are preferential day the time: the part of known knowledge, or the solution of the problem that relates to of known and this description is relevant.

Alkaloid

Alkaloid is as medicinal with a long history.These chemical compounds extract from plant at first, comprise that those have the nitrogen compound of physiological action to the people as medicine and drugs.The term that uses in this specification and claims book " alkaloid " (alkaloid) comprises that all comprise the substituent natural or synthetic reactive compound of primary amine, secondary amine or tertiary amine.Amido can be added in one or two ring, in still non-ring structure is also included within.For example, comprising:

Tertiary amine, it is:

Alicyclic (for example: morphine, atropina, quinine) of three shared nitrogen-atoms of ring; Or

Nitrogen added monocycle and by alkylating circulus (for example: nicotine or fenspiride); Or

The acyclic of adding nitrogen (for example: hydrochloric acid fluorine amine);

The secondary amine that nitrogen is added alicyclic structure (for example: Conline, fendiline) or linear structure (for example: epinephrine);

Primary amine (for example: ephedrine);

Pyridine (for example: nicotine);

Carbonamidine (Methamidine) derivant;

Quinoline (for example: cinchonine);

Guanidine (for example: arginine)

Most of alkaloids are all water insoluble but be dissolved in organic solvent.But all alkaloids all are also can combining with acid of alkalescence forms crystal salt, and this salt is partially soluble in water usually at least.Usually, alkaloid oral or intravenous injection with the form of salt.Alkaloid is the general not medicine of transdermal administration of a class, and this is because the hydrophilic nmature of salt can limit Transdermal absorption usually.For example morphine and atropina are exactly to use in clinical but do not adopt the alkaloid of transdermal administration.In addition, owing to alkaloid is considered to work by lymphsystem, so the alkaloidal oral administration route of expectation improvement.

Topical

Topical is meant directly medicament administration is arrived certain position of health, comprises transdermal administration (being administered on the skin) and buccal (using in the oral cavity).

Skin is the organ of human body maximum, and its function is that the protection internal is not injured by outside chemistry, physics and pathology.Normal skin is divided into three layers: epidermis, corium and subcutaneous tissue.The outside keratinization layer of epidermis is that horny layer has intensity, pliability, high resistance and dry attribute, stops the intrusion and the breeding of microorganism.Horny layer still is the major obstacle of Transdermal absorption.

The transdermal administration technology comprises the independent application of medicine and as the application of preparation, described preparation contains the material that can improve percutaneous absorption rate usually.Transdermal administration Ceng Zuowei ointment, ointment, paste, plaster use in history, so that effectively contact with skin.Afterwards, this technology was through improving, and plaster made " patch " and made it can adhere on the skin better and can control transmission rates better.

It has been recognized that transdermal administration has some potential advantages, these advantages comprise: the level that blood Chinese medicine concentration is reached near slowly vein injection does not but have vein to inject the inconvenience that brings; Compare with oral, better control absorbs and metabolism; Lasting medicine is particularly for short medicine of half-life; Owing to walked around liver first-pass effect, therefore reducing drug dose also can reach equal curative effect; Propellant quantity not sufficient or excessive risk are low; Simplification by dosage regimen obtains better patient dependence.

Be not that all medicines can both reach the medicative blood drug level of systematic treating with sufficiently high speed transdermal administration.For example, molecular weight may be with different speed Transdermal absorption with the approaching medicine of molecular size.Developed the Transdermal absorption that skin promoting agent (skinenhancer) and various preparation technique improve medicine.But caused the concern of people, because the raising of medicine permeability is a cost to destroy the extremely important protective layer of skin to long-term risk.

The various schemes of current improvement transdermal treatments are not success fully also, remains in further improved space.Particularly need to transport the application of alkaloidal transdermal drug delivery system.

People are also increasing to the interest of buccal administration, because the liver metabolism problem that this instructions of taking can produce when having avoided oral drugs.Usually, medicine is made lozenge and place the Sublingual.The oral cavity interior surface layers is not equivalent to the structure of keratodermatitis, therefore the buccal administration is not difficult, and still, this method is not generally adopted, this is because if oral film does not allow to see through or active transport, and transmitance may be lower and can not obtain effective result.For example, international patent application no PCT/AU03/00998 has disclosed a kind of pharmaceutical carrier, this carrier comprises the complex (complex) of the phosphate derivative of medicinal acceptable chemical compound, for example, the amino dipropionic acid tocopheryl phosphate (laurylaminodipropionic acidtocopheryl phosphates) of lauryl alcohol.PCT/AU03/000998 has disclosed tocopheryl phosphate and chelating agent complexation, and described chelating agent is selected from: amphoteric surfactant, cationic surfactant, have the aminoacid of nitrogen functional group and be rich in these amino acid whose protein.Shown that this carrier can improve the topical of Testosterone, estrogen, atropina and morphine.But,, also need further to improve skin and see through for morphine and atropina.

Oral administration

Many medicines all are that employing is oral, are given it up owing to can not pass intestinal wall but large quantities of potential useful medicines are arranged.Be appreciated that material such as fat can see through intestinal wall effectively and transport, transport but have many materials such as tocopherol just to be difficult to see through intestinal wall.Therefore be necessary to provide a kind of drug-supplying system that can improve the alkaloid oral result.

Summary of the invention

Have been found that: when alkaloid compound directly was complexed to the phosphate derivative of electron transfer agent, administering effect can be significantly increased.For example, after morphine directly was complexed to tocopheryl phosphate (tocopheryl phosphate), its administering effect improved.

The invention provides a kind of alkaloid formulations, comprise the product of one or more multiple phosphate derivatives of one or more multiple alkaloids and one or more multiple electron transfer agents.

Preferably, the phosphate derivative of described electron transfer agent is selected from: the phosphoric acid derivatives of one or more tocopherols.

Preferably, described alkaloid formulations is topical or oral administration.

A second aspect of the present invention has provided a kind of method that improves the alkaloid curative effect, and the step that this method comprises has: one or more phosphate derivatives of described alkaloid and one or more electron transfer agents are reacted.

The present invention also provides the product and the application of excipient in preparation is produced of one or more phosphate derivatives of one or more alkaloids and one or more electron transfer agents.

The present invention also provides a kind of pharmaceutical composition, comprises a kind of product that comprises one or more alkaloids and a kind of or a kind of one or more phosphate derivatives with electron transfer agent (for example phosphate derivative of tocopherol).

Preferably, alkaloid is selected from following tertiary amine:: alicyclic (for example: morphine, atropina, quinine) of (1) three shared nitrogen-atoms of ring; (2) nitrogen is added monocycle and by alkylating ring (for example: nicotine or fenspiride); Or (3) do not have contain nitrogen circulus (for example: hydrochloric acid fluorine amine).Preferred, described alkaloid is by comprising atropina, quinine, opioids (as morphine), fentanyl, nicotine, fenspiride, hydrochloric acid fluorine amine and codeine.

Term " electron transfer agent " in this article refers to a class and can be accepted an electronics by phosphorylation and (in the non-phosphorylating form) and generate metastable molecular radical or accept two electronics and make it can participate in the chemical substance of reversible oxidation-reduction system.Can be comprised by the electron transfer immunomodulator compounds of phosphorylation: hydroxyl chromanane (hydroxy chromans) comprises α, β, γ and the δ tocol of isomer and racemization form; The hydroquinone of vitamin K1 and coenzyme Q10 reduction form; The hydroxy kind carotene (hydroxycarotenoid) that comprises retinol; Ergocalciferol and ascorbic acid.Preferably, described electron transfer agent is selected from: tocopherol and other tocols, retinol, vitamin K1 and their mixture.Preferred, described electron transfer agent is selected from mother and educates alcohol and composition thereof.Described tocol comprises whole isomers of 6-hydroxy-2-methyl chromanane (referring to following structural formula) derivant, R in the formula ₁, R ₂, R ₃Can be hydrogen or methyl, that is, and α-5,7,8 trimethyls, β-5,8 dimethyl, γ-7,8 dimethyl; δ 8 methyl-derivatives.In tocopherol, R ₄By 4,8,12 trimethyl tridecyls replace, and comprise various stereoisomers and optical isomer (chiral centre is represented with *).In tocotrienol, R ₄By 4,8,12 trimethyls (just) 13 (carbon) alkane-3,7, the three-dimensional activity that 11 trialkenyl replace and 2 can have as R or S stereoisomer.Most preferred, described electron transfer agent is an alpha-tocopherol.

Term " phosphate derivative " thus in this article refer to the chemical compound that phosphorus atoms covalent bond by oxygen and phosphate group forms carbon-oxygen-phosphorus key.Described oxygen atom is normally derived by the hydroxyl on the electron transfer agent.This term comprises: the sour form of phosphorylation electron transfer agent, comprise the phosphate of slaine (as sodium, magnesium, potassium, calcium), and the derivant that replaced by other substituent groups (as ethyl, methyl or phosphatidyl etc.) of other phosphate protons.This term comprises the mixture of phosphate derivative, particularly phosphorylation reaction product, and independent various phosphate.For example, this term comprises the mixture of single tocopheryl phosphate (TP) and two tocopheryl phosphate (T2P) and independent TP and T2P.The mixture that is fit to is stated in international patent application no PCT/AU01/01475.

Term " phosphate derivative " does not comprise the complex of phosphate derivative and chelating agent, and described chelating agent is selected from: amphoteric surfactant, cationic surfactant, have nitrogen functional group's aminoacid and be rich in the protein of this seed amino acid.

Preferably, one or more phosphate derivatives of described one or more electron transfer agents are selected from single tocopheryl phosphate (TP) and two tocopheryl phosphate (T2P) and composition thereof.More preferably, one or more phosphate derivatives of described one or more electron transfer agents are mixture of single tocopheryl phosphate (TP) and tocopheryl phosphate (T2P).

In some cases, may use the phosphate derivative as phospholipid, its additional character (as better water-solubility) is preferred.Phosphatidyl derivant is the aminoalkyl derivant of organic phosphate.These derivants can be from having R ₁R ₂N (CH ₂) _nThe amine preparation of OH structure, wherein n is the integer between 1 to 6, R ₁And R ₂Both can be that H has 3 or less than the short alkyl chain of 3 carbon atoms.R ₁And R ₂Can be the same or different.The preparation method of phosphatidyl derivant is: with the hydroxyl proton and the conversion of phosphate entity of electron transfer agent, generate the phosphatidyl derivant of electron transfer agent then with certain amine (as ethanolamine or N, N ' dimethylethanolamine) reaction.A kind of method for preparing phosphatidyl derivant is to utilize basic solvent (as pyridine or triethylamine) and phosphorous oxychloride to prepare intermediate product, the hydroxyl reaction of intermediate and amine generates the corresponding phospholipids acyl derivative then, as P cholyl P tocopherol dihydrogen orthophosphate.

This alkaloid formulations can be applied to the human or animal by various dosage form modes, as additive, Elental, intravenous injection, suppository, nasal-cavity administration mode, percutaneous drug delivery mode (comprising patch and emulsifiable paste), buccal administering mode.Oral or buccal administering mode is particularly suitable for having the alkaloid of low aqueous solubility.

Preferably, oral alkaloid formulations of the present invention also comprises enteric coating.Oral formulations can be tablet, powder, chewing agent, capsule, oral suspensions, suspensoid, Emulsion or liquid agent, child's preparation, Elental, nutraceutical, functional food.

Above-mentioned dosage form mode also can further comprise the additive that when preparation is commonly used, as starch or polymeric binder, sweeting agent, go up toner, emulsifying agent, coating etc.The another kind of additive that is fit to is the complex of the phosphate derivative of electron transfer agent, need to be used to the situation of some additional character (as stability and transporting property).Term " complex of phosphate derivative " is meant the product of the phosphate derivative of one or more chelating agent and one or more electron transfer agents, as in this manual with reference to disclosed among the international patent application no PCT/AU01/01476 that quotes, described chelating agent is selected from amphoteric surfactant, cationic surfactant, has the aminoacid of nitrogen functional group and is rich in these amino acid whose protein.If use this kind additive, importantly guarantee to have excessive electron transfer agent in the preparation.Other additives that are fit to it will be apparent to those skilled in the art that.

Description of drawings

Fig. 1 is the influences of various atropinas to the heart rate of pig.Data are to the cumulative mean value during 10 minutes, and have adopted the co-variation analysis that base value has been carried out proofreading and correct (average 1h before the administration).

Fig. 2 is the typical differential of heart rate to time graph.The pig 1 (that is employed first pig) that data are handled through formulation C during from parallel laboratory test 1.Processing started from 0 minute and had continued 6 minutes.Straight line represents that integration is by during after average.

Fig. 3 is the effects of various substrate unguentum to the heart rate of pig.Data are to cumulative mean during 10 minutes, and utilize the co-variation analysis through overcorrect base value (basal).

Fig. 4 is that typical heart rate is to time graph.The pig 1 (that is employed first pig) that data are handled through formulation C during from parallel laboratory test 1.Processing started from 0 minute and had continued 6 minutes.Straight line represents that integration is by during after average.

Fig. 5 uses the treatment effect after the thermal probe and contracts the pawl response time.

Fig. 6 be morphine 1.35,2.7 and 5.4mg/kg in the TPM-01/M preparation to the influence of the pawl response latency that contracts, Therapy lasted 8 hours.

The specific embodiment

Below with reference to non-limiting example embodiments of the invention/aspect is elaborated.

Example 1

This case study atropina preparation of the present invention carries out transdermal administration to pig.This experimentation the transdermal administration of the atropina used with the gel form to the influence of the heart rate of pig.

Method and material

Atropina (20mg/kg) is prepared in following substrate unguentum, is used for experiment.Except following special component, all contain following composition in all unguentum: 12% Ultrez 10Carbomer-3% solution, 0.25% triethanolamine, 0.1%Surcide DMDMH and be up to 100% deionized water.

Compositions f, H and J and atropina combination results preparation of the present invention.Compositions B, D and E produce existing preparation, and compositions A, C and I show the effect of excipient.

Code	Component
		A	1.27％Deriphat 160
B	40% TP disodium lauryliminodipropionate and the di(2-ethylhexyl)phosphate tocopherol of 40%disodium lauryliminodipropionate monotocopheryl phosphate and lauryliminodipropionate ditocopheryl phosphate 7.5%
		C	0.77% arginine
D	7.5% 40% argininephosphoric acid list tocopherol and argininephosphoric acid two tocopherols
		E	7.5% 40% argininephosphoric acid list tocopherol
F
		3% TP
G
		3% TP and di(2-ethylhexyl)phosphate tocopherol
H			7.5% TP disodium lauryliminodipropionate
	I	1.5% triethanolamine
J			Tocopheryl phosphate and di(2-ethylhexyl)phosphate tocopherol

Used 10 male hybrids (Large White x Land race) pig (just making average weight 51.5kg, final average weight 61.0kg) in this experiment.Preceding 4 days of research beginning with 14 only a pig weigh and be assigned randomly in the individual pen in experiment base that (1.75m * 0.65m) carries out environmental adaptation.Use animal shears (U.S. produces Oster) to wipe out the dorsal body setae of pig during this period, use electric shaver (Philishave HQ5041-Philips Aust Pty company) regularly to shave hair then.Placing elastic webbing around the chest of pig makes it adapt to heart rate monitor.When beginning experiment, select ten environment and operation adapted to best pig and with its overlap, no longer include pig near the circle making.The signal that separation on this health has been avoided may existing between the heart rate monitor of working under the same frequency disturbs.These ten pigs are divided into two groups, and five every group (single even numbers) also are used alternatingly by the sky in experiment.Therefore per two treatment day is carried out a repeated experiments continuously.These 10 pigs are randomized to either in ten treatment groups in each repeated experiments, and therefore every pig all is used for data capture by 5 times, and each treatment all repeats 5 times.

5 pigs that will experimentize about when each measures day 08:00 are weighed, and Cardio kickboxing is installed and is begun interval recorded heart rate with 1 minute.The end user catches heart rate data with heart rate monitor (Polar Sport Tester PE4000-Polar Electro Finland).The pectoral girdle that will have built-in sensors and a transmitter is strapped in the position, front behind the pig foreleg.Pick off contact area on these bands has applied enough ultrasound wave glue (Virbac Aust Pty Ltd), so that guarantee to obtain good heart rate signal.Be placed with second band that the wide elasticity Velcro of 100mm is made around the transmitter band.During writing down, this band protection transmitter is not damaged, and has one and be used for depositing the unitary pocket of monitor records (being similar to wrist-watch).Shave only with a zone of electric shaver and pig back then.Use a template and permanent marker in this zone, to sketch the contours of 172.5cm ²(75 * 230mm) rectangle treatment region.Then with the 100g/kg live-weight ^0.75(for example: 55kg pig=2020g/ days).Opening entry heart rate begin treatment after at least 1 hour.Three relevant personnel wear the proof rubber glove and use each experimental preparation with the 5ml syringe.This work comprises rubs skin into pig with product, and assistant blows to area for treatment with the warm braw of hair drier simultaneously.Approximately 8-10 minute skin surface touches and stops to rub when being clamminess.(10 * 12cm) transparent binders (Tegaderm-3M Health Care USA) place on the area for treatment with 3 then.Treatment after handling stays pig not to its disturbance, keeps 6-7 hour record cycle.Before and after implementing, the syringe and the glove that use in the treatment are weighed, so that guarantee that the actual true Rapid Dose Calculation that is applied on the pig is accurate.During the record end cycle, heart rate monitor and transparent binder are removed, and use the warm water that contains a small amount of handwashing liquid that area for treatment is cleaned.

The result

The various atropina preparations of table 1. were to the influence of average heart rate at interval in 60 minutes

	A	B	C	D	E	F	G	H	I	J	sed	x 2
													Heart rate (bpm)
-60-0 minute	148	147	148	154	148	152	151	149	150	146	5.52	0.916
													0-60 minute	173	155	176	155	165	162	180	170	155	154	9.33	0.007
60-120 minute	186	170	184	169	170	175	196	190	164	165	10.91	0.011
													120-180 minute	161	156	162	154	148	165	168	171	144	153	10.46	0.124
180-240 minute	145	148	146	149	139	156	152	164	144	149	9.87	0.353
													240-300 minute	144	146	150	142	147	147	146	155	139	136	7.93	0.471
300-360 minute	143	142	144	131	137	142	147	150	135	136	7.60	0.271
													Difference (bpm) with baseline
0-60 minute	24.2	8.7	28.5	1.1	16.1	10.3	30.7	20.0	4.9	7.1	10.41	0.021
													60-120 minute	37.8	22.8	35.6	14.1	21.7	22.6	46.8	40.9	13.2	19.0	12.58	0.045
120-180 minute	13.0	8.9	13.2	-1.4	-0.8	12.8	20.1	21.2	-6.8	8.0	11.71	0.196

The various atropina preparations of table 2 were to the influence of average heart rate at interval in 60 minutes

	A	B	C	D	E	F	G	H	I	J	sed	x 2
													Log peakedness ratio (bpm)	2.341	2.307	2.33	2.29	2.313	2.326	2.351	2.321	2.301	2.288	0.0233	0.078
	(219)	(203)	(214)	(195)	(206)	(212)	(224)	(209)	(200)	(194)
													Log time peak value min)	1.790	1.904	1.762	1.872	1.726	1.787	1.738	1.734	1.764	1.786	0.0953	0.452
	(61.7)	(80.2)	(57.8)	(74.5)	(53.2)	(61.2)	(54.7)	(54.2)	(58.1)	(61.1)
													The Log rate of rise 1	0.125	0.003	0.171	-0.060	0.061	0.229	0.434	0.250	0.211	0.117	0.1568	＜0.001
	(1.33)	(1.01)	(1.48)	(0.87)	(1.15)	(1.69)	(2.72)	(1.78)	(1.62)	(1.31)
													The Log descending slope 1，2	-0.244	-0.312	-0.206	-0.124	-0.186	-0.393	-0.375	-0.427	-0.299	-0.049	0.1095	＜0.001
	(0.57)	(0.49)	(0.62)	(0.75)	(0.65)	(0.40)	(0.42)	(0.37)	(0.50)	(0.89)
													Slope Log ratio 2	0.354	0.292	0.393	0.072	0.264	0.624	0.808	0.680	0.495	0.196	0.2052	＜0.001
	(2.26)	(1.96)	(2.47)	(1.18)	(1.84)	(4.21)	(6.43)	(4.79)	(3.13)	(1.57)

¹Unit is the bpm per minute ², unit should be negative value, but multiply by-1 so that carry out logarithmic transformation

The various substrate unguentum of table 3. preparation was to the influence of average heart rate at interval in 60 minutes

	A	B	C	D	E	F	G	H	I	J	sed	x 2
													Heart rate (bpm)
-60-0 minute	146	147	147	143	145	127	145	135	124	132	11.1	0.283
													0-60 minute	139	140	129	144	138	123	142	120	123	128	10.7	0.141
60-120 minute	125	132	124	137	134	122	139	120	120	132	10.9	0.587
													120-1 80 minutes	128	126	126	131	135	119	130	125	119	124	6.7	＜0.001
180-240 minute	125	121	132	134	129	121	132	122	114	122	8.7	0.358
													240-300 minute	137	122	130	132	120	112	139	130	121	122	9.0	0.040
300-360 minute	131	120	1 32	127	116	110	134	126	110	125	6.0	＜0.001
													Difference (bpm) with baseline
0-60 minute	-4.4	-5.1	-16.5	1.4	-6.6	-6.3	-2.7	-12.5	-0.9	-5.8	6.16	0.162
													60-120 minute	-16.7	-15.3	-20.1	-3.8	-10.3	-7.0	-6.5	-13.7	-5.5	-4.4	11.44	0.708
120-180 minute	-15.0	-16.0	-21.1	-9.9	-9.8	-9.8

Discuss and conclusion

Data show that the atropina transdermal administration can increase the heart rate of pig, and peak value approximately occurs in uses back 60 minutes.Data show that also basic cream itself can not increase heart rate, and the influence of prepared product comes free atropina itself.

The preparation G that contains tocopheryl phosphate/T2P mixture provides the best system that transports for atropina.Heart rate is accelerated and is compared the persistent period that has kept longer with other preparations.This embodies in Fig. 1 to some extent, the numerical value maximum of G in 0-60 minute and 60-120 minute under " with the difference of baseline " title.It is more effective that table 1 shows that preparation G contains the atropina of the similar concentration in the compositions of lauryliminodipropionate-tocopheryl phosphate consistently.

Data evaluation in the table 2 demonstrates preparation G Log peak value digit rate, Log time of preparation H is had consistent heightening the effect of a treatment to peak value and the important Log rate of rise and Log descending slope.

Also have, preparation of the present invention can not cause inflammation, therefore it seems might allow the contact skin of long period and can not cause inflammation.

Example 2

This case study morphine the transdermal of pig is transported.The skin of pig has the attribute close with people's skin, so pig is the ideal model that research medicine skin transports.

This research is the transdermal that pig carries out morphine to be transported the back postpone evaluation analgesia degree by the withdrawing reaction of measuring tail and being opposite to buttocks thermal source (62 ℃).

With Therapeutic Method and time be fixed model, and the recedence time during with pig, repeated experiments and time zero is stochastic model, by residual maximum likelihood (REML, Residualmaximum likelihood) the method analysis experimental data of shrinking back.Initial Log certificate has been carried out preliminary analysis, but because therefore some deviation data of the 6th hour carry out the Log conversion so that analyze to these data.Two kinds of analyses have all provided essential identical explanation.

Following preparation is tested:

Code	Compositions
		AGM	Morphine is in the preparation G of example 1
AG	The preparation G of no morphine
		AHM	Morphine is in the preparation H of example 1
AH	The preparation H of no morphine

Generally, use the recedence time of the pig of prepared product AGM processing to be longer than other any processing methods (see Table 4, the recedence time that AG, AH, AGM and AHM handle was respectively 2.63 seconds, 2.88 seconds, 4.82 seconds and 3.17 seconds).Interesting is, handles back 6 hours reaction maximum (Fig. 5), shows to have lasting effect, particularly when comparing with contrast AG.Here, the pig of using AGM to handle handles 133% 6 hours the experiment of shrinking back greater than AG.AHM, but does not continue greater than contrast AH in the back 2 hours recedence time of processing.The result of the persistence that AHM does not have AGM and had.

In a word, by 1 to 6 hour the measurement data of delay of tail withdrawing reaction behind the heat treatment is shown,, the morphine in the preparation of the present invention (AGM) provides rapid persistent pain forfeiture.Also have, preparation of the present invention can not cause inflammation, therefore appears to have may allow long-time contact skin and can not cause inflammation.

Table 4 is used the treatment effect after the thermal probe and is contracted the pawl response time (second ¹)

Handle the back time (h)						Meaning (x 2)
										1	2	4	6	sed 1	Handle	Time	Tr x Ti
AG	1.83	2.69	3.26	2.75	1.087	＜0.001	0.062	0.45
									AH	2.10	2.34	3.60	3.50
AGM	3.96	3.40	5.49	6.42
									AHM	2.85	3.87	2.97	3.00
AG	(0.260)	(0.411)	(0.461)	(0.413)	0.0858	0.003	0.011	0.85
									AH	(0.313)	(0.335)	(0.465)	(0.438)
AGM	(0.460)	(0.470)	(0.570)	(0.622)
									AHM	(0.410)	(0.466)	(0.440)	(0.458)

¹Numerical value in the bracket is through the Log conversion

²The standard error of the difference that time x handles.Multiply by 0.511 and 0.497 respectively for processing and chronergy.

Example 3

This case study various preparations of the present invention use the tocopheryl phosphate of complexation to compare in contrast to giving the effect of mice transdermal administration.

Method

Animal: every group of Sprague Dawley rat (～280 gram) n=6 that waking state is arranged

Preparation capable of permeating skin prepared product: morphine hydrochloride, Glaxo Australia Pty Ltd (Catalog Number 22284).By adding potassium carbonate, in aqueous solution, derive the morphine free alkali by the HCL form.This process is finished (morphine HCl can not use with unguentum, therefore uses free alkali) in Monash university.

Morphine (10mg/kg) is used for each preparation that table 5 is listed.By rat the delayed response of heat is detected effect, because the effect of morphine makes the time delay of rat withdrawal claw.

Table 5: the preparation of tocopheryl phosphate

Composition	Purposes	Vital-ET TM	TP/T2P	TPM-01	TPM-01/ M
						The disodium tocopheryl phosphate	Transdermal agent	2.00％	2.00％	2.00％	7.20％
T2P	-	1.00％	1.00％	1.00％	3.60％
						Lauryldiaminopropionic acid	Chelating agent	3.00％	-	-	-
Morphine HCl (USP-NF)	Active component	-	-	-	5.4％
						Ultrez-10 carbomer-3% solution	Excipient	0.36％	0.36％	-	-
Carbomer 934 USP-NF	-	-	-	0.36％	0.36％
						Triethanolamine (triethanolamine) USP	Excipient	0.25％	0.25％	0.25％	0.25％
Surcide DMDMH	Antiseptic	0.10％	0.10％	-	-
						Germall 115	Antiseptic	-	-	-	-
Methyl parahydroxybenzoate USP-NF, BP	Antiseptic	0.10％	-	0.10％	0.10％
						USP-NF purifies waste water	Solvent	QS	100％	QS	100％	QS	100％	QS	100％

Base gel in contrast comprises all the components except that the phosphoric acid tocopherol.Do not use Vital ET in this experiment, list as Vital ET and formulation components of the present invention comparing here.

Experimental technique

Vola odynometer (plantar analgesiometer) is to design for the pain forfeiture degree that sieves out quickly and effectively small test chamber animal.This device be used for thermal source (by infrared light send～45 ℃) be applied to rear solid end, and the rear solid end used time of withdrawal is measured (contracting the pawl waiting time).Hot plate provides lasting surface temperature, and built-in precision is the timer that 0.1 ℃ Digital Hygrometer and precision are 0.1 second.Animal is placed on the hot plate, be loaded in the clear acrylic cage of hot plate, monitor licking the pawl reaction.Lick pawl response time lengthening and show the generation analgesia.

Rat before using transdermal patch at least 24 hours is at back leg skin of back Zoned application depilatory cream (under the narcotism).Sprague Dawley rat under the waking state (～400 gram) is accepted the morphine HCl that dose of morphine is every kg body weight 10mg.Said preparation contains 10%w/w morphine HCl.Use morning once, analgesia is measured in different time points.To be exposed to the skin area covering of medicine/excipient then with the Tegaderm transparent dressing.To all animals all carry out morphine use before and use after analgesia experiment.

Experimental result:

Fig. 6 has showed every kind of result that preparation produces.This result shows that the response time is depended on dosage and increases to some extent, shows analgesia to occur.Have morphine but do not have the gel control experiment of TPM to show to make transdermal route effectively to the basic demand of TPM.Experimental result with the variation of withdrawal time compared with the control mode express, control value is from using incomplete preparation (that is: do not have morphine or TPM) to handle the value that rat obtains, and the zero-time value of using the rat that complete preparation handles, TPM-01/M).

The preparation that uses in this research comprises the excipient of listing in TP/T2P (or TPM), morphine HCl and other tables 5.

Fig. 6 has showed tangible dose response and lasting effect.Compare with two types contrast (that is, only have excipient not have morphine and the blended control gel of TP/T2P, have excipient and morphine but do not have the control gel of TP/T2P), the transport result of morphine was best when the result showed with the TP/T2P mixed preparing.

The vocabulary that occurs in this specification and claims book " contains " other expressions that reach " containing " and various variations and interpolation is not limited to outside the interest field that the present invention advocates.Apparent to modifications and variations of the present invention for those skilled in the art.This modifications and variations all belong in the scope of technical solution of the present invention.

Claims (22)

1, a kind of alkaloid formulations comprises the product of one or more phosphate derivatives of one or more alkaloids and one or more electron transfer agents.

2, alkaloid formulations according to claim 1, the phosphate derivative of wherein said electron transfer agent is selected from: one or more phosphate derivatives of tocopherol.

3, alkaloid formulations according to claim 1, wherein said preparation is a topical formulations.

4, alkaloid formulations according to claim 1, wherein said preparation is an oral formulations.

5, want 4 described alkaloid formulations according to right, it also comprises enteric coating.

6, want 4 described alkaloid formulations according to right, wherein said preparation is selected from: tablet, powder, chewing tablets, capsule, oral suspensions, suspensoid, Emulsion or liquid preparation, child's preparation, enteral nutrition preparation, dietetic product, functional food.

7, alkaloid formulations according to claim 1, wherein said preparation is to contain agent.

8, according to the described alkaloid formulations of aforementioned arbitrary claim, wherein said electron transfer agent is selected from: the hydroxyl chromanane comprises α, β, γ, the δ tocol of isomer and racemization form; Hydroquinone as vitamin K1 and coenzyme Q10 reduction form; Hydroxy kind carotene comprises retinol; Ergocalciferol, ascorbic acid and composition thereof.

9, want 8 described alkaloid formulations according to right, wherein said electron transfer agent is selected from: tocopherol and other tocol, retinol, vitamin K1 and composition thereof.

10, alkaloid formulations according to claim 9, wherein said electron transfer agent is selected from: tocol and composition thereof.

11, alkaloid formulations according to claim 9, wherein said electron transfer agent is an alpha-tocopherol.

12, alkaloid formulations according to claim 11, the multiple phosphate derivative of one or more of wherein said one or more multiple electron transfer agents is selected from: biphosphate tocopherol, phosphoric acid hydrogen two tocopherols and composition thereof.

13, alkaloid formulations according to claim 12, the multiple phosphate derivative of one or more of wherein said one or more multiple electron transfer agents are the mixture of biphosphate tocopherol, phosphoric acid hydrogen two tocopherols.

14, alkaloid formulations according to claim 12, the multiple phosphate derivative of one or more of wherein said one or more multiple electron transfer agents is a phospholipid.

15, according to the described alkaloid formulations of above-mentioned arbitrary claim, wherein said alkaloid: be selected from tertiary amine and composition thereof, described tertiary amine is the alicyclic of three shared nitrogen-atoms of ring, or nitrogen is added monocycle and by alkylating circulus, or does not add the circulus of nitrogen.

16, alkaloid formulations according to claim 15, wherein said alkaloid is selected from: atropina, quinine, opioids, fentanyl, nicotine, fenspiride, hydrochloric acid fluorine amine and codeine.

17, according to the described alkaloid formulations of aforementioned arbitrary claim, wherein said alkaloid is an atropina.

18, according to the described alkaloid formulations of aforementioned arbitrary claim, wherein said alkaloid is a morphine.

19, a kind ofly improve the method that alkaloid is renderd a service, this method comprises the step that one or more the multiple phosphate derivatives with this alkaloid and one or more multiple electron transfer agents react.

20, the product of one or more multiple phosphate derivatives of one or more multiple alkaloids and one or more multiple electron transfer agents and the excipient application in preparation is produced.

21, a kind of pharmaceutical composition comprises the product of one or more multiple phosphate derivatives of one or more multiple alkaloids and one or more multiple electron transfer agents.

22, pharmaceutical composition according to claim 21, wherein said electron transfer agent are tocopherol.

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