CN102451169B - Loratadine freeze-drying tablet and preparation method thereof - Google Patents
Loratadine freeze-drying tablet and preparation method thereof Download PDFInfo
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- CN102451169B CN102451169B CN201110176708.9A CN201110176708A CN102451169B CN 102451169 B CN102451169 B CN 102451169B CN 201110176708 A CN201110176708 A CN 201110176708A CN 102451169 B CN102451169 B CN 102451169B
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- freeze
- loratadine
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- preparation
- drying
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Abstract
A kind of loratadine freeze-drying tablet and preparation method thereof, the present invention relates to loratadine freeze-drying tablet and uses freeze-drying to prepare prescription and the technique of loratadine freeze-drying tablet.Loratadine freeze-drying tablet of the present invention is prepared from by principal agent loratadine and pharmaceutic adjuvant, without with water when taking, after entrance can disintegrate rapidly, be suitable for the medication of the dysphagia patients such as old man, child；It is suitable for simultaneously in tourism way, is difficult to the medication under conditions of acquisition water source；Have taking convenience, absorb fast, first pass effect is little, to advantages such as digestive tract mucous membrane irritation are little, market application foreground is wide, and the freeze-drying tablet of the present invention can substantially reduce the side effect of loratadine.It addition, the invention still further relates to the preparation method of a kind of loratadine freeze-drying tablet.
Description
Technical field:
The present invention relates to a kind of loratadine freeze-drying tablet and preparation method thereof, use lyophilization legal system particularly to one
Standby loratadine freeze-drying tablet.
Background technology:
Loratadine (Loratadine), chemical entitled 4-(8-chloro-5,6-dihydro-11H-benzo [5,6] cycloheptyl also [1,
2-b] pyridine-11-subunit)-1-piperidine carboxylate.Belong to tricyclic antidepressants long-acting oral second filial generation antihistaminic.Main
For alleviating the symptom relevant with allergic rhinitis, as sneeze, watery nasal discharge and rhinocnesmus, nasal obstruction and eye are itched and burn feeling.Also fit
For alleviating symptom and the sign of chronic urticaria, itching skin disease and other anaphylaxis dermatosis.In therapeutic dose scope
In, acardia toxic action, not easily pass through blood brain barrier, without maincenter sedation, be that antihistamine drug uses more product
Kind.
The dosage form of the most granted the most domestic loratadine have conventional tablet, capsule, granule, syrup, effervescent tablet,
Dispersible tablet and oral cavity disintegration tablet etc..When common oral preparation patient takes, it is necessary to water delivery service or be inherently liquid preparation, no
Only take inconvenience, be difficult to swallow, and absorb slower.Further, there is xerostomia after taking in the preparation of current loratadine, addicted to
Sleep or the side effect such as tired or stomachache.
The technology of preparing starting ratio of oral cavity disintegration tablet is later at home, the most mostly uses direct compression process to prepare oral cavity
Disintegrating tablet, but owing to the method mainly being made preparation disintegrate rapidly in the oral cavity by use disintegrating agent, and most of
Disintegrating agent water insoluble, the oral cavity disintegration tablet mouth that therefore uses this method to prepare usually has grittiness after tasting, thus affects trouble
Mouthfeel when person takes and compliance；And the disintegrate of preparation also can be the slowest.Domestic also have scholar to use freeze-drying to prepare
This dosage form, but majority has all followed the shortcoming of direct compression process, adds substantial amounts of disintegrating agent and other excipient so that preparation
Oral cavity disintegration tablet poor-performing.When the freeze-drying that the present invention uses is prepared, it is not necessary to add disintegrating agent, used
Adjuvant be all water miscible, and consumption is less so that preparation in the oral cavity can disintegrate rapidly, without grittiness, thus overcome
The oral cavity disintegration tablet disintegrate in the oral cavity using direct compression process to prepare is slow, the shortcoming of grittiness.
Additionally, found by the research of volunteer's oral mucosa permeability test, the chlorine thunder in human mouth, prepared by the present invention
He determines freeze-drying tablet and has bigger transmucosal rate, thus illustrates that it can be absorbed by oral mucosa, and rapid-onset subtracts
Little first pass effect.By clinical trial, present inventors have surprisingly found that the loratadine prepared with ordinary tablet and employing pressing
Oral cavity disintegration tablet is compared, the chlorine thunder with specific adjuvant and adjuvant and the specific usage ratio of loratadine prepared by the present invention
He determines the bioavailability raising of freeze-drying tablet, side effect substantially reduces, also increases in curative effect.
Chinese patent CN100479809C discloses and uses the oral loratadine disintegrating tablet prepared of freeze-drying
A kind of formula, but this formula exists a lot of not enough.Use the loratadine freeze-drying tablet prepared by formula of the present invention with disclosed
Formula prepare preparation compare, bioavailability improve, side effect substantially reduce, also increase in curative effect, have aobvious
The clinical advantage write.
Summary of the invention:
The technical problem to be solved is low for loratadine bioavailability, the obvious shortcoming of side effect,
High in order to prepare bioavailability, side effect is little, the preparation of the loratadine that curative effect strengthens, and this application provides one can improve
The prescription of the loratadine freeze-drying tablet of the defect that prior art exists and preparation method, by using suitable adjuvant and adjuvant
With the specific consumption proportion of loratadine, prepare that bioavailability is higher, side effect substantially reduces, also had in curative effect
The loratadine freeze-drying tablet improved.
The present inventor is by substantial amounts of experiment, it is determined that the adjuvant of the present invention and with the usage ratio of loratadine and work
Skill.Find to use the adjuvant of the present invention by volunteer's oral mucosa permeability test, Bioequivalence Test and clinical trial
And the loratadine freeze-drying tablet prepared with usage ratio and the technique of loratadine exists oral mucosal absorption, onset is rapid,
And have surprisingly found that the oral loratadine disintegrating tablet with ordinary tablet, using pressing to prepare and use disclosed formula made
Standby oral loratadine disintegrating tablet is compared, and the bioavailability of loratadine freeze-drying tablet prepared by the present invention improves, side effect
Substantially reduce, also increase in curative effect.
The loratadine freeze-drying tablet that the present invention relates to, comprises loratadine, skeleton proppant, binding agent, suspending agent and
Other adjuvant.Wherein other adjuvant is sweeting agent or aromatic or comprises sweeting agent and aromatic simultaneously.
The percentage by weight of each component of loratadine freeze-drying tablet of the present invention is as follows:
Remaining is sweeting agent or aromatic or sweeting agent and aromatic, and the most each weight percentages of components sum is 100%.
The preferably percentage by weight of each component is as follows:
Remaining is sweeting agent or aromatic or sweeting agent and aromatic, and the most each weight percentages of components sum is 100%.
The most preferably percentage by weight of each component is as follows:
Remaining is sweeting agent or aromatic or sweeting agent and aromatic, and the most each weight percentages of components sum is 100%.
The bone that skeleton proppant of the present invention is known to those skilled in the art when can be to prepare oral cavity disintegration tablet
The adjuvant of frame supporting function, preferably glycine, serine, arginine, mannitol, sorbitol, maltose alcohol, xylitol, lactose
Alcohol, erythritol, hydroxyl isomaltulose, dextran, xylose, cottonseed sugar, maltose, glucose, galactose, trehalose, dextrin,
Hydroxypropyl cyclodextrin, sodium phosphate, sodium chloride, aluminium silicate or the mixture with upper skeleton agent, particularly preferably mannitol, red moss
Sugar alcohol, dextran, glycine, serine, arginine or their mixture, most preferably glycine or mannitol or its
Mixture；The binding agent that described binding agent is known to those skilled in the art when can be to prepare oral cavity disintegration tablet, the most general Shandong
Orchid, alginate, cellulose and its derivates, hyaluronic acid, modified starch, polyvinyl alcohol, chitosan or their mixture,
Particularly preferably Pullulan, alginate, cellulose and its derivates or their mixture, most preferably Pullulan or
Alginate or its mixture；Described suspending agent when can be to prepare oral cavity disintegration tablet known to those skilled in the art rising help
The adjuvant of outstanding effect, preferably be selected from xanthan gum, Konjac glucomannan, natural origin glue, synthetic macromolecular compound, polypeptide, polysaccharide or they
Mixture, wherein said natural origin glue selected from alginate jelly, arabic gum, guar gum, agar, hydroxymethyl cellulose,
Carrageenin or pectin, described synthetic macromolecular compound is polyvinylpyrrolidone, particularly preferably xanthan gum, Rhizoma amorphophalli
Glue, alginate jelly, polyvinylpyrrolidone or combinations thereof, most preferably xanthan gum or Konjac glucomannan or its mixture；Described
Sweeting agent be that acesulfame potassium, sucralose, aspartame, sucrose etc. are natural or one or several in the sweeting agent of synthetic
Kind；Described aromatic is that Herba Menthae, Fructus Citri sinensis, Fructus Ananadis comosi, Fructus Fragariae Ananssae etc. are natural or one or more in the aromatic of synthetic.
The preparation method of the loratadine freeze-drying tablet of the present invention for using freeze-drying to prepare, pre-in this preparation technology
Freezing in the research that freeze-drying tablet is affected by temperature and find, pre-freezing temperature is relatively big to the appearance effects of freeze-drying tablet, when temperature is too high, and system
The freeze-drying tablet rough surface obtained；When the temperature is too low, then energy consumption is higher in commercial process；In the pre-freeze time to freeze-drying tablet
Finding in the research of impact, the shortest when the time, solution does not freezes reality, then can occur bubbling phenomenon in dry run, will also result in
Reducing of freeze-drying tablet volume；Oversize when the time, then can cause the waste of the energy；At freezing dry process on grinding that freeze-drying tablet affects
Studying carefully middle discovery, freezing dry process all has bigger shadow for the water content of freeze-drying tablet, mouldability, microstructure, disintegrating property
Ring.Pre-freezing temperature when we finally determine that freeze-drying prepares loratadine freeze-drying tablet by substantial amounts of experimentation, time
Between and the temperature of freezing dry process, time, wherein in the preparation method of loratadine freeze-drying tablet, pre-freezing temperature is-40 DEG C
～-170 DEG C, the pre-freeze time is 1～60min；Lyophilization temperature is-30 DEG C～30 DEG C；Sublimation drying is 1～10h；Cold
Vacuum during lyophilizing is dry is 0.01mbar～10mbar.
The preparation method of loratadine freeze-drying tablet of the present invention comprises the steps:
The preparation of (a) matrix liquid: loratadine, skeleton proppant, binding agent and other adjuvant are joined fully dissolving
In good suspending agent aqueous solution, form matrix liquid；
B () deaerates: the matrix liquid preparing above-mentioned (a) step is de-gassed；
(c) injection molding: the matrix liquid that step (b) processes through degassing is injected in mould；
(d) pre-freeze: the mould being marked with matrix liquid in step (c) is carried out pre-freeze；
E () lyophilization: the preparation lyophilization (d) obtained, removes solvent, to obtain final product.
The preparation method of currently preferred described loratadine freeze-drying tablet is:
The preparation of (a) matrix liquid: by 2-53.37%, or 54.75-75% loratadine, 2-21.24%, or 21.99-
85% skeleton proppant, 4-23.43%, or 24.12-90% binding agent and other adjuvant join the 0.02-fully dissolved
In 0.51%, or 0.57-25% suspending agent aqueous solution, form matrix liquid；
B () deaerates: the matrix liquid preparing above-mentioned (a) step is de-gassed；
(c) injection molding: the matrix liquid that step (b) processes through degassing is injected in mould；
(d) pre-freeze: the mould being marked with matrix liquid in step (c) is carried out pre-freeze；
E () lyophilization: the preparation lyophilization (d) obtained, removes solvent, to obtain final product.
The percentage by weight of each component of loratadine freeze-drying tablet of the present invention is as follows:
Remaining is sweeting agent or aromatic or sweeting agent and aromatic, and the most each weight percentages of components sum is 100%.
The preferably loratadine freeze-drying tablet of the present invention, consists of the following components in percentage by weight:
Remaining is sweeting agent or aromatic or sweeting agent and aromatic, and the most each weight percentages of components sum is 100%.
The most preferably loratadine freeze-drying tablet of the present invention, consists of the following components in percentage by weight:
Remaining is sweeting agent or aromatic or sweeting agent and aromatic, and the most each weight percentages of components sum is 100%.
The particularly preferred formula of invention formulation consists of the following components in percentage by weight:
Remaining is sweeting agent or aromatic or sweeting agent and aromatic, and the most each weight percentages of components sum is 100%.
The preparation method of loratadine freeze-drying tablet of the present invention is:
The preparation of (a) matrix liquid: by loratadine, glycine or mannitol or its mixture, Pullulan or sodium alginate
Or its mixture and sweeting agent or aromatic or sweeting agent and aromatic, join the xanthan gum or Konjac glucomannan fully dissolved
Or in the solution of its mixture, form uniform solution；
B () deaerates: be de-gassed by the solution of (a) step；
(c) injection molding: the solution after (b) step being deaerated injects in mould；
(d) pre-freeze: by the pre-freeze 1 under conditions of temperature is for-40 DEG C～-170 DEG C of the mould being marked with solution in (c) step
～60min；
E then mould is proceeded in freeze dryer by (), at 0.01mbar～10mbar pressure, under conditions of-30 DEG C to 30 DEG C
Lyophilization 1～10h, i.e. obtains the loratadine freeze-drying tablet of the present invention,
The step of ice crystal hatching also can be added before said method proceeds to freeze dryer after pre-freeze step, will be after pre-freeze
The mould being marked with solution, put in the low temperature environment of-5 DEG C～-60 DEG C, the time is 0.5～15h.
The loratadine freeze-drying tablet of the present invention is made up of the component of following weight percentage ratio:
Currently preferred loratadine freeze-drying tablet is made up of the component of following weight percentage ratio:
The present invention most preferred loratadine freeze-drying tablet is made up of the component of following weight percentage ratio:
The loratadine freeze-drying tablet of the present invention is made up of following components in parts by weight:
Currently preferred loratadine freeze-drying tablet is made up of following components in parts by weight:
The present invention most preferred loratadine freeze-drying tablet is made up of following components in parts by weight:
Currently preferred formula is made up of following components in parts by weight:
The most preferred formula of the present invention is made up of the component of following weight:
Its preparation method is: by loratadine, glycine or mannitol or its mixture, Pullulan or sodium alginate or its
Mixture and sweeting agent, aromatic, join in the solution of xanthan gum or Konjac glucomannan or its mixture fully dissolved, mixed
Conjunction becomes uniform solution；After solution is de-gassed, accurately inject in mould；Pre-freeze 1 under conditions of-40 DEG C～-170 DEG C
～after 60min, proceed in freeze dryer, 0.01mbar～10mbar pressure, under conditions of-30 DEG C to 30 DEG C lyophilization 1～
10h, i.e. obtains the loratadine freeze-drying tablet of the present invention；Also can add before said method proceeds to freeze dryer after pre-freeze step
The step of ice crystal hatching, will the mould being marked with solution after pre-freeze, put in the low temperature environment of-5 DEG C～-60 DEG C, the time is 5
～15h.The loratadine freeze-drying tablet that the present invention provides, supplementary product consumption is less, and owing to not using disintegrating agent, the adjuvant used
The most water miscible, the principle of disintegrate is the concrete dynamic modulus by staying after solvent seasoning in preparation so that preparation is at mouth
In chamber after disintegrate, medicine and adjuvant can quickly and completely be scattered in saliva, thus overcome mouth prepared by direct compression process
Chamber disintegrating preparations has the defect of grittiness in the oral cavity.
The loratadine freeze-drying tablet of the present invention has the advantage that
1, good mouthfeel, taking convenience: the loratadine freeze-drying tablet materials of the present invention are simple, and good mouthfeel, without grittiness；
Need not use water delivery service, saliva can make its disintegrate or dissolving, is particularly suited for old man, children's, the patient of dysphagia and water intaking
Inconvenience person takes medicine；It is suitable for simultaneously in tourism way, is difficult to the medication under conditions of acquisition water source.
It is 2, rapid-action, it is to avoid the first pass effect of liver: loratadine freeze-drying tablet prepared by the present invention is rapid disintegrate in mouth,
Considerable part direct oral cavity is had to absorb, thus rapid-action, and first pass effect is little.
3, bioavailability improve: in animal body from the point of view of Bioequivalence Test result, chlorine thunder prepared by the present invention he
Determine freeze-drying tablet and ordinary tablet, the oral loratadine disintegrating tablet using pressing to prepare and use the chlorine prepared by disclosed formula
Lei Tading oral cavity disintegration tablet is compared, Cmax and AUC0-tAll significantly increasing, bioavailability improves.
4, gastrointestinal absorption is fast, it is little to stimulate: loratadine freeze-drying tablet prepared by the present invention is before medicine arrives gastrointestinal tract
Energy disintegrate rapidly is also dispersed into trickle granule, causes medicine to be distributed in gastrointestinal tract large area, and absorption point increases, and substantially increases
Medicine is in gastrointestinal infiltration rate, it is to avoid medicine is too high at gastrointestinal tract local concentration, causes gastrointestinal local excitation
Shortcoming, untoward reaction reduce.
5, side effect is little, and curative effect improves: through clinical trial it is surprisingly found that the loratadine lyophilizing prepared of the present invention
Sheet and ordinary tablet, use oral loratadine disintegrating tablet prepared by pressing and use the loratadine prepared by disclosed formula
Oral cavity disintegration tablet is compared, and side effect significantly reduces, and curative effect increased.
The loratadine freeze-drying tablet that the present invention provides is in good taste, volume is little, tablet weight is moderate, the most broken, preparation technology is simple
Single, rapid-action, side effect is little, curative effect is high, be suitable for industrialized great production.
Accompanying drawing explanation
Fig. 1 gives the blood concentration-time curve after R5 and R1
Fig. 2 gives the blood concentration-time curve after R5 and R2
Fig. 3 gives the blood concentration-time curve after R5 and R3
Fig. 4 gives the blood concentration-time curve after R5 and R4
Fig. 5 gives the blood concentration-time curve after R5 and T1
Fig. 6 gives the blood concentration-time curve after R5 and T2
Fig. 7 gives the blood concentration-time curve after R5 and T3
Fig. 8 gives the blood concentration-time curve after R5 and T4
Fig. 9 gives the blood concentration-time curve after R5 and T5
Figure 10 gives the blood concentration-time curve after R5 and T6
Figure 11 gives the blood concentration-time curve after R5 and T7
Figure 12 gives the blood concentration-time curve after R5 and T8
Figure 13 gives the blood concentration-time curve after R5 and T9
Figure 14 gives the blood concentration-time curve after R5 and T10
Figure 15 gives the blood concentration-time curve after R5 and T11
Figure 16 gives the blood concentration-time curve after R5 and T12
Figure 17 gives the blood concentration-time curve after R5 and T13
Figure 18 gives the blood concentration-time curve after R5 and T14
Figure 19 gives the blood concentration-time curve after R5 and T15
Figure 20 gives the blood concentration-time curve after R5 and T16
Figure 21 gives the blood concentration-time curve after R5 and T17
Figure 22 gives the blood concentration-time curve after R5 and T18
Figure 23 gives the blood concentration-time curve after R5 and T19
Figure 24 gives the blood concentration-time curve after R5 and T20
Figure 25 gives the blood concentration-time curve after R5 and T21
Figure 26 gives the blood concentration-time curve after R5 and T22
Detailed description of the invention:
Describe the present invention in detail below by embodiment, but the present invention should not be construed as limited to this.
Embodiment 1
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by loratadine, glycine, Pullulan, join the Huang fully dissolved
In virgin rubber solution, mixing becomes uniform solution；After solution is de-gassed, accurately inject in mould；At-40 DEG C～-170 DEG C
Under conditions of after pre-freeze 1～60min, proceed in freeze dryer, in 0.01mbar～10mbar pressure, the condition of-30 DEG C to 30 DEG C
Lower lyophilization 1～10h, i.e. obtains the loratadine freeze-drying tablet of the present invention；Said method proceeds to lyophilizing after pre-freeze step
Also can add the step of ice crystal hatching before machine, will the mould being marked with solution after pre-freeze, put into the low temperature of-5 DEG C～-60 DEG C
In environment, the time is 5～15h.
Embodiment 2
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by the loratadine of above-mentioned consumption, mannitol, Pullulan, joins fully
In the xanthan gum solution dissolved, mixing becomes uniform solution；Remaining preparation method is with embodiment 1.
Embodiment 3
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by the loratadine of above-mentioned consumption, glycine, mannitol, Pullulan, Sargassum
Acid sodium, Mint Essence, join in the Konjac glucomannan solution fully dissolved, and mixing becomes uniform solution；Remaining preparation method
With embodiment 1.
Embodiment 4
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by the loratadine of above-mentioned consumption, mannitol, Pullulan, sucrose, minty note
Essence, joins in the xanthan gum solution fully dissolved, and mixing becomes uniform solution；Remaining preparation method is with embodiment 1.
Embodiment 5
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by the loratadine of above-mentioned consumption, glycine, Pullulan, joins fully
In the xanthan gum solution dissolved, mixing becomes uniform solution；Remaining preparation method is with embodiment 1.
Embodiment 6
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by the loratadine of above-mentioned consumption, glycine, Pullulan, sucralose, thin
Lotus essence, joins in the xanthan gum solution fully dissolved, and mixing becomes uniform solution；The same embodiment of remaining preparation method
1。
Embodiment 7
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by the loratadine of above-mentioned consumption, glycine, mannitol, Pullulan, Sargassum
Acid sodium, aspartame, flavoring pineapple essence, join in the polyvinylpyrrolidonesolution solution fully dissolved, and mixing becomes homogeneous
Solution；Remaining preparation method is with embodiment 1.
Embodiment 8
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by the loratadine of above-mentioned consumption, glycine, mannitol, Pullulan, A Si
Pa Tan, orange flavor, join in the Konjac glucomannan solution fully dissolved, and mixing becomes uniform solution；Remaining preparation method
With embodiment 1.
Embodiment 9
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by the loratadine of above-mentioned consumption, mannitol, Pullulan, sodium alginate, peace
Match honey, joins in the solution of xanthan gum and the Konjac glucomannan fully dissolved, and mixing becomes uniform solution；Remaining preparation method
With embodiment 1.
Embodiment 10
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by the loratadine of above-mentioned consumption, glycine, mannitol, Pullulan, sugarcane
Sugar, orange flavor, join in the Konjac glucomannan solution fully dissolved, and mixing becomes uniform solution；Remaining preparation method is same
Embodiment 1.
Embodiment 11
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by the loratadine of above-mentioned consumption, glycine, Pullulan, joins fully
In the xanthan gum solution dissolved, mixing becomes uniform solution；Remaining preparation method is with embodiment 1.
Embodiment 12
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by the loratadine of above-mentioned consumption, mannitol, Pullulan, sodium alginate, add
Entering in the xanthan gum solution fully dissolved, mixing becomes uniform solution；Remaining preparation method is with embodiment 1.
Embodiment 13
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by the loratadine of above-mentioned consumption, glycine, Pullulan, joins fully
In the xanthan gum solution dissolved, mixing becomes uniform solution；Remaining preparation method is with embodiment 1.
Embodiment 14
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by the loratadine of above-mentioned consumption, glycine, Pullulan, sodium alginate, add
Entering in the xanthan gum solution fully dissolved, mixing becomes uniform solution；Remaining preparation method is with embodiment 1.
Embodiment 15
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by the loratadine of above-mentioned consumption, mannitol, hydroxypropyl methyl cellulose,
Joining in the xanthan gum solution fully dissolved, mixing becomes uniform solution；Remaining preparation method is with embodiment 1.
Embodiment 16
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by the loratadine of above-mentioned consumption, glycine, Pullulan, joins fully
In the xanthan gum solution dissolved, mixing becomes uniform solution；Remaining preparation method is with embodiment 1.
Embodiment 17
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by the loratadine of above-mentioned consumption, glycine, sodium alginate, joins and fills
Dividing in the xanthan gum solution dissolved, mixing becomes uniform solution；Remaining preparation method is with embodiment 1.
Embodiment 18
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by the loratadine of above-mentioned consumption, mannitol, sodium alginate, sucrose, Fructus Citri sinensis
Essence, joins in the Konjac glucomannan solution fully dissolved, and mixing becomes uniform solution；Remaining preparation method is with embodiment 1.
Embodiment 19
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by the loratadine of above-mentioned consumption, mannitol, dextran, Pullulan, sea
Sodium alginate, acesulfame potassium, flavoring pineapple essence, join in the Konjac glucomannan solution fully dissolved, and mixing becomes uniform solution；Remaining
Preparation method is with embodiment 1.
Embodiment 20
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by the loratadine of above-mentioned consumption, glycine, Pullulan, joins fully
In the Konjac glucomannan solution dissolved, mixing becomes uniform solution；Remaining preparation method is with embodiment 1.
Embodiment 21
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by the loratadine of above-mentioned consumption, glycine, dextran, Pullulan, sea
Sodium alginate, aspartame, strawberry essence, join in the Konjac glucomannan solution fully dissolved, and mixing becomes uniform solution；Its
Remaining preparation method is with embodiment 1.
Embodiment 22
Invention formulation formula is composed of the following components:
Concrete preparation method is as described below: by the loratadine of above-mentioned consumption, glycine, Pullulan, joins fully
In the xanthan gum solution dissolved, mixing becomes uniform solution；Remaining preparation method is with embodiment 1.
Comparative example 1
Comparative example 1 formula is composed of the following components:
Concrete preparation method is as described below: by glycine and the Pullulan mixing of above-mentioned weight, add appropriate purification
Water, room temperature is stirred well to all dissolve；Xanthan gum individually with purified water the most swelling after, add loratadine mixing, then
After mixing homogeneously with above-mentioned glycine and Pullulan solution, add appropriate purified water so that the purified water that all of the above adds
Total amount is 181.5mg, prepares medicinal liquid；Medicinal liquid sonic oscillation is deaerated, is the most accurately injected in 1 milliliter of mould, spray through liquid nitrogen
Drench refrigeration after-110 DEG C of freezings 5 minutes, proceed in freeze dryer, in 0.5 millibar of pressure, lyophilizing 5 under conditions of-20 DEG C to 25 DEG C
Hour, i.e. obtain oral loratadine disintegrating tablet.
Comparative example 2
Comparative example 2 formula is composed of the following components:
Concrete preparation method is as described below: the method that each component of above-mentioned consumption is repeated comparative example 1, prepares
Oral loratadine disintegrating tablet.
Comparative example 3
Comparative example 3 formula is composed of the following components:
Concrete preparation method is as described below: the method that each component of above-mentioned consumption is repeated comparative example 1, prepares
Oral loratadine disintegrating tablet.
Comparative example 4
The preparation of comparative example 4 is oral loratadine disintegrating tablet prepared by pressing, and manufacturer is that Chongqing health is carved
That pharmaceutical Co. Ltd.
Comparative example 5
The preparation of comparative example 5 is loratadine ordinary tablet, and manufacturer is He'nan Tianfang Pharmaceutical Co., Ltd.
In order to be better understood from the present invention, below with the dissolution of loratadine freeze-drying tablet prepared, mouthfeel description of test
Advantages of the present invention；By volunteer's oral mucosa permeability test and clinical trial, illustrate chlorine thunder prepared by the present invention he
Determining freeze-drying tablet and there is the effect of oral mucosal absorption, onset is rapid, and its with disclosed in Chinese patent CN100479809C
Oral loratadine disintegrating tablet and ordinary tablet prepared by oral loratadine disintegrating tablet, employing pressing are compared, and side effect is bright
Show reduction, also increase in curative effect.
1, dissolution:
Take the loratadine prepared by the preparation prepared by comparative example 1-5 (R1-R5 group) and embodiment 1-22 to freeze
Dry tablet (T group) (T1-T22 represents freeze-drying tablet prepared by embodiment 1-embodiment 22 respectively), measures by the following method: take this
Product, according to dissolution method (Chinese Pharmacopoeia two annex X C the first methods of version in 2010), with hydrochloric acid solution (9 → 1000ml)
500ml is solvent, and rotating speed is 75 turns per minute, operates in accordance with the law, through 30 minutes time, takes solution 5ml, filters, and subsequent filtrate is as confession
Test sample solution；Another precision weighs 105 DEG C and is dried to the loratadine reference substance of constant weight appropriate, adds hydrochloric acid solution (9 → 1000ml)
Dissolve and be quantitatively diluted in every 1ml the solution containing loratadine 20 μ g, as reference substance solution.According to Ultraviolet spectrophotometry
(Chinese Pharmacopoeia two annex IVA of version in 2010), measure trap at the wavelength of 275nm respectively, calculate the stripping quantity of every.
Limit is the 80% of labelled amount, should meet regulation.
The dissolution results of each sample measured according to the method described above is shown in Table 1.
Table 1 each sample dissolution determination result
| Group | Dissolution (%) |
| R1 | 96.5 |
| R2 | 96.2 |
| R3 | 96.3 |
| R4 | 92.3 |
| R5 | 87.2 |
| T1 | 100.4 |
| T2 | 100.1 |
| T3 | 100.3 |
| T4 | 99.1 |
| T5 | 100.2 |
| T6 | 100.1 |
| T7 | 99.6 |
| T8 | 99.2 |
| T9 | 99.8 |
| T10 | 99.5 |
| T11 | 100.3 |
| T12 | 99.3 |
| T13 | 100.2 |
| T14 | 100.1 |
| T15 | 99.1 |
| T16 | 100.4 |
| T17 | 99.2 |
| T18 | 100.3 |
| T19 | 99.3 |
| T20 | 99.4 |
| T21 | 99.1 |
| T22 | 99.2 |
From the measurement result of dissolution it can be seen that the dissolution of loratadine freeze-drying tablet prepared by the present invention is higher than
The dissolution of the preparation prepared by comparative example 1-5.
2, mouthfeel experiment:
Loratadine freeze-drying tablet prepared by Example 1-22 respectively, after 90 healthy volunteer's mouths are tasted, this preparation
Good mouthfeel: after being placed on tongue, disintegrate is rapid, and sugariness, aromaticity are moderate, without bitter, without grittiness.
3, volunteer's oral mucosa permeability test
Experimental technique:
Take the loratadine prepared by the preparation prepared by comparative example 1-5 (R1-R5 group) and embodiment 1-22 to freeze
Dry tablet (T group) (T1-T22 represents freeze-drying tablet prepared by embodiment 1-embodiment 22 respectively), is individually placed on tongue, containing 1min, reaching
Discharge medicine rinse oral cavity after the time, measure discharge medicament contg, thus calculate oral mucosa permeability.
Checking according to the method described above, the transmucosal rate of each group the results are shown in Table 2.
Transmucosal rate result respectively organized by table 2
Table 2 continues each group of transmucosal rate result
Table 2 continues each group of transmucosal rate result
As known from Table 2, in human mouth, it is right that the transmucosal rate of the loratadine freeze-drying tablet prepared by the present invention is higher than
The ratio transmucosal rate of the preparation prepared by embodiment 1-5, thus illustrate that the loratadine freeze-drying tablet prepared by the present invention is permissible
Absorbed by oral mucosa, reduce first pass effect.
5, Bioequivalence Test
Experimental program:
Using the loratadine tablet (R5 group) of comparative example 5 as reference preparation, respectively prepared by comparative example 1-4
(T1-T22 represents embodiment 1-embodiment respectively to loratadine freeze-drying tablet (T group) prepared by preparation (R1-R4 group) and the present invention
The freeze-drying tablet of 22 preparations) carry out Bioequivalence Test.
104 beasle dogs are randomly divided into 26 groups, often group 4.Often organize and all use random crossover medication to carry out
Test, 4 beasle dogs often organized are randomly divided into two groups, and after fasting 12h, 2 are only given the loratadine tablet 20mg of comparative example 5
(R5 group), 2 are only given the preparation 20mg (R1-R4 group) prepared by comparative example 1-4 or loratadine prepared by the present invention freezes
Dry tablet 20mg (T group) (T1-T22 represents freeze-drying tablet prepared by embodiment 1-embodiment 22 respectively), 4 beasle dogs are being administered 2 weeks
Rear crossover is administered.0.25,0.5,1,1.5,2,3,5,8 and 12h lower limb venous blood sampling 3ml before being administered and after administration,
Blood sample is performing centrifugal separation on serum, and film is honored as a queen and is put-20 DEG C of pending analyses of Refrigerator store.LC/MS/MS method is used to measure loratadine
Blood drug level, use DAS software processes, calculate main pharmacokinetic parameter tmax、Cmax、AUC0-tAnd AUC0-∞, according to respectively
Group AUC0-tCalculate relative bioavailability.
Main pharmacokinetic parameter and relative bioavailability the results are shown in Table 3, blood concentration-time curve see Fig. 1～
26。
Table 3 respectively organizes main pharmacokinetic parameter and relative bioavailability (n=4, Mean ± SD)
*Relative bioavailability is each group of result calculated compared with the loratadine tablet of comparative example 5
In animal body from the point of view of Bioequivalence Test result, loratadine freeze-drying tablet prepared by the present invention is implemented with contrast
Preparation prepared by example 1-5 is compared, Cmax and AUC0-tAll significantly increasing, bioavailability improves.
6, clinical trial
Experimental program
Choose standard compliant outpatient service chronic urticaria patients 945 example, be randomly divided into 27 groups, often organize each 35 people.Every day is given
Give 27 groups of patients take respectively the chlorine thunder prepared by preparation 10mg (R1-R5 group) or the present invention prepared by comparative example 1-5 he
Determining freeze-drying tablet 10mg (T group) (T1-T22 represents freeze-drying tablet prepared by embodiment 1-embodiment 22 respectively), every day 1 time, during treatment
It is limited to 28d.After being administered, patients symptomatic is amassed by the 1st week (7d ± 1d), the 2nd week (14d ± 1d) and the 4th week (28d ± 1d)
Dividing and be estimated, record adverse events is also analyzed.1 routine blood test, routine urinalysis, hepatic and renal function and the heart is respectively looked into before and after treatment
Electrograph.
After medication, symptom integral decline index (therapeutic index) as evaluating basis, circular is: curative effect refers to
Number=(adding up to score value after adding up to score value-treatment before treatment)/(adding up to score value before treatment) × 100%.
Curative effect judging standard: (1) fully recovers: gargalesthesia disappears, and erythra disappears completely, erythra score value reduces by more than 90%；(2) aobvious
Effect: gargalesthesia substantially alleviates, erythra score value reduces by more than 60%；(3) progressive: gargalesthesia alleviates, erythra score value reduces by 20%～60%；
(4) invalid: gargalesthesia is the same or aggravates, and erythra score value reduces less than 20%.Total effective rate (%)=(recovery from illness number of cases+effective example
Number) total number of cases × 100% of/this group.
The most each group of preparation is carried out clinical trial, the results are shown in Table 4-table 5.
Clinical efficacy comparison (n=35, number of cases) respectively organized by table 4
| Group | Recovery from illness | Effective | Progressive | Invalid | Total effective rate (%) |
| R1 | 21 | 8 | 6 | 0 | 82.9 |
| R2 | 20 | 9 | 6 | 0 | 82.9 |
| R3 | 21 | 8 | 6 | 0 | 82.9 |
| R4 | 11 | 12 | 9 | 3 | 65.7 |
| R5 | 10 | 12 | 9 | 4 | 62.9 |
| T1 | 26 | 6 | 3 | 0 | 91.4 |
| T2 | 26 | 6 | 3 | 0 | 91.4 |
| T3 | 25 | 7 | 3 | 0 | 91.4 |
| T4 | 22 | 8 | 5 | 0 | 85.7 |
| T5 | 24 | 8 | 3 | 0 | 91.4 |
| T6 | 25 | 7 | 3 | 0 | 91.4 |
| T7 | 22 | 9 | 4 | 0 | 88.6 |
| T8 | 20 | 10 | 5 | 0 | 85.7 |
| T9 | 22 | 9 | 4 | 0 | 88.6 |
| T10 | 21 | 9 | 5 | 0 | 85.7 |
| T11 | 24 | 8 | 3 | 0 | 91.4 |
| T12 | 21 | 9 | 5 | 0 | 85.7 |
| T13 | 25 | 7 | 3 | 0 | 91.4 |
| T14 | 24 | 8 | 3 | 0 | 91.4 |
| T15 | 21 | 9 | 5 | 0 | 85.7 |
| T16 | 24 | 8 | 3 | 0 | 91.4 |
| T17 | 21 | 9 | 5 | 0 | 85.7 |
| T18 | 25 | 7 | 3 | 0 | 91.4 |
| T19 | 20 | 10 | 5 | 0 | 85.7 |
| T20 | 20 | 10 | 5 | 0 | 85.7 |
| T21 | 19 | 11 | 5 | 0 | 85.7 |
| T22 | 19 | 11 | 5 | 0 | 85.7 |
The comparison (n=35) that untoward reaction occurs respectively organized by table 5
| Group | Xerostomia | Drowsiness or tired | Stomachache |
| R1 | 8.57% (3 people) | 8.57% (3 people) | 0% |
| R2 | 8.57% (3 people) | 8.57% (3 people) | 0% |
| R3 | 8.57% (3 people) | 8.57% (3 people) | 0% |
| R4 | 25.71% (9 people) | 25.71% (9 people) | 2.86% (1 people) |
| R5 | 31.43% (11 people) | 28.57% (10 people) | 5.71% (2 people) |
| T1 | 5.71% (2 people) | 2.86% (1 people) | 0% |
| T2 | 5.71% (2 people) | 2.86% (1 people) | 0% |
| T3 | 5.71% (2 people) | 2.86% (1 people) | 0% |
| T4 | 8.57% (3 people) | 5.71% (2 people) | 0% |
| T5 | 5.71% (2 people) | 2.86% (1 people) | 0% |
| T6 | 5.71% (2 people) | 2.86% (1 people) | 0% |
| T7 | 5.71% (2 people) | 5.71% (2 people) | 0% |
| T8 | 8.57% (3 people) | 5.71% (2 people) | 0% |
| T9 | 5.71% (2 people) | 5.71% (2 people) | 0% |
| T10 | 8.57% (3 people) | 5.71% (2 people) | 0% |
| T11 | 5.71% (2 people) | 2.86% (1 people) | 0% |
| T12 | 8.57% (3 people) | 5.71% (2 people) | 0% |
| T13 | 5.71% (2 people) | 2.86% (1 people) | 0% |
| T14 | 5.71% (2 people) | 5.71% (2 people) | 0% |
| T15 | 8.57% (3 people) | 5.71% (2 people) | 0% |
| T16 | 5.71% (2 people) | 2.86% (1 people) | 0% |
| T17 | 8.57% (3 people) | 5.71% (2 people) | 0% |
| T18 | 5.71% (2 people) | 2.86% (1 people) | 0% |
| T19 | 8.57% (3 people) | 5.71% (2 people) | 0% |
| T20 | 8.57% (3 people) | 5.71% (2 people) | 0% |
| T21 | 8.57% (3 people) | 5.71% (2 people) | 0% |
| T22 | 8.57% (3 people) | 5.71% (2 people) | 0% |
From the result of clinical trial it can be seen that the loratadine freeze-drying tablet prepared of the present invention and comparative example 1-5 institute
The preparation of preparation is compared, and side effect substantially reduces, and curative effect increases.Thus the more favourable loratadine demonstrating the present invention
Several big advantage of freeze-drying tablet and feature: 1) can be absorbed by oral mucosa；2) decrease gastrointestinal stimulation,
Alleviate xerostomia, drowsiness or tired.
Claims (2)
1. a loratadine freeze-drying tablet, it is characterised in that freeze-drying tablet is made up of following components:
Loratadine 5.00g
Glycine 3.80g
Pullulan 4.20g
Xanthan gum 0.098g
Purified water 186.902g
Make 1000 altogether,
The preparation method of described loratadine freeze-drying tablet is as described below: by loratadine, glycine, Pullulan, joins fully
In the xanthan gum solution dissolved, mixing becomes uniform solution；After solution is de-gassed, accurately inject in mould；-40
DEG C～-170 DEG C under conditions of after pre-freeze 1～60min, proceed in freeze dryer, 0.01mbar～10mbar pressure ,-30 DEG C extremely
Lyophilization 1～10h under conditions of 30 DEG C, i.e. obtains described loratadine freeze-drying tablet.
2. loratadine freeze-drying tablet as claimed in claim 1, it also can add before proceeding to freeze dryer after pre-freeze step
The step of ice crystal hatching, will the mould being marked with solution after pre-freeze, put in the low temperature environment of-5 DEG C～-60 DEG C, the time is 5
～15h.
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| CN201110176708.9A CN102451169B (en) | 2010-10-22 | 2011-06-28 | Loratadine freeze-drying tablet and preparation method thereof |
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| CN104873443B (en) * | 2015-06-25 | 2017-08-25 | 湖南一九生物科技有限公司 | A kind of SOD skin care item and preparation method |
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| CN1449280A (en) * | 2000-07-04 | 2003-10-15 | Lts罗曼治疗方法有限公司 | Rapidly disintegrating dosage forms for release of active ingredients in the oral cavity or body cavity |
| CN1689649A (en) * | 2004-04-30 | 2005-11-02 | 量子高科（北京）研究院有限公司 | Oral cavity quick dissolving preparation and production method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1449280A (en) * | 2000-07-04 | 2003-10-15 | Lts罗曼治疗方法有限公司 | Rapidly disintegrating dosage forms for release of active ingredients in the oral cavity or body cavity |
| CN1689649A (en) * | 2004-04-30 | 2005-11-02 | 量子高科（北京）研究院有限公司 | Oral cavity quick dissolving preparation and production method thereof |
| CN100479809C (en) * | 2004-04-30 | 2009-04-22 | 量子高科（北京）研究院有限公司 | Oral disintegration preparation and preparing method thereof |
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