CN1552312A - Oral solid quick releasing agent - Google Patents

Abstract

A quick-releasing solid medicine for oral application is disclosed, which has the active component with poor taste. Its advantage is high disintegrability and solubility in oral cavity.

Description

Oral cavity solid fast dissolving dosage form

The present invention relates to a kind of solid dosage forms, relate to contain the oral cavity solid fast dissolving dosage form of the active component of uncomfortable taste specifically.

Background technology

Oral cavity solid quick releasing formulation comprises oral cavity quick disintegrating slice and oral instant-dissolving tablet, mainly be meant can be after taking in the oral cavity quick disintegrate or rapidly-soluble solid preparation, its can dissolving or the disintegrate rapidly in 15 seconds to 2 minutes after meeting water or saliva.This dosage form can be dispersed or dissolved in saliva rapidly after putting into mouth, and medicine can pass through oral cavity or intraesophageal mucosa absorption, and bioavailability has special effect than ordinary preparation height in the occasion of wishing the medicine quick acting.This dosage form listing of FDA approved.

The disintegrating property of preparation and physical property are the ultimate challenges of such formulation development.Particularly disadvantageously, when containing uncomfortable taste active component in the preparation, usually to adopt special process, for example add a large amount of correctives (Bixx etc., Method Drug Development and Industrial Pharmacy, 1999,25 (5): 571), perhaps active ingredient particle is carried out the coating (CN1328446A) of complex process.With the granule coating is example, and it all has in various degree influence to the hardness of preparation and medicine stripping, and cost is raise.

Different with the ordinary preparation used swallowed, oral cavity solid fast dissolving dosage form must solve the mouthfeel and the taste problem of preparation.For the low medicine of uncomfortable taste threshold value, the stripping of trace medicine is also stayed and can be caused the insufferable uncomfortable sense of taste in the oral cavity, and patient's treatment compliance is significantly reduced, and is unfavorable for carrying out smoothly of clinical treatment work.A difficult problem of Chan Shenging for example comprises thereupon: how to regulate the balance between disintegrate and the stripping, preparation was not discharged in the quickly disintegrated while more have uncomfortable taste active component, it is minimum promptly uncomfortable taste to be reduced to; Perhaps how to make above-mentioned uncomfortable taste reduce to minimum preparation and have suitable hardness and crisp broken degree etc.Yet, do not find the clearly instruction of relevant solution in the prior art.

Summary of the invention

An object of the present invention is to provide a kind of oral cavity solid fast dissolving dosage form that contains the active component of uncomfortable taste.Said preparation has excellent Orally disintegrating and dissolubility and suitable hardness, and takes Shi Buhui and feel undesirable medicine taste.According to the needs of active component and specific adaptations disease, described preparation can be made oral cavity quick disintegrating slice and oral instant-dissolving tablet.

In the present invention, the active component with uncomfortable taste comprises the active skull cap components of water solublity and/or slightly solubility, and described uncomfortable taste is the taste of instigating the user unhappy, for example bitterness, astringent taste or tart flavour.Described active skull cap components includes but not limited to: Radix Salviae Miltiorrhizae extract, Semen Ginkgo extrac, Radix Notoginseng extract, breviscapine extract, Fructus Schisandrae Chinensis extrat, Radix Ginseng extract, Rhizoma Chuanxiong extract, Radix Astragali extract, Lignum Dalbergiae Odoriferae extract, Borneolum Syntheticum etc. or their mixture.Can adopt the mode of drug combination, above-mentioned active component is added in the described preparation simultaneously, for example can prepare the oral cavity solid fast dissolving dosage form that contains Semen Ginkgo-Radix Salviae Miltiorrhizae, Semen Ginkgo-Radix Notoginseng, Radix Salviae Miltiorrhizae-Radix Notoginseng-Borneolum Syntheticum, the Radix Salviae Miltiorrhizae-Radix Notoginseng-Radix Astragali-Borneolum Syntheticum, the Radix Salviae Miltiorrhizae-Radix Notoginseng-Radix Astragali-Lignum Dalbergiae Odoriferae, Radix Notoginseng-breviscapine, Rhizoma Chuanxiong-Borneolum Syntheticum etc. respectively.Being suitable for active component of the present invention can be solid, powder or granule, crystal form.Advantageously, can before preparation, described active skull cap components be handled, make it to be more suitable for preparing required dosage form.For example, can carry out spray drying method to active skull cap components and handle, improve its water solublity, make it need not further pulverizing, avoid moisture absorption.Randomly, mouthfeel or dissolving/performances such as release for the further described preparation of improvement/control can adopt conventional capsule material (for example Eudragit E100, EC etc.) with active skull cap components bag microcapsule, thereby improve its mouthfeel, and avoid moisture absorption; Or active skull cap components made cyclodextrin (for example, beta-schardinger dextrin-, HYDROXYPROPYL BETA-CYCLODEXTRIN etc.) clathrate, and improve its mouthfeel, promote instantly, also can avoid moisture absorption simultaneously; Perhaps in advance active skull cap components and suitable gellant (for example pregelatinized Starch, sodium alginate, calcium alginate, L-HPC etc.) are mixed and made into granule.

Specifically, oral cavity of the present invention solid fast dissolving dosage form comprises active skull cap components and the pharmaceutically acceptable auxiliaries with uncomfortable taste, and described pharmaceutic adjuvant comprises filler, disintegrating agent.For example one of mannitol, xylitol, sorbitol, erythrose, microcrystalline Cellulose, maltose, lactose or their mixture of filler wherein.Described disintegrating agent for example comprises one of crospolyvinylpyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl methylcellulose, cross-linked cellulose sodium or their mixture.

Advantageously, dosage form of the present invention also can comprise effervescent, with further regulation and control disintegration rate.Acid source citric acid, tartaric acid, fumaric acid, caproic acid, water-soluble amino acid, the acid of rare ore deposit (hydrochloric acid for example for example wherein?), acid salt (for example citric acid sodium dihydrogen potassium, potassium hydrogen tartrate, fumaric acid sodium), be preferably citric acid.For example sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium carbonate-sodium bicarbonate (1: 9) of carbon dioxide source wherein.The ratio of described acid source and carbon dioxide source is 0.5: 1-0.8: 1, and preferable ratio is 0.6: 1-0.76: 1.

Randomly, can add correctives, for example essence, bitterness masking agent, aspartame, saccharin sodium etc.

In one embodiment of the invention, provide the oral cavity solid fast dissolving dosage form that comprises following composition:

Each amounts of components of table 1, function and amount ranges:

	Consumption (mg/ sheet)	Function	Effect	Consumption (%)	Preferable amount (%)
						Principal agent	????25	Active component
Mannitol	????80	Filler	Improve taste	????30-70	????45-55
						Microcrystalline Cellulose	????15	Filler	Increase compressibility	????7-20	????10-15
Citric acid	????5	Effervescent	Quicken disintegrate	????2-7	????3-4
						Cross-linked pvp	????7	In with disintegrating agent	Disintegrate	4-8 (contain and add)	(6.5-7.5 contain and add)
Sodium bicarbonate	????7	Effervescent	Quicken disintegrate	?????*	????*
						Cross-linked pvp	????3.5	Add disintegrating agent	Disintegrate	?????**	????**
Borneolum Syntheticum	????2.5
						Micropowder silica gel	????0.75	Fluidizer	Increase mobile	????0.3-1	????0.4-0.6

^*: the consumption of sodium bicarbonate is suitable with the amount of substance of citric acid;

^*: the consumption that adds disintegrating agent is generally and collapses the 25%-50% of agent with consumption.

In another embodiment of the invention, also provide a kind of method for preparing oral cavity solid fast dissolving dosage form.Compare with consuming time, complex process, solid fast dissolving dosage form preparation process (for example freeze drying process, solid solution technology, drying process with atomizing, direct compression technology) that manufacturing cost is high, the cost of wet method secondary granulation tablet forming technique of the present invention is low, technology is simpler, and available adjuvant scope is wideer.

When adopting the active skull cap components of spray powder form, drug dose is big, and bulk density is little, and hygroscopicity is strong, needs to add a large amount of mobile good adjuvants usually.Be not subjected to the restriction of any theory, we infer it is because active component and adjuvant form eutectic through the secondary back of granulating, thereby make the hygroscopicity reduction of active component, and have good flowability, but voltage supply sheet and sticking not, and mouthfeel is good, does not have grittiness.Simultaneously slice, thin piece has good surface appearance and suitable hardness, can adopt common aluminum-plastic packaged, transportation and from individual packaging take out still can be complete the process of taking profile.

Preparation of the present invention has remarkable disintegrative or solvability in the oral cavity, so it can be used as and can and be easy to the preparation of the orally disintegrable of administration when not having water to old people or child's administration, is used for the treatment of or prevents various diseases.And, because preparation of the present invention contains the fine grained with mean diameter,, it produces sand type in the oral cavity so will can not making, it can be easily, without any the administration of uncomfortable ground.

Embodiment 1 contains the preparation of Semen Ginkgo extrac

Prescription:

Form every consumption (mg)

Principal agent microcapsule 120

Pregelatinized Starch 40

Microcrystalline Cellulose 30

Citric acid 10

Sodium bicarbonate 14

Cross-linked pvp 16

Aspartame 2

Fragrant citrus essence 2

Micropowder silica gel 2

Preparation technology:

1. to cross 80 mesh sieves standby for each adjuvant and principal agent microcapsule;

2. accurately take by weighing principal agent microcapsule, pregelatinized Starch, microcrystalline Cellulose, citric acid, sodium bicarbonate, cross-linked pvp recipe quantity, mixing adds an amount of dehydrated alcohol system soft material, crosses 20 mesh sieves and granulates, and drying is 40 minutes under 50 ℃ of conditions, crosses 20 mesh sieve granulate;

3. in the gained granule, add all the other adjuvants, be punched in suitable pressure lower sheeting with No. 9 scrobiculas behind the mixing.

The preparation of principal agent microcapsule:

(Eudragit E100 40mg, EC 80mg) dissolves in 500ml with the capsule material, in 95% ethanol, adds principal agent 40mg again, fully stirs, and mixing obtains suspension, and spray drying promptly.

Embodiment 2 contains the preparation of Radix Salviae Miltiorrhizae extract

Adopt the water extract of Radix Salviae Miltiorrhizae, Radix Notoginseng, adopt the compound Salviae Miltiorrhizae fine powder of spray drying method for preparation.Because Radix Salviae Miltiorrhizae, Radix Notoginseng two flavor medical materials adopt and mix traditional leaching method of frying in shallow oil, guarantee the synergism of fried according to a certain ratio and each main constituent of each main constituent.

Prescription:

Form every consumption (mg)

Principal agent 25

Mannitol 80

Microcrystalline Cellulose 15

Citric acid 5

Crospolyvinylpyrrolidone 7 (in add)

Sodium bicarbonate 7

Crospolyvinylpyrrolidone 3.5 (adding)

Borneolum Syntheticum 2.5

Fragrant citrus essence 1.5

Odor mask 1.5

Aspartame 1

Micropowder silica gel 0.75

Magnesium stearate 0.75

Preparation technology:

1. it is standby that adjuvant is crossed 100 mesh sieves;

2. really principal agent, mannitol, little smart cellulose and the citric acid of weighing recipe quantity, mixing, with an amount of dehydrated alcohol system soft material, the granulation of mistake 20-24 order was in 50-60 ℃ of dry 40-60 minute;

3. with 2 gained dried particles porphyrizes, cross behind 80 mesh sieves with in add cross-linked pvp, the sodium bicarbonate equivalent method mixing that progressively increases, with an amount of dehydrated alcohol system soft material, the granulation of mistake 20-24 order was in 50-60 ℃ of dry 40-60 minute;

4. 3 gained dried particles are crossed 20-24 order granulate, add fragrant citrus essence, odor mask, aspartame, micropowder silica gel, magnesium stearate again, behind the mixing with No. 8 flat oblique impact heads at suitable pressure lower sheeting.

Annotate: principal agent is that Radix Salviae Miltiorrhizae, Radix Notoginseng extracting solution or the spray-dried preparation of extractum get.In addition, also available beta-schardinger dextrin-of Borneolum Syntheticum or HYDROXYPROPYL BETA-CYCLODEXTRIN enclose promote its stripping and shelter the thorn flavor.

Embodiment 3 contains the preparation of Radix Notoginseng and breviscapine

Prescription:

Form every consumption (mg)

Principal agent 50

Pregelatinized Starch 35

Microcrystalline Cellulose 40

Citric acid 5

Sodium bicarbonate 7

Crospolyvinylpyrrolidone 25

Aspartame 2

Fragrant citrus essence 2

Micropowder silica gel 2

Preparation technology:

1. it is standby each adjuvant to be crossed 80 mesh sieves;

2. accurately take by weighing principal agent microcapsule, pregelatinized Starch, microcrystalline Cellulose, citric acid by recipe quantity, mixing adds an amount of dehydrated alcohol system soft material, crosses 20 mesh sieves and granulates, and drying is 40 minutes under 50 ℃ of conditions;

3. above-mentioned gained dried particles is pulverized sodium bicarbonate, the cross-linked pvp mixing of back and recipe quantity, the same granulation, drying are after 20 mesh sieve granulate;

4. add all the other adjuvants in the granule behind granulate, put down being punched in suitable pressure lower sheeting behind the mixing with No. 9.

Annotate: principal agent is that breviscapine, Radix Notoginseng extracting solution or the spray-dried preparation of extractum get.

Embodiment 4 contains the preparation of the HYDROXYPROPYL BETA-CYCLODEXTRIN clathrate of Radix Salviae Miltiorrhizae extract

Prescription:

Form every consumption (mg)

Principal agent HYDROXYPROPYL BETA-CYCLODEXTRIN clathrate 37.5

Pregelatinized Starch 25

Lactose 25

Microcrystalline Cellulose 35

Crospolyvinylpyrrolidone 40

Aspartame 2

Flavoring orange essence 2

Micropowder silica gel 2

Preparation technology:

1 that each adjuvant is crossed 80 mesh sieves is standby;

2 accurately take by weighing the principal cartridge compound by recipe quantity, by equivalent incremental method and each auxiliary materials and mixing, cross 80 mesh sieves 3 times, put down being punched in suitable pressure lower sheeting with No. 9.

The preparation of principal agent HYDROXYPROPYL BETA-CYCLODEXTRIN clathrate:

(Salvia miltiorrhiza and Panax notoginseng extractum: HYDROXYPROPYL BETA-CYCLODEXTRIN is about 2: 1 in right amount to take by weighing Radix Salviae Miltiorrhizae, Radix Notoginseng extractum and HYDROXYPROPYL BETA-CYCLODEXTRIN respectively, W/W), place round-bottomed flask, add water and just dissolve to the two in right amount, under 50 degrees centigrade with per minute 500 change stir 6 hours after, the heat filter, remove insoluble impurities (being mainly Plant fiber and polysaccharide), with the filtrate lyophilizing, get dry, porous solid, crushing screening is promptly.Randomly, also can carry out cyclodextrin or HYDROXYPROPYL BETA-CYCLODEXTRIN enclose, to regulate and control its stripping, while masking stimulus abnormal smells from the patient to Borneolum Syntheticum.

Embodiment 5 contains the preparation of the HYDROXYPROPYL BETA-CYCLODEXTRIN clathrate of Semen Ginkgo extrac

Prescription:

Form every consumption (mg)

Principal agent HYDROXYPROPYL BETA-CYCLODEXTRIN clathrate 60

Pregelatinized Starch 35

Microcrystalline Cellulose 50

Low-substituted hydroxypropyl methylcellulose 40

Aspartame 2

Flavoring orange essence 2

Micropowder silica gel 2

Preparation technology:

It is standby that 1 each adjuvant is crossed 80 mesh sieves;

2 accurately take by weighing the principal cartridge compound by recipe quantity, by equivalent incremental method and each auxiliary materials and mixing, cross 80 mesh sieves 3 times, put down being punched in suitable pressure lower sheeting with No. 10.

The preparation of principal agent HYDROXYPROPYL BETA-CYCLODEXTRIN clathrate:

Get 25% HYDROXYPROPYL BETA-CYCLODEXTRIN alcoholic solution (W/V), (Semen Ginkgo extrac: the HYDROXYPROPYL BETA-CYCLODEXTRIN alcoholic solution is about 1: 5 in right amount to add Semen Ginkgo extrac, W/V), under the room temperature, after 8 hours, filter evaporate to dryness with the stirring of per minute 500 rotary speeds, vacuum drying gets pressed powder, pulverizes promptly.

Embodiment 6 contains the preparation of Fructus Schisandrae Chinensis

Form every consumption (mg)

Principal agent 40mg

Mannitol 60mg

Microcrystalline Cellulose 20mg

Citric acid 5mg

Cross-linked pvp (in add) 7mg

Sodium bicarbonate 7mg

Cross-linked pvp (adding) 3.5mg

Fragrant citrus essence 1mg

Odor mask 1mg

Aspartame 0.5mg

Micropowder silica gel 0.75mg

Magnesium stearate 0.75mg

Preparation technology:

1 that each adjuvant is crossed 100 mesh sieves is standby;

The principal agent of 2 accurate weighing recipe quantities, mannitol, little smart cellulose and citric acid, mixing with an amount of dehydrated alcohol system soft material, was crossed 20 orders and is granulated, in 40 ℃ of dryings 45 minutes;

3 will be 2. gained dried particles porphyrize, cross behind 80 mesh sieves with in add cross-linked pvp, the sodium bicarbonate equivalent method mixing that progressively increases, with an amount of dehydrated alcohol system soft material, the granulation of 24 orders, in 40 ℃ of dryings 45 minutes;

4 will be 3. the gained dried particles cross 20 order granulate, add fragrant citrus essence, odor mask, aspartame, micropowder silica gel, magnesium stearate again, behind the mixing with No. 8 flat oblique impact heads at suitable pressure lower sheeting.Annotate: principal agent is that Fructus Schisandrae Chinensis extractive solution or the spray-dried preparation of extractum get.

Claims (10)

1. oral cavity solid fast dissolving dosage form, comprising the active skull cap components with uncomfortable taste, filler and disintegrating agent, described filler is selected from mannitol, xylitol, sorbitol, erythrose, microcrystalline Cellulose, maltose, lactose or their mixture and described disintegrating agent is selected from crospolyvinylpyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl methylcellulose, cross-linked cellulose sodium or their mixture.

2. according to the dosage form of claim 1, described active skull cap components is selected from Radix Salviae Miltiorrhizae extract, Semen Ginkgo extrac, Radix Notoginseng extract, breviscapine extract, Fructus Schisandrae Chinensis extrat, Radix Ginseng extract, Rhizoma Chuanxiong extract, Radix Astragali extract, Lignum Dalbergiae Odoriferae extract, Borneolum Syntheticum etc. or their mixture.

3. according to the dosage form of claim 1 or 2, described active skull cap components is treated before preparation.

4. according to the dosage form of claim 1 or 2, described active skull cap components is that spray-dried, bag microcapsule, Benexate Hydrochloride or gelatine are handled.

5. according to the dosage form of claim 1 or 2, described Borneolum Syntheticum is through the hydroxypropyl enclose.

6. according to the dosage form of one of claim 1-5, further comprise effervescent, correctives and/or fluidizer.

7. prepare the method for the described oral cavity of claim 1 solid fast dissolving dosage form, may further comprise the steps:

A) with each adjuvant sieving for standby;

B) measure active skull cap components by prescription, with auxiliary materials and mixing;

C) sieve and mixing, be punched in suitable pressure lower sheeting with suitable model flat.

8. according to the method for claim 7, be included in before the step c), add an amount of dehydrated alcohol system soft material, sieve and granulate and drying.

9. method according to Claim 8 comprises that further the gained granule is carried out the wet method secondary granulates, and adds all the other adjuvants then, is punched in suitable pressure lower sheeting with suitable model flat behind the mixing.

10. according to the method for one of claim 7-9, wherein active skull cap components is that spray-dried, bag microcapsule, Benexate Hydrochloride or gelatine are handled.