CN1714793A - Famciclovir slow-releasing capsule for anti-virus treatment and its producing method - Google Patents
Famciclovir slow-releasing capsule for anti-virus treatment and its producing method Download PDFInfo
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Abstract
The present invention relates to a kind of slow-releasing famciclovir capsule for antiviral treatment, and features that the slow-releasing famciclovir capsule is prepared through coating famciclovir medicine with supplementary material to form the pellet core, coating the pellet core with inner release controlling layer of water insoluble polymer, re-coating with outer release controlling layer of enteric polymer to form release controlling famciclovir pellet, and encapsulating famciclovir pellet to form the slow-releasing famciclovir capsule. In artificial gastric juice and artificial intestinal juice, the slow-releasing famciclovir capsule has its medicine releasing degree of 10-30 %, 30-70 % and over 70 % separately in 1.5 hr, 3 hr and 8 hr. The pellet is measured to have medicine content of 56.8-65.2 %.
Description
Technical field
The present invention relates to a kind of famciclovir sustained-release capsule and production method thereof that is used for antiviral therapy.
Background technology
(famciclovir FCV) equals the acyclic nucleoside class antiviral drugs synthetic, that GSK (GlaxoSmithKline) company develops and put on market in 1994 in 1985 by Harnden to famciclovir, is the guanosine analog.Herpes simplex virus I-type (HSV-I), II type (HSV-II), varicella zoster virus (VZV) and hepatitis B virus (HBV) etc. are had inhibitory action, and its curative effect is better than acyclovir commonly used clinically at present when being used for the treatment of herpes zoster, herpes facialis and genital herpes clinically.The effect of its treatment hepatitis B also is subject to people's attention day by day, and at present, famciclovir is carrying out clinical research as the new drug of treatment chronic hepatitis B.
Famciclovir be penciclovir (penciclovir, precursor medicine PVC) are absorbed rapidly after oral, and relevant enzyme is sloughed two acetyl group in intestinal wall and liver, and with on its purine ring 6 be oxidized to ketone group, change into penciclovir.In HSV-I, HSV-II and VZV infection cell; penciclovir is earlier by viral distinctive thymidine kinase (ThymidineKinase; TK) single phosphorylated; the penciclovir phosplate (PCV-MP) that forms; further by host enzyme catalysis two phosphorylated and three phosphorylated being taken place successively, forms intravital active component penciclovir triphosphate (PCV-TP) more at last.PCV-TP is brought in the viral DNA chain by the wrong NSC 22837 for the treatment of as of viral DNA polymerase, the synthetic of viral DNA is suppressed, thereby the effect of anti-herpesvirus takes place.On the contrary, penciclovir does not almost have effect seldom by phosphorylation to human normal cell's archaeal dna polymerase in non-infected cell, and safety is good.The mechanism of the anti-HBV of famciclovir is machine-processed different with anti-herpesvirus, and its mechanism is still not fully aware of, but the active metabolite of the anti-HBV effect of performance in vivo also is PCV-TP.
Famciclovir has overcome the low defective of direct oral penciclovir bioavailability, and bioavailability is up to 77%, reaches maximum plasma concentration in about 1 hour.Studies show that its blood halflife is about 2 hours.And in virus infected cell, the half-life of PCV-TP is 10-12 hour.There is greatest differences in half-life in its blood halflife and the virus infected cell.
The famciclovir sheet of China's listing, treatment herpes zoster and primary genitalia herpes dosage are 250mg, 3 times on the one, 7 days courses of treatment; And in the clinical research of the use famciclovir sheet that my company is just carrying out treatment chronic viral hepatitis B, the patient needs medication every day 3 times, each 500mg, and the course of treatment is half a year at least.Because every day, medicining times was many, the course of treatment is long, can cause patient's drug compliance bad, occurs because of missing the situation of the unsatisfactory curative effect that causes easily.Therefore, the exploitation of famciclovir sustained-release preparation has bigger meaning, not only can reach required blood drug level, and the energy held stationary, and can improve patient's drug compliance, thereby makes medicine bring into play due curative effect.
Preclinical study shows that the active metabolite penciclovir of famciclovir reaches the effect that shows the inhibition virus replication on duck hepatitis B animal model to the HepG2.2.15 cell strain of In vitro culture.Trepo report in 1996 is used famciclovir and is treated 330 routine chronic hepatitis B patients, confirms that famciclovir can suppress hepatitis B virus (HBV) and duplicate.In recent years along with the application of internationally recognized anti-HBV medicine alpha-interferon and lamivudine (lamivudine) at present, the effective percentage that shows alpha-interferon treatment chronic hepatitis B is about 30%, relapse rate height after the drug withdrawal, lamivudine is a cytosine nucleoside analogs, it is HBV-DNA polymerase inhibitor, its the treatment chronic hepatitis B in the time of 1 year the HBV-DNA negative conversion rate can reach 80%, but the HbeAg negative conversion rate is only about 20%--30%, and bounce after the drug withdrawal, long-term prescription causes hepatitis B virus to morph, and produces drug resistance.Recent study shows that therapeutic alliance or sequential therapy ratio use single antiviral treatment hepatitis B effective.Also there are famciclovir and other drug to unite use, comprise the report that associating lamivudine, alpha-interferon use.Famciclovir not only has the HBV-DNA of inhibition and duplicates effect, also has the effect that suppresses covalently closed circular DNA (cccDNA) in the hepatocyte, and this cccDNA is the primary template of virus replication.The clinical research report of recurrence hepatitis B after the external existing 600 many cases famciclovirs prevention liver transplantation.
Behind the famciclovir tablet oral administration, blood drug level changes greatly, and no matter for independent antiviral therapy or combination antiviral therapy, this variation is all very unfavorable.There are 1.3 hundred million hepatitis B virus carrierss (comprising 3,000,000 chronic viral hepatitis B patients) in China, at the present situation that lacks treatment hepatitis B good medicine at present clinically, is necessary to develop the novel form of famciclovir.
The inventor notices: the blood halflife of PCV-TP is about 2 hours.And in virus infected cell, the half-life of PCV-TP is 10-12 hour.There is greatest differences in half-life in its blood halflife and the virus infected cell, is necessary famciclovir is made slow releasing capsule.
Summary of the invention
The purpose of this invention is to provide efficient, low toxicity, the patient uses the high a kind of famciclovir sustained-release capsule that is used for antiviral therapy of compliance.
Further purpose of the present invention provides the capsular production method of the famciclovir sustained-release that uses in antiviral therapy.
Above-mentioned purpose of the present invention adopts following technical scheme to be achieved:
A kind of famciclovir sustained-release capsule that is used for antiviral therapy, it is characterized in that: constitute the ball core with adjuvant piller outsourcing famciclovir medicine layer, outside medicine layer, constitute the controlled release internal layer of control drug release by insoluble polymer, outside described controlled release internal layer, the controlled release outer coating that cladding is made of enteric polymer, make the famciclovir sustained-release piller, described piller filling constitutes the famciclovir sustained-release capsule in capsule.
By making 1000 calculating of slow releasing capsule, it is composed as follows that various components account for the weight percent of total charges in the every mass of 1000 kernel 192-220g, capsule:
Each component accounts for the percentage by weight of total charges and is in the ball core:
Famciclovir 56.8%-65.2%
Sucrose (or microcrystalline Cellulose) 13.1%-15%
Starch 5.1%-5.8%
Micropowder silica gel 1.1%-1.3%
Polyvidone (or hypromellose) 2.5%-2.9%
Each component accounts for the percentage by weight of total charges and is in the controlled release internal layer:
Insoluble polymer (quaternary amine methacrylate PO or ethyl cellulose) 3.6%-7.9%
Polyethylene glycol 6000 0.36%-0.79%
Antiblocking agent (Pulvis Talci) 0.91%-1.98%
Magnesium stearate 0.91%-1.98%
Each component accounts for the percentage by weight of total charges and is in the controlled release outer coating:
Enteric polymer (polyacrylic resin II) 1.26%-2.75%
Enteric polymer (polyacrylic resin III) 1.26%-2.75%
Plasticizer (polyethylene glycol 6000) 0.25%-0.55%
Antiblocking agent (Pulvis Talci) 0.63%-1.36%
The magnesium stearate surplus
The capsular famciclovir sustained-release piller of famciclovir sustained-release is done medium with simulated gastric fluid, simulated intestinal fluid, and the release scope 1.5 hours, 3 hours and 8 hours is respectively: more than 10%-30%, the 30%-70% and 70%.
The famciclovir sustained-release capsule adopts the slow release form of present most popular coated pellets, has in the safety, body advantages such as release is stable.Coated pellets serves as the adjuvant piller of preparation famciclovir ball core with sucrose piller or microcrystalline Cellulose piller, and adjuvant piller diameter is 0.5-0.7mm.In centrifugal granulator, prepare the medicine piller with poudrage.The binding agent that preparation famciclovir ball core is selected is polyvidone or hypromellose.Binding agent is mixed with aqueous solution or organic solvent solution uses.
The controlled release internal layer polymer of cladding is selected quaternary amine methacrylate or ethyl cellulose outside famciclovir piller (ball core).Can adopt polymer to be dissolved in the solution of organic solvent or the aqueous dispersion of polymer.In order to suppress famciclovir sustained-release piller rate of releasing drug faster in acid medium, the present invention clads the enteric polymer as controlled release outer coating again outside the controlled release internal layer, these enteric polymer comprise methylmethacrylate copolymer, ethyl methacrylate copolymers or hypromellose phthalate ester.Coating carries out in fluid bed (end spray).
The cladding amount of polymer is the principal element of decision rate of releasing drug.In the slow-release pill preparation, the cladding amount of the polymer of selection generally can be the 3-25% (w/w) of medicine ball core weight.But coating solution prescription of the present invention and coating operating procedure parameter also have a significant impact the rate of releasing drug of slow-release pill.The cladding amount of polymer depends on whether the piller behind the coating reaches the release that target level of product quality is stipulated in the actual coating operation.
Add an amount of plasticizer in the coating solution, for example Polyethylene Glycol, triethyl citrate, dibutyl sebacate and diethyl phthalate etc., suitable consumption is the 5-30% of polymer (w/w).Also should add an amount of antiblocking agent in the coating solution, for example Pulvis Talci, micropowder silica gel, magnesium stearate and tristerin etc., suitable consumption is the 5%-100% of polymer (w/w).
A kind of capsular production method of famciclovir sustained-release that is used for antiviral therapy, it is characterized in that: constitute the ball core with adjuvant piller outsourcing famciclovir medicine layer, outside medicine layer, constitute the controlled release internal layer of control drug release by insoluble polymer, outside described controlled release internal layer, clad the controlled release outer coating that constitutes by enteric polymer again, make the famciclovir sustained-release piller, described piller filling constitutes the famciclovir sustained-release capsule in capsule.
In famciclovir piller (ball core) preparation: sucrose piller or microcrystalline Cellulose (0.5-0.7mm) 500 weight portions are placed centrifugal coating pelletizing machine, after the start, with 15 weight portions/minute speed spray 5% polyvidone alcoholic solution, 1200 weight portions, simultaneously with 20 weight portions/minute speed be sprinkled into famciclovir powder 1500-1600 weight portion, the medicine piller that makes was placed 50 ℃ of baking ovens dry 4 hours;
In the preparation of famciclovir sustained-release piller:
With famciclovir piller (ball core) (0.9-1.25mm) 1000 weight portions place the bottom spraying type fluidized-bed coating machine, spraying cladding quaternary amine methacrylic acid ester solution, the coating solution prescription is as follows:
Quaternary amine methacrylate 100 weight portions
Polyethylene glycol 6000 10 weight portions
Water 20 weight portions
Magnesium stearate 25 weight portions
Pulvis Talci 25 weight portions
95% ethanol, 1820 weight portions
When quaternary amine methacrylate cladding amount reaches 10% (w/w) of famciclovir pellet weight, clad one deck enteric solubility methacrylate copolymer more outside, the cladding amount of enteric polymer is 5.0% of a famciclovir pellet weight, and (w/w), the prescription of enteric layer coating solution is as follows:
Polyacrylic resin II 25.0 weight portions
Polyacrylic resin III 25.0 weight portions
Polyethylene glycol 6000 5.0 weight portions
Water 10.0 weight portions
Magnesium stearate 12.5 weight portions
Pulvis Talci 12.5 weight portions
95% ethanol, 910.0 weight portions
With piller in 40 ℃ of baking ovens dry 4 hours, the medicament contg of measuring in the piller was 56.8%-65.2% behind the coating EO, and every mass of 1000 kernel 192-220g packs piller in the capsulae vacuus into, makes the famciclovir sustained-release capsule.
After the administration of famciclovir sustained-release capsule oral, blood drug level rises slowly, concentration change is steady, the blood drug level horizontal dimension of 0.5～12h is held between 1.30～3.42 μ g/ml after the administration, the concentration of 12h and 18h almost is more than the twice of ordinary tablet, slow releasing capsule is kept the time of effective penciclovir level in the blood and significantly is longer than ordinary tablet, and both relative bioavailability is suitable.The famciclovir sustained-release capsule can be widely used in treating the antiviral therapy of multiple viral diseases such as herpes zoster and genital herpes and Type B viral hepatitis, viral hepatitis C, for resembling China such hepatitis b virus carrier and the numerous country of patient thereof, acquire a special sense.
Famciclovir sustained-release capsule of the present invention is by control medicine rate of release in vivo, reduced administration number of times, administration every day is 1-2 time when treating banded herpes infection and primary genitalia herpes, each 375mg, reach the equal drug effect of ordinary preparation with administration every day 3 times, and be convenient to patient and regularly take sooner or later, help improving drug compliance, guarantee the due therapeutic effect of medicine.
The capsular release of famciclovir sustained-release is done medium with simulated gastric fluid, simulated intestinal fluid, and the burst size 1.5 hours, 3 hours and 8 hours is respectively more than 10%-30%, 30%-70% and 70%, compares with the famciclovir ordinary tablet, and tangible slow release effect is arranged.The sign content of HPLC method working sample is in the 90.0-110.0% scope.
The capsular removal outer package of famciclovir sustained-release is examined or check under high temperature and super-humid conditions, presents good stable; The famciclovir sustained-release capsule is examined or check under high temperature and super-humid conditions at commercially available back, presents good stable; The famciclovir sustained-release capsule was placed 18 months in commercially available back at ambient temperature, and every index has no significant change, and has good stability.
The specific embodiment
Embodiment 1
A kind of famciclovir sustained-release capsule that is used for antiviral therapy, it is characterized in that: constitute the ball core with adjuvant piller outsourcing famciclovir medicine layer, outside medicine layer, constitute the controlled release internal layer of control drug release by insoluble polymer, outside described controlled release internal layer, clad the controlled release outer coating that constitutes by enteric polymer again, make the famciclovir sustained-release piller, described piller filling constitutes the famciclovir sustained-release capsule in capsule.
By making 1000 calculating of slow releasing capsule, it is composed as follows that various components account for the weight percent of total charges in the every mass of 1000 kernel 192-220g, capsule:
Each component accounts for the percentage by weight of total charges and is in the ball core:
Famciclovir 56.8%
Sucrose 13.1%
Starch 5.1%
Micropowder silica gel 1.1%
Polyvidone (or hypromellose) 2.5%
Each component accounts for the percentage by weight of total charges and is in the controlled release internal layer:
Insoluble polymer (quaternary amine methacrylate or ethyl cellulose) 7.9%
Polyethylene glycol 6000 0.79%
Antiblocking agent (Pulvis Talci) 1.98%
Magnesium stearate 1.98%
Each component accounts for the percentage by weight of total charges and is in the controlled release outer coating:
Enteric polymer (polyacrylic resin II) 2.75%
Enteric polymer (polyacrylic resin III) 2.75%
Plasticizer (polyethylene glycol 6000) 0.55%
Antiblocking agent (Pulvis Talci) 1.36%
The magnesium stearate surplus
Present embodiment adopts the adjuvant piller of sucrose piller for preparation famciclovir ball core, and adjuvant piller diameter is 0.5mm.
The binding agent that preparation famciclovir ball core is selected is a polyvidone, and binding agent is mixed with aqueous solution or organic solvent solution uses.Present embodiment ball core can adopt inertia ball core outsourcing medicine method or extruding round method to produce.
The capsular release of famciclovir sustained-release is done medium with simulated gastric fluid, simulated intestinal fluid, and the burst size 1.5 hours, 3 hours and 8 hours is respectively more than 10%-30%, 30%-70% and 70%.
Embodiment 2
Other are with embodiment 1, but the weight percent of charges is composed as follows in the capsule:
By making 1000 calculating of slow releasing capsule, the weight percent that the interior various components of capsule account for total charges is composed as follows:
Each component accounts for the percentage by weight of total charges and is in the ball core:
Famciclovir 61.00%
Sucrose (or microcrystalline Cellulose) 14.05%
Starch 5.45%
Micropowder silica gel 1.20%
Binding agent: polyvidone (or hypromellose) 2.70%
Each component accounts for the percentage by weight of total charges and is in the controlled release internal layer:
Insoluble polymer (quaternary amine methacrylate or ethyl cellulose) 5.75%
Polyethylene glycol 6000 0.575%
Antiblocking agent (Pulvis Talci) 1.44%
Magnesium stearate 1.44%
Each component accounts for the percentage by weight of total charges and is in the controlled release outer coating:
Enteric polymer (polyacrylic resin II) 2.00%
Enteric polymer (polyacrylic resin III) 2.00%
Plasticizer (polyethylene glycol 6000) 0.40%
Antiblocking agent (Pulvis Talci) 1.00%
The magnesium stearate surplus
Present embodiment adopts the adjuvant piller of sucrose piller for preparation famciclovir ball core, and adjuvant piller diameter is 0.6mm.
The binding agent that preparation famciclovir ball core is selected is a hypromellose, and binding agent is mixed with aqueous solution or organic solvent solution uses.
Embodiment 3
Other are with embodiment 1, but the weight percent of charges is composed as follows in the capsule:
By making 1000 calculating of slow releasing capsule, the weight percent that the interior various components of capsule account for total charges is composed as follows:
Each component accounts for the percentage by weight of total charges and is in the ball core:
Famciclovir 65.20%
Sucrose (or microcrystalline Cellulose) 15.00%
Starch 5.80%
Micropowder silica gel 1.30%
Binding agent: polyvidone 2.90%
Each component accounts for the percentage by weight of total charges and is in the controlled release internal layer:
Insoluble polymer (quaternary amine methacrylate or ethyl cellulose) 3.6%
Polyethylene glycol 6000 0.36%
Antiblocking agent (Pulvis Talci) 0.91%
Magnesium stearate 0.91%
Each component accounts for the percentage by weight of total charges and is in the controlled release outer coating:
Enteric polymer (polyacrylic resin II) 1.26%
Enteric polymer (polyacrylic resin III) 1.26%
Plasticizer (polyethylene glycol 6000) 0.25%
Antiblocking agent (Pulvis Talci) 0.63%
The magnesium stearate surplus
Present embodiment adopts the adjuvant piller of microcrystalline Cellulose for preparation famciclovir ball core, and adjuvant piller diameter is 0.7mm.
The binding agent that preparation famciclovir ball core is selected is a polyvidone.Binding agent makes aqueous solution or organic solvent solution uses.
Embodiment 4
Other are with embodiment 1,
But adopt the adjuvant piller of microcrystalline Cellulose piller for preparation famciclovir ball core, adjuvant piller diameter is 0.5mm.
Embodiment 5
Other are with embodiment 1,
The binding agent that preparation famciclovir ball core is selected is a hypromellose.Binding agent is mixed with aqueous solution or organic solvent solution uses.
Embodiment 6
Other are with embodiment 1,
But adopt the adjuvant piller of microcrystalline Cellulose piller for preparation famciclovir ball core, adjuvant piller diameter is 0.7mm.
Embodiment 7
A kind of capsular production method of famciclovir sustained-release that is used for antiviral therapy, it is characterized in that: constitute the ball core with adjuvant piller outsourcing famciclovir medicine layer, outside medicine layer, constitute the controlled release internal layer of control drug release by insoluble polymer, outside described controlled release internal layer, clad the controlled release outer coating that constitutes by enteric polymer again, make the famciclovir sustained-release piller, described piller filling constitutes the famciclovir sustained-release capsule in capsule;
In the preparation of famciclovir medicine piller: sucrose piller or microcrystalline Cellulose (0.5-0.7mm) 500 weight portions are placed centrifugal coating pelletizing machine, after the start, with 15 weight portions/minute speed spray 5% polyvidone alcoholic solution, 1200 weight portions, simultaneously with 20 weight portions/minute speed be sprinkled into famciclovir powder 1500-1600 weight portion, the medicine piller that makes was placed 50 ℃ of baking ovens dry 4 hours;
In the preparation of famciclovir sustained-release piller:
With famciclovir piller (ball core) (0.9-1.25mm) 1000 weight portions place the bottom spraying type fluidized-bed coating machine, spraying cladding quaternary amine methacrylic acid ester solution, the coating solution prescription is as follows:
Quaternary amine methacrylate 100 weight portions
Polyethylene glycol 6000 10 weight portions
Water 20 weight portions
Magnesium stearate 25 weight portions
Pulvis Talci 25 weight portions
95% ethanol, 1820 weight portions
When quaternary amine methacrylate quaternary amine methacrylate cladding amount reaches 10% (w/w) of famciclovir pellet weight, clad one deck enteric solubility methacrylate copolymer more outside, the cladding amount of enteric polymer is 5.0% of famciclovir piller (ball core) weight, (w/w), the prescription of enteric polymer coating solution is as follows:
Polyacrylic resin II 25.0 weight portions
Polyacrylic resin III 25.0 weight portions
Polyethylene glycol 6000 5.0 weight portions
Water 10.0 weight portions
Magnesium stearate 12.5 weight portions
Pulvis Talci 12.5 weight portions
With piller in 40 ℃ of baking ovens dry 4 hours, the medicament contg of measuring in the piller was 56.8%-65.2% behind the coating EO, and every mass of 1000 kernel 192-220g packs piller in the capsulae vacuus into, makes the famciclovir sustained-release capsule.
Present embodiment adopts the adjuvant piller of microcrystalline Cellulose piller for preparation famciclovir ball core, and adjuvant piller diameter is 0.5-0.7mm.
Embodiment 8
One, famciclovir sustained-release capsule animal pharmacokinetics and bioavailability study (adopting embodiment 2 capsule that obtains)
1, the relative bioavailability experiment that intersects at random behind oral famciclovir sustained-release capsule and the ordinary tablet 750mg of 6 healthy tike single doses shows, this slow releasing capsule blood drug level rises slowly, concentration change is steady, the blood drug level horizontal dimension of 0.5～12h is held between 1.30～3.42 μ g/ml after the administration, the concentration of 12h and 18h almost is more than the twice of ordinary tablet, the C of slow releasing capsule
MaxBe 3.47 ± 0.67 μ g/ml, T
MaxBe 1.92 ± 0.20h, and the C of ordinary tablet
MaxBe 6.00 ± 0.96 μ g/ml, T
MaxBe 0.75 ± 0.19h.Elimination half-life (the T of slow releasing capsule
1/2) prolong to some extent than ordinary tablet, but slow releasing capsule is suitable with the ordinary tablet bioavailability.
2,6 healthy tike multiple doses intersect the stable state pharmacokinetic of oral famciclovir sustained-release capsule and ordinary tablet at random and show that multiple dose continuous oral famciclovir sustained-release capsule and ordinary tablet 750mg every day reach stable state substantially after 3 days.Determination of plasma concentration result by the different time behind the 6th day single administration calculates its main stable state pharmacokinetic parameter: the C of slow releasing capsule
MaxBe 4.79 ± 1.03 μ g/ml, C
MinBe that 3.14 ± 1.16 μ g/ml, R (peak-to-valley ratio) are 1.64 ± 0.43, C
AvBe that 3.04 ± 0.92 μ g/ml, DF (fluctuation degree) are 58.2 ± 18.9%; The C of ordinary tablet
MaxBe 6.66 ± 1.27 μ g/ml, C
MinBe that 2.12 ± 0.79 μ g/ml, R (peak-to-valley ratio) are 3.44 ± 1.18, C
AvBe that 2.79 ± 0.78 μ g/ml, DF (fluctuation degree) are 167.1 ± 27.0%, this slow releasing capsule of results suggest has sustained releasing character.
Present embodiment shows:
6 healthy tike single doses intersect the determination of plasma concentration and the bioavailability study result of the different time behind oral famciclovir sustained-release capsule and the famciclovir ordinary tablet 750mg and show, this slow releasing capsule can make blood drug level keep maintenance level in a long time, the concentration of administration 0.5～12h is between 1.30～3.42 μ g/ml, the concentration of 12h and 18h is kept the time of penciclovir concentration＞IC50 (for HSV) in the blood and is longer than ordinary tablet almost at more than 2 times of ordinary tablet; Relative bioavailability is calculated and is shown that slow releasing capsule is suitable with ordinary tablet, and slow releasing capsule AUC/IC50 value and ordinary tablet do not have significant difference.
6 healthy tike multiple doses intersect the stable state pharmacokinetic of oral administration famciclovir sustained-release capsule and ordinary tablet and show, the peak-to-valley ratio of slow releasing capsule is significantly less than ordinary tablet (P＜0.01), the fluctuation degree is starkly lower than ordinary tablet (P＜0.01), demonstrate sustained releasing character, the prompting said preparation is a slow releasing preparation.
The preparation of embodiment 9 famciclovir pillers (ball core)
Sucrose piller (0.7-0.8mm) 500g places centrifugal comminutor, after the start, sprays 5% polyvidone alcoholic solution 1200g, is sprinkled into famciclovir powder 1500g with suitable speed, the medicine piller that makes simultaneously.Piller was placed 50 ℃ of baking ovens dry 4 hours.
The preparation of embodiment 10 famciclovir sustained-release pillers
Famciclovir piller (ball core) (0.8-0.9mm) 200g places the bottom spraying type fluidized-bed coating machine, spraying cladding quaternary amine methacrylic acid ester solution, and the coating solution prescription is as follows:
Quaternary amine methacrylate 50.0g
Triethyl citrate 5.0g
Pulvis Talci 25.0g
95% ethanol 920.0g
In the coating process, sampling when polymer cladding amount is 12.5% (w/w), 17.0% (w/w) and 23.0% (w/) is for drug release determination.The result is as follows:
| Polymer cladding amount (%, w/w) | Release (%) | ||
| 1 hour | 2 hours | 4 hours | |
| 12.5 | 52.6 | 78.7 | 92.7 |
| 17.0 | 38.5 | 72.3 | 90.0 |
| 23.0 | 25.5 | 59.0 | 82.4 |
The preparation of embodiment 11 famciclovir sustained-release pillers
Famciclovir piller (ball core) (0.8-0.9mm) 200g places the bottom spraying type fluidized-bed coating machine, spraying cladding quaternary amine methacrylic acid ester solution, and the coating solution prescription is as follows:
Quaternary amine methacrylate 50.0g
Triethyl citrate 5.0g
Pulvis Talci 12.5g
Magnesium stearate 12.5g
95% ethanol 920.0g
In the coating process, sampling when polymer cladding amount is 5.0% (w/w) and 6.0% (w/w) is for drug release determination.The result is as follows:
| Polymer cladding amount (%, w/w) | Release (%) | ||
| 1 hour | 2 hours | 4 hours | |
| 5.0 | 35.8 | 57.4 | 76.1 |
| 6.0 | 28.5 | 48.9 | 67.7 |
Compare as seen by embodiment 10 and embodiment 11: in coating, add hydrophobic magnesium stearate, but the blocking medicine rate of release.
The preparation of embodiment 12 famciclovir sustained-release pillers
Famciclovir piller (ball core) (0.8-0.9mm) 200g places the bottom spraying type fluidized-bed coating machine, spraying cladding quaternary amine methacrylic acid ester solution, and the coating solution prescription is as follows:
Quaternary amine methacrylate 50.0g
Polyethylene glycol 6000 5.0g
Water 10.0g
Magnesium stearate 12.5g
Pulvis Talci 12.5g
95% ethanol 910.0g
In the coating process, sampling when polymer cladding amount is 6.0% (w/w) is for drug release determination.The result is as follows:
| Polymer cladding amount (%, w/w) | Release (%) | |||||
| 1 hour | 2 hours | 3 hours | 4 hours | 6 hours | 8 hours | |
| 6.0 | 24.3 | 45.3 | 56.9 | 64.7 | 74.7 | 81.2 |
The present embodiment plasticizer is used polyethylene glycol 6000 instead, but the release of gained slow-release pill is similar to embodiment 11.
The preparation of embodiment 13 famciclovir sustained-release pillers
Famciclovir piller (ball core) (1.25-1.4mm) 200g places the bottom spraying type fluidized-bed coating machine, spraying cladding quaternary amine methacrylic acid ester solution, and the coating solution prescription is as follows:
Quaternary amine methacrylate 50.0g
Polyethylene glycol 6000 5.0g
Water 10.0g
Magnesium stearate 12.5g
Pulvis Talci 12.5g
95% ethanol 910.0g
In the coating process, sampling when polymer cladding amount is 4.0% (w/w) is for drug release determination.The result is as follows:
| Polymer cladding amount (%, w/w) | Release (%) | |||||
| 1 hour | 2 hours | 3 hours | 4 hours | 6 hours | 8 hours | |
| 4.0 | 25.6 | 47.2 | 58.8 | 65.3 | 78.7 | 88.6 |
The used medicine piller granularity of the manner is bigger, and total surface area reduces, and reaches the required polymer volume of same release and also reduces thereupon.
Claims (6)
1, a kind of famciclovir sustained-release capsule that is used for antiviral therapy, it is characterized in that: constitute the ball core with adjuvant piller outsourcing famciclovir medicine layer, outside medicine layer, constitute the controlled release internal layer of control drug release by insoluble polymer, outside described controlled release internal layer, clad the controlled release outer coating that is made of enteric polymer again, make the famciclovir sustained-release piller, described piller filling is in capsule, constitute the famciclovir sustained-release capsule
By making 1000 calculating of slow releasing capsule, every mass of 1000 kernel 192-220g packs piller in the capsulae vacuus into, makes the famciclovir sustained-release capsule, and it is composed as follows that various components account for the weight percent of total charges in the capsule:
Each component accounts for the percentage by weight of total charges and is in the ball core:
Famciclovir 56.8%-65.2%
Sucrose (or microcrystalline Cellulose) 13.1%-15.0%
Starch 5.1%-5.8%
Micropowder silica gel 1.1%-1.3%
Binding agent: polyvidone (or hypromellose) 2.5%-2.9%
Each component accounts for the percentage by weight of total charges and is in the controlled release internal layer:
Insoluble polymer (quaternary amine methacrylate or ethyl cellulose) 3.6%-7.9%
Polyethylene glycol 6000 0.36%0.79%
Antiblocking agent (Pulvis Talci) 0.91%-1.98%
Magnesium stearate 0.91%-1.98%
Each component accounts for the percentage by weight of total charges and is in the controlled release outer coating:
Enteric polymer (polyacrylic resin II) 1.26%-2.75%
Enteric polymer (polyacrylic resin III) 1.26%-2.75%
Plasticizer (polyethylene glycol 6000) 0.25%-0.55%
Antiblocking agent (Pulvis Talci) 0.63%-1.36%
The magnesium stearate surplus
The capsular famciclovir sustained-release piller of famciclovir sustained-release is done medium with simulated gastric fluid, simulated intestinal fluid, and the release scope 1.5 hours, 3 hours and 8 hours is respectively: more than 10%-30%, the 30%-70% and 70%,
Adopt sucrose piller or the microcrystalline Cellulose piller adjuvant piller for preparation famciclovir ball core, adjuvant piller diameter is 0.5-0.7mm,
The binding agent that preparation famciclovir ball core is selected is polyvidone or hypromellose, and binding agent is mixed with aqueous solution or organic solvent solution uses,
The controlled release internal layer polymer of cladding is selected quaternary amine methacrylate or ethyl cellulose outside the famciclovir piller, adopt polymer to be dissolved in the solution of organic solvent, or the aqueous dispersion of polymer, clad the enteric polymer as controlled release outer coating outside the controlled release internal layer again, these enteric polymer are selected from methylmethacrylate copolymer, ethyl methacrylate copolymers or hypromellose phthalate ester.
2, a kind of famciclovir sustained-release capsule that is used for antiviral therapy according to claim 1 is characterized in that: the weight percent that the interior various components of capsule account for total charges is composed as follows:
Each component accounts for the percentage by weight of total charges and is in the ball core:
Famciclovir 56.8%
Sucrose 13.1%
Starch 5.1%
Micropowder silica gel 1.1%
Binding agent: polyvidone (or hypromellose) 2.5%
Each component accounts for the percentage by weight of total charges and is in the controlled release internal layer:
Insoluble polymer (quaternary amine methacrylate or ethyl cellulose) 7.9%
Polyethylene glycol 6000 0.79%
Antiblocking agent (Pulvis Talci) 1.98%
Magnesium stearate 1.98%
Each component accounts for the percentage by weight of total charges and is in the controlled release outer coating:
Enteric polymer (polyacrylic resin II) 2.75%
Enteric polymer (polyacrylic resin III) 2.75%
Plasticizer (polyethylene glycol 6000) 0.55%
Antiblocking agent (Pulvis Talci) 1.36%
The magnesium stearate surplus
Adopt the adjuvant piller of sucrose piller for preparation famciclovir ball core, adjuvant piller diameter is 0.5mm,
The binding agent that preparation famciclovir ball core is selected is a polyvidone, and binding agent is mixed with aqueous solution or organic solvent solution uses.
3, a kind of famciclovir sustained-release capsule that is used for antiviral therapy according to claim 1 is characterized in that: the weight percent that the interior various components of capsule account for total charges is composed as follows:
Each component accounts for the percentage by weight of total charges and is in the ball core:
Famciclovir 61.00%
Sucrose (or microcrystalline Cellulose) 14.05%
Starch 5.45%
Micropowder silica gel 1.20%
Polyvidone (or hypromellose) 2.70%
Each component accounts for the percentage by weight of total charges and is in the controlled release internal layer:
Insoluble polymer (quaternary amine methacrylate or ethyl cellulose) 5.75%
Polyethylene glycol 6000 0.575%
Antiblocking agent (Pulvis Talci) 1.44%
Magnesium stearate 1.44%
Each component accounts for the percentage by weight of total charges and is in the controlled release outer coating:
Enteric polymer (polyacrylic resin II) 2.00%
Enteric polymer (polyacrylic resin III) 2.00%
Plasticizer (polyethylene glycol 6000) 0.40%
Antiblocking agent (Pulvis Talci) 1.00%
The magnesium stearate surplus
Adopt the adjuvant piller of sucrose piller for preparation famciclovir ball core, adjuvant piller diameter is 0.6mm,
The binding agent that preparation famciclovir ball core is selected is a hypromellose, and binding agent is mixed with aqueous solution or organic solvent solution uses.
4, a kind of famciclovir sustained-release capsule that is used for antiviral therapy according to claim 1 is characterized in that: the weight percent that the interior various components of capsule account for total charges is composed as follows:
Each component accounts for the percentage by weight of total charges and is in the ball core:
Famciclovir 65.2%
Sucrose (or microcrystalline Cellulose) 15.00%
Starch 5.80%
Micropowder silica gel 1.30%
Binding agent: polyvidone 2.90%
Each component accounts for the percentage by weight of total charges and is in the controlled release internal layer:
Insoluble polymer (quaternary amine methacrylate or ethyl cellulose) 3.60%
Polyethylene glycol 6000 0.36%
Antiblocking agent (Pulvis Talci) 0.91%
Magnesium stearate 0.91%
Each component accounts for the percentage by weight of total charges and is in the controlled release outer coating:
Enteric polymer (polyacrylic resin II) 1.25%
Enteric polymer (polyacrylic resin III) 1.25%
Plasticizer (polyethylene glycol 6000) 0.25%
Antiblocking agent (Pulvis Talci) 0.63%
The magnesium stearate surplus
It is the adjuvant piller of preparation famciclovir ball core that the present invention adopts microcrystalline Cellulose, and adjuvant piller diameter is 0.7mm,
The binding agent that preparation famciclovir ball core is selected is a polyvidone, and binding agent is mixed with aqueous solution or organic solvent solution uses.
5, a kind of capsular production method of famciclovir sustained-release that is used for antiviral therapy, it is characterized in that: with adjuvant piller outsourcing famciclovir medicine layer structure ball core, outside medicine layer, constitute the controlled release internal layer of control drug release by insoluble polymer, outside described controlled release internal layer, clad the controlled release outer coating that constitutes by enteric polymer again, make the famciclovir sustained-release piller, described piller filling constitutes the famciclovir sustained-release capsule in capsule;
In the preparation of ball core: sucrose piller or microcrystalline Cellulose (0.5-0.7mm) 500 weight portions are placed centrifugal coating pelletizing machine, after the start, with 15 weight portions/minute speed spray 5% polyvidone alcoholic solution, 1200 weight portions, simultaneously with 20 weight portions/minute speed be sprinkled into famciclovir powder 1500-1600 weight portion, the medicine ball core that makes was placed 50 ℃ of baking ovens dry 4 hours;
In the preparation of famciclovir sustained-release piller:
Ball core (0.9-1.25mm) 1000 weight portions are placed the bottom spraying type fluidized-bed coating machine, spraying cladding quaternary amine methacrylic acid ester solution, the coating solution prescription is as follows:
Quaternary amine methacrylate 100 weight portions
Polyethylene glycol 6000 10 weight portions
Water 20 weight portions
Magnesium stearate 25 weight portions
Pulvis Talci 25 weight portions
95% ethanol, 1820 weight portions
When quaternary amine methacrylate cladding amount reaches 10% (w/w) of famciclovir pellet weight, clad one deck enteric solubility methacrylate copolymer more outside, the cladding amount of enteric polymer is 5.0% of a ball core weight, and (w/w), the prescription of enteric layer coating solution is as follows:
Polyacrylic resin II 25.0 weight portions
Polyacrylic resin III 25.0 weight portions
Polyethylene glycol 6000 5.0 weight portions
Water 10.0 weight portions
Magnesium stearate 12.5 weight portions
Pulvis Talci 12.5 weight portions
95% ethanol, 910.0 weight portions
With piller in 40 ℃ of baking ovens dry 4 hours, the medicament contg of measuring in the piller was 56.8%-65.2% behind the coating EO, every mass of 1000 kernel 192-220g,, piller is packed in the capsulae vacuus, make the famciclovir sustained-release capsule.
6, a kind of capsular production method of famciclovir sustained-release that is used for antiviral therapy according to claim 5 is characterized in that: described ball core adopts inertia ball core outsourcing medicine method or extruding round method to produce.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200410027929XA CN100406014C (en) | 2004-06-30 | 2004-06-30 | Famciclovir slow-releasing capsule for anti-virus treatment and its producing method |
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| Application Number | Priority Date | Filing Date | Title |
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| CNB200410027929XA CN100406014C (en) | 2004-06-30 | 2004-06-30 | Famciclovir slow-releasing capsule for anti-virus treatment and its producing method |
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| CN1714793A true CN1714793A (en) | 2006-01-04 |
| CN100406014C CN100406014C (en) | 2008-07-30 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103462930A (en) * | 2013-09-05 | 2013-12-25 | 南京正亮医药科技有限公司 | Ganciclovir capsule preparation and preparation method thereof |
| CN103479782A (en) * | 2013-08-30 | 2014-01-01 | 贵阳新天药业股份有限公司 | Slow-release capsule and preparation method thereof |
| CN103622934A (en) * | 2013-11-13 | 2014-03-12 | 青海互丰农业科技集团有限公司 | Sustained-release cordycepin capsule and preparation method thereof |
| CN104622891A (en) * | 2014-09-22 | 2015-05-20 | 青海大学 | Sustained-release pellets prepared from Tibetan medicine Zhaxun and sustained-release capsules |
| CN109288802A (en) * | 2018-10-25 | 2019-02-01 | 安徽鼎旺医药有限公司 | A kind of preparation method of spherical shape famciclovir sustained-release capsule |
| CN115530377A (en) * | 2022-10-13 | 2022-12-30 | 扬州市扬大康源乳业有限公司 | Slow-release probiotics and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1179717A (en) * | 1995-02-06 | 1998-04-22 | 阿斯特拉公司 | Novel pharmaceutical composition |
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2004
- 2004-06-30 CN CNB200410027929XA patent/CN100406014C/en active Active
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103479782A (en) * | 2013-08-30 | 2014-01-01 | 贵阳新天药业股份有限公司 | Slow-release capsule and preparation method thereof |
| CN103479782B (en) * | 2013-08-30 | 2015-10-07 | 贵阳新天药业股份有限公司 | A kind of slow releasing capsule and preparation method thereof |
| CN103462930A (en) * | 2013-09-05 | 2013-12-25 | 南京正亮医药科技有限公司 | Ganciclovir capsule preparation and preparation method thereof |
| CN103622934A (en) * | 2013-11-13 | 2014-03-12 | 青海互丰农业科技集团有限公司 | Sustained-release cordycepin capsule and preparation method thereof |
| CN104622891A (en) * | 2014-09-22 | 2015-05-20 | 青海大学 | Sustained-release pellets prepared from Tibetan medicine Zhaxun and sustained-release capsules |
| CN109288802A (en) * | 2018-10-25 | 2019-02-01 | 安徽鼎旺医药有限公司 | A kind of preparation method of spherical shape famciclovir sustained-release capsule |
| CN115530377A (en) * | 2022-10-13 | 2022-12-30 | 扬州市扬大康源乳业有限公司 | Slow-release probiotics and preparation method thereof |
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|---|---|
| CN100406014C (en) | 2008-07-30 |
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