CN101513395B - Taxol double-layer soft capsule oral preparation medicament - Google Patents
Taxol double-layer soft capsule oral preparation medicament Download PDFInfo
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- CN101513395B CN101513395B CN2008100104397A CN200810010439A CN101513395B CN 101513395 B CN101513395 B CN 101513395B CN 2008100104397 A CN2008100104397 A CN 2008100104397A CN 200810010439 A CN200810010439 A CN 200810010439A CN 101513395 B CN101513395 B CN 101513395B
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Abstract
The invention relates to a taxol double-layer soft capsule oral preparation medicament. The taxol double-layer soft capsule oral preparation medicament adopts the technical proposal that an inner layer is a taxol anticancerogen soft capsule, and an outer layer is a ciclosporin A solid or semisolid capsule; and the taxol double-layer soft capsule oral preparation medicine comprises taxol anticancerogen, the inner layer soft capsule, the ciclosporin A solid or semisolid and an outer layer capsule from the inside to the outside, wherein the taxol anticancerogen comprises taxol active substances and medicinal carriers; the ciclosporin A solid or semisolid comprises ciclosporin A and matched carriers; and the weight ratio of the taxol active substances to the ciclosporin A is 1:2-1:20 in unit dose. The medicament preparation method of the invention comprises the following steps: preparing the taxol anticancerogen; wrapping the taxol anticancerogen in the inner layer soft capsule; preparing the ciclosporin A solid or semisolid; coating the ciclosporin A solid or semisolid outside the inner layer soft capsule; and then wrapping the outer layer capsule outside the ciclosporin A solid or semisolid. The taxol double-layer soft capsule oral preparation medicament has the advantages of small toxicity, convenient taking and good anticancer treatment effect.
Description
Technical field: the present invention relates to drug world, relate in particular to a kind of double-deck antineoplastic taxane alcohols double-layer soft capsule oral preparation medicament that has.
Background technology: paclitaxel (Paclitaxel) and Docetaxel (docetaxel) injection are the choice drugs of present anticancer chemotherapy.Although paclitaxel and Docetaxel have been proved to be the best of current chemotherapy and have selected medicine, the shortcoming that injection dosage form now still exists some to be difficult to overcome.First toxic and side effects is big, and paclitaxel itself has certain toxic and side effects, and the solvent Oleum Ricini of adding the injection use also has intensive toxic and side effects, must neutralize with the another one medicine.The 2nd, dosage form is single, and the unique dosage form of paclitaxel is an injection, and production and use are all comparatively complicated, and it is more outstanding that the while toxic and side effects shows.The 3rd, affect the treatment.Use injection, the serum-concentration of paclitaxel is higher than toxic concentration in short-term, because toxic and side effects is bigger, can not continuous use, influence therapeutic effect, paclitaxel itself is water insoluble simultaneously, can only make solvent with castor oil derivative and make medicine enter human body, therefore paclitaxel can not all be absorbed, and to a certain degree also affects the treatment.
Because following two are reduced bioavailability, up to the present independent oral paclitaxel also is not applied.The first, the gallbladder of hepatic metabolism and metabolite is got rid of.In liver, by the catalytic action of cytochrome enzyme P450 (CYP) 2C8, paclitaxel (paclitaxel) is oxidized to 6-hydroxyl paclitaxel (6-hydroxypaclitaxel), and this derivant continues metabolism, and justacrine is gone into bile and got rid of.The second, paclitaxel is to being distributed in the medicine backflow transport protein in intestinal and gallbladder road, and P-glycoprotein (P-gp) has high affinity, very easily is excluded by this mechanism.
Summary of the invention: in order to address the above problem, it is little to the invention provides a kind of toxicity, is convenient to oral medication, the taxol double-layer soft capsule oral preparation medicament that anticancer therapy is effective.The technical solution used in the present invention is: a kind of taxol double-layer soft capsule oral preparation medicament, internal layer are the paclitaxel kind anti-cancer drugs soft capsule, and skin is ciclosporin A solid or semi-solid capsule; Be followed successively by paclitaxel kind anti-cancer drugs, internal layer soft capsule, ciclosporin A solid or semi-solid and outer capsule from inside to outside.
Among the present invention, double-deck capsular internal layer is the paclitaxel kind anti-cancer drugs soft capsule, is paclitaxel kind anti-cancer drugs in the internal layer soft capsule promptly, and paclitaxel kind anti-cancer drugs comprises paclitaxel active substance and pharmaceutical carrier, and the paclitaxel active substance is paclitaxel or Docetaxel.In the unit dose (unit dose is measurement unit with the grain, and promptly unit dose refers to a taxol double-layer soft capsule), the paclitaxel activity substance content is the 5-30 milligram, preferred 10-20 milligram; Pharmaceutical carrier content is the 60-370 milligram, preferred 120-250 milligram.
Pharmaceutical carrier can promote the dissolving and the absorption of paclitaxel active substance, pharmaceutical carrier can be D-α-cetomacrogol 1000 succinate (TPGS, D-alpha-tocopheryl polyethylene glycol1000 succihate) and/or sad polyethyleneglycol glyceride and/or capric acid polyethyleneglycol glyceride (Labrasol, caprylocaproyl macrogol-8 glycerides) and/or the mixture of single oleic acid sorbitan ester (Sorbitan monooleate) and/or ascorbyl palmitate (Ascorbylpalmitate) and/or polyoxyethylene olein (LabraWl M 1944 CS, polyoxyethylated oleic glycerides) and/or Polyethylene Glycol and/or dehydrated alcohol.
Among the present invention, double-deck capsular skin is ciclosporin A solid or semi-solid capsule, is ciclosporin A solid or semisolid in outer capsule promptly, is coated on outside the internal layer together then.Ciclosporin A solid or semisolid comprise ciclosporin A and matching vector.In the unit dose, ciclosporin A content is the 10-100 milligram, preferred 30-60 milligram, and matching vector content is the 200-400 milligram, preferred 200-350 milligram.
Matching vector comprises self emulsifying plant oil and organic polymer solvent preferably.This kind solvent, can dissolve ciclosporin A but not destroy pharmaceutically active down for liquid at high temperature (50-70 ℃), at room temperature is solid-state or semisolid, forms needed pharmaceutical dosage form characteristic.This kind solvent includes but not limited to glyceryl linoleate class and other polymer such as Polyethylene Glycol, Myrj 52 etc.
Among the present invention, in the unit dose, the weight ratio of paclitaxel or Docetaxel and ciclosporin A is 1: 2～20.
The preparation method of taxol double-layer soft capsule oral preparation medicament is characterized in that step is as follows:
1) preparation paclitaxel kind anti-cancer drugs;
2) paclitaxel kind anti-cancer drugs is wrapped in the internal layer soft capsule, makes internal layer, the internal layer soft capsule is the slow release soft capsule;
3) preparation ciclosporin A solid or semisolid;
4) ciclosporin A solid or semisolid are applied outside internal layer; Outside ciclosporin A solid or semisolid, coat the outer capsule of one deck then, make skin.
Mechanism of the present invention is: after taking, outer field ciclosporin A discharges earlier, gastrointestinal P-gp is stopped up, and after absorption the CYP3A4 of liver is suppressed.The paclitaxel paclitaxel active substance of internal layer is being taken release in 0.5-3 hour.So when paclitaxel discharged, the intestinal that can reduce or avoid to be caused by P-gp was got rid of, the liver degraded that can reduce or avoid simultaneously CYP3A4 to cause again.
Therapeutic dose of the present invention is 5-80mg/kg every day in the total amount of paclitaxel active substance and ciclosporin A, divides and takes for 3 times.
The invention has the beneficial effects as follows:
1. outer dosage form design is solid or semisolid, and the advantage of following two aspects is arranged.The first, outer field solid or semisolid dosage form can " be reinforced " the internal layer soft capsule, and manufacturing process is simple relatively, are convenient to store and transportation.The second, outer field solid or semisolid can play and prevent the evaporable effect of alcohols solvent in the internal layer soft capsule, and not only itself has bioactive functions, and can further surely change internal layer paclitaxel anticarcinogen.
2. the invention solves the toxicity and the curative effect problem of injection now.Reduce and eliminated the toxicity of castor oil derivative.In addition, because of peroral dosage form easier, easier adjusting taking dose and time, regulate and control the serum-concentration of paclitaxel easily, after taking the present invention, the serum-concentration long-term stability of paclitaxel is 0.10～0.30 μ mol and Most patients is effectively treated concentration between 0.10～0.40 μ mol, takes as seen that the serum-concentration of paclitaxel maintains effective treatment concentration all the time and is lower than toxic concentration behind the present invention.Compare with the paclitaxel of prior art injection dosage form, can lack at interval (1-6 days at interval) and take for a long time and reach continuous therapeutic purposes, thereby " flooding " of having treated again after having avoided wanting drug withdrawal to wait to regain one's strength after one section of the treatment that patient body is damaged.
3. ciclosporin A (cyclosporin A) is a kind of immunosuppressant, just is used for clinically the beginning of the eighties, is mainly used in the rejection after the organ transplantation.But ciclosporin A is also tried out in the treatment of autoimmune diseasees such as lupus erythematosus, dermatomyositis in recent years.Ciclosporin A is the inhibitor of CYP3A4 and P-gp simultaneously.Among the present invention,, can suppress the degraded of paclitaxel at gastrointestinal eliminating and liver owing to added ciclosporin A.Paclitaxel is worked as in the zoopery demonstration and ciclosporin A share, and the oral utilization rate of paclitaxel significantly improves.Zoopery: animal, Sprague Dawley rat (public affairs) on an empty stomach, anesthesia back conduit feed 10mg/kg paclitaxel (matched group), or the present invention is (in the total amount of paclitaxel active substance and ciclosporin A, be 30mg/kg, wherein ciclosporin A 20mg/kg and paclitaxel 10mg/kg) (experimental group).The serum paclitaxel concentration of regularly taking a blood sample after the medication.Experiment show share with ciclosporin A after, the oral utilization rate of paclitaxel is brought up to 40-60% by individually dosed 2-6%, has improved the biological absorption and the bioavailability of oral paclitaxel greatly.Be used for clinically, can effectively treat cancer, tumor, hyperplasia class disease, and any the taxanes medicine be had the patient of reflection, reach and make things convenient for the patient, the effect of efficacy enhancing and toxicity reducing.
4. owing to when making internal layer, used slow release soft capsule technology, make take after, outer field ciclosporin A discharges earlier, gastrointestinal P-gp is stopped up, and after absorption the CYP3A4 of liver is suppressed.Because the slow releasing function of internal layer soft capsule just discharges the paclitaxel active substance of internal layer after taking 0.5-3 hour, reduced the liver that intestinal is got rid of and CYP3A4 the causes degraded that paclitaxel paclitaxel active substance is caused by P-gp.The paclitaxel active substance is absorbed by big portion, has improved the bioavailability of paclitaxel active substance, has improved curative effect.
Description of drawings:
Fig. 1 is a structural representation of the present invention;
Fig. 2 is preparation technology's flow chart of internal layer;
Fig. 3 is outer field preparation technology's flow chart.
The specific embodiment: following illustration is for invention is described, is not the restriction invention.
Embodiment 1
Taxol double-layer soft capsule oral preparation medicament, internal layer are the paclitaxel kind anti-cancer drugs soft capsule, and skin is the semi-solid capsule of ciclosporin A; As shown in Figure 1, be followed successively by paclitaxel kind anti-cancer drugs 1, internal layer soft capsule 2, ciclosporin A semi-solid 3 and outer capsule 4 from inside to outside.
The preparation method of taxol double-layer soft capsule oral preparation medicament is as follows:
1) preparation paclitaxel kind anti-cancer drugs:
1.5 gram paclitaxels are dissolved in 10 gram D-α-cetomacrogol 1000 succinate (TPGS, D-alpha-tocopheryl poiyethylene glycol 1000 succinate), the mixture, 3 gram single oleic acid sorbitan esters (Sorbitan monooleate), 0.2 gram ascorbyl palmitate (Ascorbylpalmitate) and the 1 gram dehydrated alcohol that add 5 sad polyethyleneglycol glyceride of gram and capric acid polyethyleneglycol glyceride successively.With this prescription mixing, be the amount of 100 unit dose.
2) paclitaxel kind anti-cancer drugs is wrapped in the internal layer soft capsule:
As shown in Figure 2, be preparation technology's flow chart of internal layer.The internal layer soft capsule is the slow release soft capsule, and its manufacturing process and material adopt routine techniques.The 1st paclitaxel kind anti-cancer drugs that makes of step and slow release soft capsule by automatic encapsulating machine pill and rolling typing, are descended drying at 20～30 ℃, select ball, wash ball, 30～35 ℃ of dryings, the internal layer that makes 100 unit dose is the paclitaxel kind anti-cancer drugs soft capsule.
3) preparation ciclosporin A semisolid:
6 gram polyoxyethylene castor oil double glycerides, 6 gram polyoxyethylene, 6 gram sorbitol glyceride, 4 gram poloxamers, 10 gram Polyethylene Glycol-4000 are mixed, be heated to 60-70 ℃ of dissolving.Add the abundant mixed dissolution of 4 gram ciclosporin As.Be cooled to room temperature and be frozen into semisolid.This prescription is the amount of 100 unit dose.
4) as shown in Figure 3, be outer field preparation technology's flow chart.Outer capsular manufacturing process and material adopt routine techniques.Semi-solid and the outer capsule of the ciclosporin A that the 2nd internal layer that obtains of step and the 3rd step are made passes through automatic encapsulating machine pill, rolling typing, and 20～30 ℃ of dryings are selected ball, wash ball, and 30～35 ℃ of dryings make the finished product of 100 unit dose.
Embodiment 2
Different with embodiment 1, paclitaxel kind anti-cancer drugs in the internal layer and preparation method thereof difference just:
Preparation paclitaxel kind anti-cancer drugs: 1.5 gram paclitaxels are dissolved in 10 gram D-α-cetomacrogol 1000 succinate (TPGS, D-alpha-tocopheryl polyethylene glycol 1000succinate), add 3 gram polyoxyethylene oleins (LabraWl M 1944 CS, polyoxyethylated oleic glycerides), 5 gram PEG400s (PEG 400:polyethylene glycol 400), 0.2 gram ascorbyl palmitate (Ascorbylpalmitate) and 1 gram dehydrated alcohol then successively.This mixing of filling a prescription is the amount of 100 unit dose.
Embodiment 3
Preparation paclitaxel kind anti-cancer drugs: 0.5 gram Docetaxel is dissolved in 3 gram D-α-cetomacrogol 1000 succinate (TPGS, D-alpha-tocopheryl polyethylene glycol 1000succinate), add 1 gram polyoxyethylene olein (LabraWl M 1944 CS, polyoxyethylated oleic glycerides), 1.5 gram PEG400s (PEG 400:polyethylene glycol 400), 0.1 gram ascorbyl palmitate (Ascorbylpalmitate) and 0.4 gram dehydrated alcohol then successively.This mixing of filling a prescription is the amount of 100 unit dose.
Preparation ciclosporin A semisolid: 7 gram polyoxyethylene castor oil double glycerides, 7 gram polyoxyethylene, 7 gram sorbitol glyceride, 7 gram poloxamers, 12 gram Polyethylene Glycol-4000 are mixed, be heated to 60-70 ℃ of dissolving.Add the abundant mixed dissolution of 10 gram ciclosporin As.Be cooled to room temperature and be frozen into semisolid.This prescription is the amount of 100 unit dose.
Internal layer is identical with embodiment 1 with outer field preparation technology.
Embodiment 4
Preparation paclitaxel kind anti-cancer drugs: 1 gram Docetaxel is dissolved in 17 gram D-α-cetomacrogol 1000 succinate (TPGS, D-alpha-tocopheryl polyethylene glycol 1000succinate), the mixture, 2 gram single oleic acid sorbitan esters (Sorbitan monooleate), 0.1 gram ascorbyl palmitate (Ascorbyl palmitate) and the 0.5 gram dehydrated alcohol that add 3.5 sad polyethyleneglycol glyceride of gram and capric acid polyethyleneglycol glyceride successively.With this prescription mixing, be the amount of 100 unit dose.
Preparation ciclosporin A semisolid: 7 gram polyoxyethylene castor oil double glycerides, 7 gram polyoxyethylene, 7 gram sorbitol glyceride, 3 gram poloxamers, 16 gram Polyethylene Glycol-4000 are mixed, be heated to 60-70 ℃ of dissolving.Add the abundant mixed dissolution of 10 gram ciclosporin As.Be cooled to room temperature and be frozen into semisolid.This prescription is the amount of 100 unit dose.
Internal layer is identical with embodiment 1 with outer field preparation technology.
Claims (6)
1. a taxol double-layer soft capsule oral preparation medicament is characterized in that internal layer is the paclitaxel kind anti-cancer drugs soft capsule, and skin is ciclosporin A solid or semi-solid capsule; Be followed successively by paclitaxel kind anti-cancer drugs, internal layer soft capsule, ciclosporin A solid or semi-solid and outer capsule from inside to outside;
Described internal layer soft capsule is the slow release soft capsule;
Described paclitaxel kind anti-cancer drugs comprises paclitaxel active substance and pharmaceutical carrier, and wherein the paclitaxel active substance is paclitaxel or Docetaxel;
Described ciclosporin A solid or semisolid comprise ciclosporin A and matching vector;
In the unit dose, the weight ratio of paclitaxel or Docetaxel and ciclosporin A is 1: 2～20.
2. according to the described taxol double-layer soft capsule oral preparation medicament of claim 1, it is characterized in that in the unit dose that the paclitaxel activity substance content is the 5-30 milligram, pharmaceutical carrier content is the 60-370 milligram.
3. according to the described taxol double-layer soft capsule oral preparation medicament of claim 2, it is characterized in that in the unit dose that the paclitaxel activity substance content is the 10-20 milligram, pharmaceutical carrier content is the 120-250 gram.
4. according to the described taxol double-layer soft capsule oral preparation medicament of claim 1, it is characterized in that in the unit dose that ciclosporin A content is the 10-100 milligram, matching vector content is the 200-400 milligram.
5. according to the described taxol double-layer soft capsule oral preparation medicament of claim 4, it is characterized in that in the unit dose that described ciclosporin A content is the 30-60 milligram, pharmaceutical carrier content is the 200-350 milligram.
6. the preparation method of the described taxol double-layer soft capsule oral preparation medicament of claim 1 is characterized in that step is as follows:
1) preparation paclitaxel kind anti-cancer drugs;
2) paclitaxel kind anti-cancer drugs is wrapped in the internal layer soft capsule, makes internal layer;
3) preparation ciclosporin A solid or semisolid;
4) ciclosporin A solid or semisolid are applied outside internal layer; Outside ciclosporin A solid or semisolid, coat the outer capsule of one deck then, make skin.
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| CN102028934A (en) * | 2009-09-28 | 2011-04-27 | 付金坤 | Taxol complex preparation drug |
| CN106692758A (en) * | 2017-01-10 | 2017-05-24 | 威海百合生物技术股份有限公司 | Double-layer medicinal and edible dual-purpose soft capsule capable of protecting liver and preparation method thereof |
| CN106858591B (en) * | 2017-03-03 | 2020-12-11 | 威海百合生物技术股份有限公司 | Yellow spot-removing wrinkle-removing health food and preparation method thereof |
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| CN1285741A (en) * | 1997-12-17 | 2001-02-28 | 阿克斯肯制药公司 | Double capsule for the administration of active principles in multiple therepies |
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Effective date of registration: 20230221 Address after: B-2-6, Building 10, No. 59, Shennong Street, Hi-tech Industrial Development Zone, Benxi, Liaoning, 117000 Patentee after: Liaoning Aojia Biopharmaceutical Co.,Ltd. Address before: No. 67-22, Baishan Road, Yuhong District, Shenyang, Liaoning 110000 Patentee before: Shan Baohua |