CN106474095B - Oral mucosa adhesive for treating oral fungi and preparation method thereof - Google Patents
Oral mucosa adhesive for treating oral fungi and preparation method thereof Download PDFInfo
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- CN106474095B CN106474095B CN201611005538.7A CN201611005538A CN106474095B CN 106474095 B CN106474095 B CN 106474095B CN 201611005538 A CN201611005538 A CN 201611005538A CN 106474095 B CN106474095 B CN 106474095B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
Abstract
The invention provides an oral mucosa adhesive, which is characterized in that the oral mucosa adhesive takes a compound shown as a formula (I) as a medicinal active ingredient:
wherein R is1And R2Each independently F or H. The mucosa adhesive has enough adhesive force on oral mucosa, has stable drug release speed, and can keep the drug concentration at MIC all the time90The medicine can hardly enter blood, and can reduce the occurrence of systemic toxic and side effects.
Description
Technical Field
The invention particularly relates to an oral mucosa adhesive for treating oral fungi and a preparation method thereof.
Background
Oral mycoses are a disease caused by infection of fungi in the oral cavity, and an increase in immunosuppression such as chemotherapy for cancer or bone marrow transplantation or infection with aids is an important factor in inducing oral mycoses. Oral mycosis is mainly oral candidiasis (abbreviated as OPC), which is usually the initial symptom of HIV infection. More than 90% of AIDS patients are reported to be accompanied by OPC (Pharmacotherapy,19(1): 76-87)). OPC is also a common complication in anticancer therapy, and chemotherapy, bone marrow transplantation or local radiotherapy in particular are all important factors contributing to local candidiasis infection. An analysis of 27 clinical trials reported that the incidence of oral Candida was 30% -70% depending on the location of the cancer (Cochrane Database Syst Rev.2000; (2): CD 000978). In addition, candida infections may also be caused by long-term administration of antibiotics, steroid hormones, and the like. From a survey at university of Sichuan, the detection rate of oral fungi was as high as 52.1% in older people over 60 years of age, with women higher than men. Because cancer and AIDS are difficult to cure, the immunity of patients is inhibited all the time, and oral mucositis often has repeated attacks. The recurrence rate of oral mucositis is reported to be over 60% within 3 months.
OPC treatments are divided into systemic and topical treatments. Systemic treatment is oral administration or injection of antifungal drugs such as ketoconazole, fluconazole, itraconazole and the like. The medicine enters blood and is distributed to the whole body, and is easy to cause drug resistance, induce drug interaction and other toxic and side effects. Resistance to antifungal drugs in patients with AIDs has become a problematic concern today. Triazole antifungal drugs have different degrees of inhibition effects on liver CYP3A4 isomerase, and the problem of relatively serious drug interaction generally exists. They can interact with antiviral drugs, antibacterial drugs and other drugs requiring CYP3A4 isomerase metabolism, and the patients with mild symptoms need to adjust the dosage and the patients with severe symptoms can have high toxic and side effects. Various guidelines indicate that the use of azole drugs should be monitored for drug concentration for at least 4-7 days, and therefore, minimal or no systemic treatment should be used unless it is highly necessary.
The local treatment medicine is directly applied to the fungus-infected part, and the concentration of the medicine in the fungus-infected part is high, so that the method is an ideal superficial fungal infection treatment mode.
OPC is a superficial fungal infection, but the infectious bacteria site is in the oral cavity or esophagus, so the treatment has specificity. There are currently three types of OPC topical treatments at home and abroad: clotrimazole buccal tablets, miconazole gel and miconazole oral patches. Clotrimazole and miconazole are the first generation antifungal agents on the market in the last 70 th century, and the antifungal effect is relatively weak. The buccal tablet and the gel have short contact time between the medicine and the infected part, low saliva concentration and poor treatment effect. More OPC treatment medicines which have better sterilization effects and can maintain the effective saliva concentration of the medicines for a long time are expected in clinic.
Therefore, it is very important to research an oral drug which has an excellent antifungal effect, little medicinal active ingredient enters blood, and almost no influence on the whole system.
Disclosure of Invention
In order to achieve the above object, the present invention provides an oral mucosa-sticking agent comprising a compound represented by the formula (I):
wherein R is1And R2Each independently is F or H;
preferably, R is as described in said formula (I)1And R2At least one of which is F;
more preferably, said R1＝F，R2H or R1＝H，R2＝F；
Preferably, the amount of the pharmaceutical active ingredient is 5-100 mg, preferably 10-50 mg, more preferably 25mg or 50mg per unit dose;
wherein when R is1＝F，R2When H, the compound of formula (I) is rilfluconazole (Ravuconazole); when R is1＝H，R2When F, the compound of formula (I) is Isavuconazole (isavuconazol);
preferably, the pharmaceutically active component is selected from at least one of the group consisting of rilfluconazole and isaconazole.
The Lifluconazole and isaconazole (structural formula shown below) are third-generation antifungal agents, and have good inhibitory effect on Candida albicans, MIC90Less than 1ug/ml, as shown in tables 1 and 2.
TABLE 1 comparison of in vitro antibacterial Activity of Lifluconazole against Candida fungus (MIC)50(μg/ml))
TABLE 2 comparison of the in vitro antibacterial Activity of Isaconazole against Candida fungi
Note: MIC is minimum inhibitory concentration
Although the two compounds have been reported to have good antifungal effects, the compounds are not developed as oral antifungal agents, nor are the compounds reported to be used for treating oral mycoses, nor are the compounds reported to be prepared into oral mucosa adhesive preparations. At present, the two compounds are only used as intermediates for synthesizing medicaments BMS-292655 and BAL-8557-002:
the applicant surprisingly found that when the Lifluconazole or the Isaconazole is directly used as the active ingredient to prepare the oral mucosa adhesive agent, the oral mycosis can be well treated within the dosage range of the pharmaceutical active ingredient provided by the invention, and even if the Lifluconazole or the Isaconazole is swallowed or swallowed, the medicine can not enter blood or even enter the blood, the concentration of the medicine in the blood is extremely low, and the medicine has little influence on the whole system.
The applicant further provides an adhesive drug release system, which is applied to the oral mucosa adhesive, so that the oral mucosa adhesive of the invention is better improved in the following performances:
(1) the oral mucosa adhesive of the invention has enough adhesive force on the oral mucosa, can not melt and disintegrate quickly in the oral cavity, and is not easy to fall off, can keep the oral mucosa adhesive of the invention staying on the mucosa for at least 10 hours, and effectively prolongs the action time of the medicine;
(2) the drug release speed is ensured while the action time of the drug is prolonged, and the concentration of the saliva drug is kept at MIC for a long time90The above;
(3) the normal diet and drinking water are not affected during the period of using the medicine.
Preferably, the oral mucosa adhesive agent of the invention contains a mucosa adhesive medicine release system;
preferably, the adhesive drug delivery system is selected from one or more of, but not limited to, hydroxypropylmethyl cellulose (HPMC), polyacrylic acid resin, hydroxypropyl cellulose, hydroxyethyl cellulose, milk protein, chitosan, sodium alginate, carbomer, polyvinylpyrrolidone, polyethylene glycol, Sodium Dodecyl Sulfate (SDS);
preferably, the adhesive drug release system is selected from one or more of hydroxypropyl methylcellulose, milk protein, chitosan, sodium alginate and sodium dodecyl sulfate;
preferably, the dosage of the adhesive drug release system accounts for 5-80% of the total amount of the oral mucosa adhesive agent prescription, preferably 10-60%, more preferably 25-50%, and most preferably 27.5-46.1% by weight;
preferably, the adhesive drug release system consists of hydroxypropyl methyl cellulose, milk protein and sodium dodecyl sulfate; preferably, the adhesive drug release system comprises the following components in percentage by weight:
25 to 50 percent of hydroxypropyl methyl cellulose,
5 to 15 percent of sodium dodecyl sulfate,
40-65% of milk protein;
more preferably, the adhesive drug release system comprises the following components in percentage by weight:
29.2 to 43.3 percent of hydroxypropyl methyl cellulose,
8.3 to 10.9 percent of sodium dodecyl sulfate,
46.7-62.5% of milk protein;
preferably, the adhesive drug release system consists of hydroxypropyl methylcellulose, chitosan and sodium dodecyl sulfate; more preferably, the adhesive drug release system comprises the following components in percentage by weight:
25 to 50 percent of hydroxypropyl methyl cellulose,
5 to 15 percent of sodium dodecyl sulfate,
40-65% of chitosan;
most preferably, the composition of the adhesive drug release system comprises the following components in percentage by weight:
29.2-43.3% of hydroxypropyl methyl cellulose;
8.3-10.9% of sodium dodecyl sulfate;
46.7-62.5% of chitosan;
preferably, the adhesive drug release system consists of hydroxypropyl methyl cellulose, sodium alginate and sodium dodecyl sulfate; more preferably, the adhesive drug release system comprises the following components in percentage by weight:
25 to 50 percent of hydroxypropyl methyl cellulose,
5 to 15 percent of sodium dodecyl sulfate,
40-65% of sodium alginate;
most preferably, the composition of the adhesive drug release system comprises the following components in percentage by weight:
29.2 to 43.3 percent of hydroxypropyl methyl cellulose,
8.3 to 10.9 percent of sodium dodecyl sulfate,
and 46.7-62.5% of sodium alginate.
The oral mucosa adhesive can contain or not contain other pharmaceutical excipients; preferably, the pharmaceutical excipients are selected from one or more of diluents, binders, lubricants, disintegrants, and flavoring agents;
preferably, the diluent is a pharmaceutically acceptable diluent for formulation; preferably, the diluent is selected from one or more of cellulose, such as powdered cellulose and microcrystalline cellulose, lactose, such as lactose monohydrate, starch, such as direct compressible starch, mannitol, glucose; more preferably, the diluent is microcrystalline cellulose or lactose monohydrate;
preferably, the diluent accounts for 0.2-30% of the total amount of the oral mucosa adhesive agent prescription, preferably 0.9-20%, and more preferably 0.9-15% by weight;
preferably, the binder is a pharmaceutically acceptable binder for the formulation; preferably, the binder is selected from one or more of acacia, sucrose, starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone; more preferably, the binder is starch or polyvinylpyrrolidone such as PVP K30;
preferably, the adhesive accounts for 0.2-35% of the total amount of the oral mucosa adhesive agent, preferably 7.6-30.2%, and more preferably 7.6-26.7% by weight;
preferably, the lubricant is a pharmaceutically acceptable lubricant for formulation; preferably, the lubricant is selected from one or more of stearate, hydrogenated vegetable oil, talcum powder and sodium stearyl fumarate; more preferably, the lubricant is selected from one or more of magnesium stearate, talc and sodium stearyl fumarate; most preferably, the lubricant is magnesium stearate and talc;
preferably, the lubricant accounts for 0.1-10% of the total weight of the oral mucosa adhesive agent prescription, preferably 0.2-8%, more preferably 0.2-5%, and most preferably 2-2.3%;
preferably, the disintegrant is a pharmaceutically acceptable disintegrant for use in a formulation; preferably, the disintegrant is selected from one or more of starches such as pregelatinized starch, sodium carboxymethyl cellulose, crospovidone, sodium alginate, gums;
preferably, the disintegrating agent accounts for 0.2-30% of the total amount of the oral mucosa adhesive agent prescription, preferably 0.2-20%, and most preferably 0.2-15% by weight;
preferably, the flavoring agent is a pharmaceutically acceptable flavoring agent for formulation; preferably, the flavoring agent is selected from a sweetener or a mint agent; preferably, the sweetener is selected from one or more of sucrose, lactose, sodium cyclamate, aspartame and neotame, and is preferably lactose or neotame;
preferably, the flavoring agent accounts for 0.1-10% of the total amount of the oral mucosa adhesive agent prescription in percentage by weight, and preferably 0.1-3%.
Preferably, according to the oral mucosa adhesive, the oral mucosa adhesive consists of the following components in percentage by weight: 2.5-50% of the active ingredients of the medicine, preferably 20-50%, more preferably 25-43.5%; 5-80% of an adhesion drug release system, preferably 10-60%, more preferably 25-50%, and most preferably 27.5-46.1%; 0.2-30% of diluent, preferably 0.9-20%, more preferably 0.9-15%; 0.2-35% of a binder, preferably 7.6-30.2%, more preferably 7.6-26.7%; 0.1-10% of a lubricant, preferably 0.2-8%, more preferably 0.2-5%, and most preferably 2-2.3%;
the adhesive drug release system is selected from one or more of but not limited to hydroxypropyl methylcellulose, polyacrylic resin, hydroxypropyl cellulose, hydroxyethyl cellulose, milk protein, chitosan, sodium alginate, carbomer, polyvinylpyrrolidone, polyethylene glycol and sodium dodecyl sulfate;
more preferably, the adhesive drug release system is selected from one or more of hydroxypropyl methylcellulose, milk protein, chitosan, sodium alginate and sodium dodecyl sulfate;
preferably, the adhesive drug release system consists of hydroxypropyl methyl cellulose, milk protein and sodium dodecyl sulfate; more preferably, the adhesive drug release system comprises the following components in percentage by weight:
25 to 50 percent of hydroxypropyl methyl cellulose,
5 to 15 percent of sodium dodecyl sulfate,
40-65% of milk protein;
most preferably, the composition of the adhesive drug release system comprises the following components in percentage by weight:
29.2 to 43.3 percent of hydroxypropyl methyl cellulose,
8.3 to 10.9 percent of sodium dodecyl sulfate,
46.7-62.5% of milk protein;
preferably, the adhesive drug release system consists of hydroxypropyl methylcellulose, chitosan and sodium dodecyl sulfate; more preferably, the adhesive drug release system comprises the following components in percentage by weight:
25 to 50 percent of hydroxypropyl methyl cellulose,
5 to 15 percent of sodium dodecyl sulfate,
40-65% of chitosan;
most preferably, the composition of the adhesive drug release system comprises the following components in percentage by weight:
29.2 to 43.3 percent of hydroxypropyl methyl cellulose,
8.3 to 10.9 percent of sodium dodecyl sulfate,
46.7-62.5% of chitosan;
preferably, the adhesive drug release system consists of hydroxypropyl methyl cellulose, sodium alginate and sodium dodecyl sulfate; more preferably, the adhesive drug release system comprises the following components in percentage by weight:
25 to 50 percent of hydroxypropyl methyl cellulose,
5 to 15 percent of sodium dodecyl sulfate,
40-65% of sodium alginate;
most preferably, the composition of the adhesive drug release system comprises the following components in percentage by weight:
29.2 to 43.3 percent of hydroxypropyl methyl cellulose,
8.3 to 10.9 percent of sodium dodecyl sulfate,
46.7-62.5% of sodium alginate;
preferably, in the adhesive drug release system, the viscosity of the hydroxypropyl methyl cellulose is 100-150000 poise, more preferably 4000-100000 poise; preferably, the hydroxypropyl methyl cellulose accounts for 5-60% of the total amount of the oral mucosa adhesive agent, preferably 10-30%, more preferably 10-20%, and most preferably 10.5-17.8% by weight;
the hydroxypropyl methylcellulose suitable for use in the present invention is exemplified by E4M, E10M, K100LV, K4M, K10M and K100M of Dow, or 90SH-100, 90SH-400, 90SH-4000, 90SH-15000 and 90SH-100000 of Japan.
Preferably, the milk protein is edible or medicinal milk protein, and the preferred purity is more than 85%; preferably, the milk protein accounts for 5-60% of the total amount of the oral mucosa adhesive agent prescription, preferably 15-35%, more preferably 15-25%, and most preferably 17.5-23.9% by weight;
preferably, the chitosan is water-soluble chitosan; preferably, the chitosan accounts for 5-60% of the total amount of the oral mucosa adhesive agent prescription, preferably 15-35%, more preferably 15-25%, and most preferably 17.5-23.9% by weight;
preferably, the sodium alginate is oligomeric sodium alginate, preferably having an average molecular weight of about 35000; preferably, the sodium alginate accounts for 5-60% of the total amount of the oral mucosa adhesive agent prescription, preferably 15-35%, more preferably 15-25%, and most preferably 17.5-23.9% by weight;
preferably, the sodium dodecyl sulfate accounts for 0.5-10%, preferably 3-7%, and more preferably 3-4.3% of the total amount of the oral mucosa adhesive agent prescription in percentage by weight;
preferably, the diluent is a pharmaceutically acceptable diluent for formulation; preferably, the diluent is selected from one or more of cellulose, such as powdered cellulose and microcrystalline cellulose, lactose, such as lactose monohydrate, starch, such as direct compressible starch, mannitol, glucose; more preferably, the diluent is microcrystalline cellulose or lactose monohydrate;
preferably, the binder is a pharmaceutically acceptable binder for the formulation; preferably, the binder is selected from one or more of acacia, sucrose, starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone; more preferably, the binder is starch or polyvinylpyrrolidone such as PVP K30;
preferably, the lubricant is a pharmaceutically acceptable lubricant for formulation; preferably, the lubricant is selected from one or more of stearate, hydrogenated vegetable oil, talcum powder and sodium stearyl fumarate; more preferably, the lubricant is selected from one or more of magnesium stearate, talc and sodium stearyl fumarate; most preferably, the lubricant is magnesium stearate and talc;
preferably, according to the oral mucosa adhesive, the oral mucosa adhesive consists of, by weight, 25% -43.5% of a pharmaceutically active component, 10.5% -17.8% of hydroxypropyl methylcellulose, 3% -4.3% of sodium dodecyl sulfate, 14% -23.9% of milk protein or 17.5% -23.9% of chitosan or 17.5% -23.9% of sodium alginate, 7.6% -30.2% of starch, 0.9% -15% of lactose, 0.9% -1% of talcum powder and 1.1% -1.3% of magnesium stearate.
The composition and content combination of the adhesive drug release system can well control the balance between the adhesive property and the release speed of the drug, ensure enough adhesive force and maintain uniform and lasting release speed, thereby ensuring the retention time of the drug in the oral cavity and ensuring that the saliva concentration of the drug in the oral cavity can be maintained at MIC for a long time when the adhesive drug release system is combined with the active ingredient (within the prescription amount range) shown in the formula (I)90So as to achieve the effect of treating the oral mycosis.
Of course, a second or third active ingredient, such as steroidal anti-inflammatory drugs, non-steroidal anti-inflammatory drugs, antibacterial drugs, antiviral drugs, etc., may be added to the oral mucosa adhesive agent described herein as necessary.
The oral mucosa adhesive agent of the present invention may be an oral mucosa adhesive sheet or an oral mucosa adhesive film, and is preferably an oral mucosa adhesive sheet.
When the oral mucosa adhesive agent is used, the oral mucosa adhesive agent is only adhered to the upper gingival part such as a canine dental fossa, and the placed oral mucosa adhesive agent can be slowly dissolved to release the medicament and provide the medicinal active ingredients at high concentration for a long time, and the detailed operation is shown in figure 1.
On the other hand, the invention also provides a method for preparing the oral mucosa adhesive, which can be a wet granulation method, a dry granulation method or a direct compression method, and preferably is the wet granulation method;
preferably, in the wet granulation, the adhesive drug release system in the oral mucosa adhesive agent prescription is added in two parts; preferably, the wet granulation method comprises the steps of respectively crushing, sieving and mixing the pharmaceutical active ingredient, the first part of the adhesive drug delivery system, the adhesive and the diluent according to the prescription amount, adding water for granulation, then adding the lubricant and the second part of the adhesive drug delivery system, uniformly mixing and tabletting;
preferably, the adding amount of the first part of the adhesive drug release system is 85-95%, preferably 89.1-91.7% of the prescription amount of the adhesive drug release system, and the rest is the second part of the adhesive drug release system;
preferably, the first part adhesive release system and/or the second part adhesive release system is selected from one or more of but not limited to hydroxypropyl methylcellulose, polyacrylic acid resin, hydroxypropyl cellulose, hydroxyethyl cellulose, milk protein, chitosan, sodium alginate, carbomer, polyvinylpyrrolidone, polyethylene glycol, sodium lauryl sulfate;
more preferably, the first part of the adhesive drug-release system and/or the second part of the adhesive drug-release system is selected from one or more of hydroxypropyl methylcellulose, milk protein, chitosan, sodium alginate and sodium dodecyl sulfate;
most preferably, the first part of the adhesive drug release system is hydroxypropyl methylcellulose and milk protein or chitosan or sodium alginate, and the second part of the adhesive drug release system is sodium dodecyl sulfate.
Drawings
The following figures are included to aid in the description of embodiments of the invention, in which:
figure 1 is a schematic view of the placement of an oral mucosal adhesive;
fig. 2 is a graph of drug concentration versus time in human saliva for an oral mucoadhesive.
Detailed Description
The invention is further illustrated below with reference to specific examples. It should be understood that the examples given herein are for illustrative purposes only and are not intended to limit the scope of the present invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, and the preferred methods and materials described herein are exemplary only.
The experimental procedures in the following examples are conventional unless otherwise specified. The raw materials and reagents used in the following examples are commercially available chemically pure or analytically pure reagents or pharmaceutical raw materials and excipients, and may be used with or without treatment, unless otherwise specified.
Preparation of adhesive preparation for oral mucosa
Rifluconazole was prepared according to the method of Pesti J et al (cf. Organic Process Research & Development,2009,13(4):716-728.) and Issatonazole was prepared according to this method by replacing 2, 4-difluorobromobenzene with 2, 5-difluorobromobenzene.
1. Preparation examples 1 to 10
Respectively pulverizing and sieving the components of the Lifluconazole, the HPMC15000, the milk protein (or the chitosan or the sodium alginate), the starch and the lactose monohydrate according to the prescription dose shown in the table 3, mixing, adding proper water for granulating, drying, pulverizing and granulating. Adding pulvis Talci, magnesium stearate and sodium laurylsulfate, mixing, tabletting, and packaging.
TABLE 3 recipes for preparation examples 1-10 (Components in mg)
2. Preparation examples 11 to 20
The isavuconazole, HPMC15000, milk protein (or chitosan or sodium alginate), starch and lactose monohydrate are respectively ground and sieved according to the prescription dose shown in the table 4, mixed, granulated by adding proper water, dried, ground and granulated. Adding pulvis Talci, magnesium stearate and sodium laurylsulfate, mixing, tabletting, and packaging.
TABLE 4 recipes for preparation examples 11-20 (Components in mg)
Second, Effect evaluation experiment
1. In vitro dissolution test
The in vitro dissolution test is an index for evaluating the quality of a pharmaceutical preparation in vitro.
The instrument model is as follows:
dissolution instrument: RCZ-8M dissolution instrument, manufactured by Tianjin Tianda Tianfa science and technology Limited
High performance liquid chromatograph: agilent 1260, ultraviolet detector
A chromatographic column: agilent XDB C18 chromatography column (4.6X100mm,3.5 μm)
The method comprises the following steps: taking the product, taking 1000ml of 0.5% sodium dodecyl sulfate aqueous solution with the pH of 6.0-7.0 as a dissolution medium according to a dissolution determination method (XC first method which is an appendix of 2010 edition of Chinese pharmacopoeia) and the rotating speed of 60 revolutions per minute, carrying out operation according to the method for 1, 2,4, 6, 8, 10 and 12 hours, taking the dissolution liquid, determining the drug concentration of the dissolution liquid by using a high performance liquid chromatography, and calculating the cumulative dissolution amount at each time point.
As a result: the in vitro dissolution test results of the oral cavity patch are shown in Table 5.
TABLE 5 dissolution results of drugs
From the above results, it can be seen that: the oral mucosa adhesive prepared in all preparation examples 1-20 has good slow release effect, and can release the medicine for a long time, and the dissolution rate is over 88% after the active ingredients are basically released in 10 th hour.
2. Adhesion test
The adhesive force is an index for evaluating the ability of the oral adhesive patch to adhere to the oral mucosa. It has some effect on the release of the drug.
The instrument comprises the following steps: digital display type push-pull dynamometer, model HP-5, manufacturer: leqing Edinburg instruments ltd, Wenzhou, Zhejiang
The testing process comprises the following steps: a stainless steel plate was placed horizontally in a petri dish and deionized water was added until approximately 1mm of the plate was soaked.
Fixing the tablet to be tested on a flat-head probe of the push-pull meter by using glue, enabling the probe to be vertically downward, immersing the tablet in water to be in close contact with a steel plate for one minute, slowly moving the push-pull meter upwards, and reading a figure (maximum value) displayed at the moment when the tablet is separated from the steel plate, wherein the figure is the adhesive force of the tablet.
As a result: the adhesion test results are shown in table 6.
TABLE 6 results of adhesion test of oral mucosa-sticking agent
As is apparent from Table 6, the oral mucosa-sticking agents prepared in preparation examples 1 to 20 had an average value of adhesive force exceeding 3.5N, and as high as 4.12N and as close to 3N as possible, and thus, the oral mucosa-sticking agents prepared in the present invention could be firmly stuck to the oral mucosa for a long period of time.
3. Measurement of saliva and blood concentration of human drug
None of the 9 healthy volunteers took the test drug or other drugs 2 days before the experiment. Each of the five test drugs of preparation 1, preparation 6, preparation 7, preparation 8 and preparation 18 was used, one at a time. The administration sequence was random, and the administration time was 1 hour after breakfast on days 1, 4, 7, 10, and 13.
The administration method comprises applying a piece of the test medicine to the upper gum (canine dentures), taking water at normal meals during the application period, taking saliva and blood at the specified time points, and determining the concentration of the medicine.
The sampling time of saliva is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours, and the sampling time of blood is 0, 0.5, 1, 2, 3, 4, 6, 8, 12 hours.
Evaluation indexes are as follows: 1. observing whether the tested medicine falls off or not, and recording the falling-off time if the tested medicine falls off; if the melting is not fallen, recording the time of melting completion; 2. taste; 3. (ii) saliva concentration; 4. blood concentration.
As a result:
1. the test drug is not dropped off in all the volunteers during the test period; the tested medicines are melted in 11-12 hours.
2. The results of the drug saliva concentration test are shown in table 7 and figure 2.
TABLE 7 human saliva concentrations of five tested drugs
As can be seen from Table 7 and FIG. 2, the concentrations of the five test drugs in saliva exceed 2. mu.g/ml, some even reach 8. mu.g/ml, and all exceed the MIC of Lifluconazole or Isaconazole for inhibiting most Candida90The value of 1. mu.g/ml, which is the concentration required to inhibit 90% of fungi, indicates that the oral mucoadhesive preparation provided by the present invention can provide an effective drug concentration in saliva for a long period of time.
3. The drugs of preparation 8 and preparation 18 were able to detect the test drug in the blood at individual time points, but the concentrations of the detected drug were below the limit of quantitation. The test drug is not detected in blood at other test drugs and test time points, and the result shows that the oral mucosa adhesive of the invention has extremely low blood drug concentration during the application period and has little influence on the whole system of a patient.
Third, comparison of administration routes
The isaconazole or the rilfluconazole is prepared into a common tablet, is orally administered, and a blood sample and saliva are collected. The blood concentration and the saliva concentration of the drugs were compared with those of the oral mucoadhesive patches prepared in production examples 1, 6, 7, 8 and 18 of the present invention. For effective comparison, the dosage of the comparative example isavuconazole or rilfluconazole oral tablet is increased to 100 mg/tablet.
1. Preparation of ansa-conazole or lifoconazole oral tablet
The isavuconazole or the riloconazole, the pregelatinized starch, the lactose, the sodium carboxymethyl starch, the PVP k30 and the sodium lauryl sulfate were respectively pulverized in the amounts shown in table 8, and sieved through a 60-mesh sieve. Then mixing the isavuconazole or the rilfluconazole, the pregelatinized starch, the lactose, the sodium carboxymethyl starch (half amount), the PVP k30 and the sodium dodecyl sulfate, granulating by a wet method, drying, mixing with the sodium carboxymethyl starch (the rest half amount), the superfine silica gel powder and the magnesium stearate, and tabletting to obtain the isavuconazole or the rilfluconazole oral tablet.
TABLE 8 Isaconazole or Lifluconazole oral tablet formulation (composition in mg)
2. Measurement of human saliva drug concentration and blood drug concentration
No test drug or other medicines were taken by 9 healthy volunteers two days before the experiment. Everyone takes one tablet of the isaconazole oral tablet prepared by the method and the prescription before breakfast and one tablet of the lifoconazole oral tablet after one week. Saliva and blood were taken at prescribed time points and drug concentrations were determined for normal meals. Saliva was sampled at 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours and blood was sampled at 0, 0.5, 1, 2, 3, 4, 6, 8, 12 hours.
As a result:
1. none of the volunteers detected the test drug in saliva.
2. In addition to the test drug being detectable in the blood at the 1 hour, 2 hour time points, no test drug was detected in the blood at any of the other test drugs and the test time points. In blood where the test drug can be detected, the blood drug concentration is below 1ug/ml, i.e., below the MIC90 of both drugs.
The results show that when the isavuconazole or the rilfluconazole is prepared into the oral tablet, effective saliva and blood concentration cannot be provided even if the dosage of the oral tablet is increased to 2-4 times (100 mg in table 6) of the preparation example, so that the oral tablet is difficult to produce a better treatment effect on the candida buccal cavity compared with the oral mucosa adhesive.
Fourthly, determination of medicine dosage range
Preparation procedures of preparation examples 21 to 24:
the preparation method comprises pulverizing and sieving riliconazole, HPMC15000, milk protein, starch, and lactose monohydrate respectively, mixing, adding water, granulating, oven drying, pulverizing, and grading. Adding pulvis Talci, magnesium stearate and sodium laurylsulfate, mixing, tabletting, and packaging.
TABLE 9 recipes for preparation examples 21 to 24
The oral mucosa adhesive preparation was prepared in different doses according to the prescription in table 9. The saliva is taken from 1, 4 and 8 hours, the drug concentration is measured, and the drug dosage range is determined.
None of the 9 healthy volunteers took the test drug or other drugs 2 days before the experiment. Each of the test drugs of preparation 1, preparation 8 and preparations 21 to 24 was used one at a time. The order of administration was randomized and the time of administration was 1 hour after breakfast on days 1, 4, 7, 10, 13 and 16.
The application method comprises applying a piece of the medicine to the upper gum (canine teeth), taking water at 0, 1, 4, and 8 hr, and measuring the concentration of the medicine.
Evaluation indexes are as follows: 1. observing whether the tested medicine falls off or not, and recording the falling-off time if the tested medicine falls off; if the melting is not fallen, recording the time of melting completion; 2. taste; 3. salivary drug concentration.
As a result:
1. the test drug is not dropped off in all the volunteers during the test period; the tested medicines are melted in 10-12 hours.
2. The results of the drug saliva concentration test are shown in Table 10
TABLE 10 saliva concentration of preparation examples 1, 8, 21 to 24
As can be seen from Table 10, the concentration of drug in saliva was below the MIC of Lifluconazole when the dose of drug active ingredient was below 5mg per tablet90(ii) a When the active dose per tablet is higher than 50mg, the increase in the concentration of the saliva drug is insignificant.
Five, other tests
1. Stability test
The product prepared by the preparation example of the invention is respectively placed under the conditions of illumination (45000lx +/-500 lx), high temperature (60 ℃), high humidity (RH 92.5%, 25 ℃) and the like for 5 days and 10 days to carry out influence factor tests; and the stability change is inspected in accelerated tests (at 40 ℃ +/-2 ℃ and RH 75%) for 1 month, 2 months, 3 months and 6 months and at room temperature (at 25 ℃ +/-2 ℃ and RH 60% +/-10%) for 0 month, 3 months, 6 months, 9 months and 12 months, and test results show that the product of the invention has stable properties and no obvious change in related substances, content, adhesion, drug release and the like, so that the product of the invention has good stability.
2. Mucosal irritation test
Before the product of the invention is used by a volunteer, a mucous membrane stimulation test is carried out on the product of the invention, the product prepared by the invention is stuck to the oral gingival emergence of the beagle dog, the reaction of the gingival mucous membranes of the beagle dog in 0 th, 1 th, 2 th, 3 th, 4 th, 5 th, 6 th, 7 th, 8 th, 9 th, 10 th, 11 th and 12 th hours after the administration is observed, and the result is not obviously different from the result of comparison with the gingival mucous membranes before the administration and on the other side, so the product of the invention has no stimulation to the mucous membranes.
Claims (14)
1. An oral mucosa adhesive agent, characterized in that the oral mucosa adhesive agent comprises the following active pharmaceutical ingredients:
wherein, the oral mucosa adhesive comprises the following components in percentage by weight: 25% -43.5% of active ingredients of the medicine; 27.5% -46.1% of an adhesion drug release system; 0.9-15% of a diluent; 7.6-26.7% of a binder; 2-2.3% of a lubricant;
the adhesive drug release system consists of hydroxypropyl methylcellulose, milk protein or chitosan or sodium alginate and lauryl sodium sulfate;
the diluent is microcrystalline cellulose or lactose monohydrate;
the adhesive is starch or polyvinylpyrrolidone;
the lubricant is selected from one or more of magnesium stearate, talcum powder and sodium stearyl fumarate;
the adhesive drug release system comprises the following components in percentage by weight:
29.2 to 43.3 percent of hydroxypropyl methyl cellulose,
8.3 to 10.9 percent of sodium dodecyl sulfate,
46.7-62.5% of milk protein, chitosan or sodium alginate.
2. The oral mucosa-sticking agent according to claim 1, wherein the amount of the pharmaceutically active ingredient is 5 to 100mg per unit formulation amount.
3. The oral mucosa-sticking agent according to claim 1, wherein the amount of the pharmaceutically active ingredient is 10 to 50mg per unit formulation amount.
4. The oral mucosa-sticking agent according to claim 1, wherein the amount of the pharmaceutically active ingredient is 25mg or 50mg per unit formulation amount.
5. The oral mucosa-sticking agent according to any one of claims 1 to 4,
in the adhesive drug release system, the viscosity of the hydroxypropyl methyl cellulose is 100-150000 centipoises.
6. The oral mucosa adhesive according to claim 5, wherein the viscosity of the hydroxypropylmethylcellulose in the adhesive drug delivery system is 4000 to 100000 cps.
7. The oral mucosa patch according to any one of claims 1 to 4, wherein the milk protein is a dietary or medicinal milk protein having a purity of 85% or more.
8. The oral mucosa patch according to any one of claims 1 to 4, wherein the sodium alginate is oligomeric sodium alginate, and has an average molecular weight of about 35000.
9. The oral mucosa-adhesive agent according to any one of claims 1 to 4, wherein the oral mucosa-adhesive agent is a mucosa-adhesive sheet.
10. A method for preparing the oromucosal adhesive of any one of claims 1 to 9, wherein the method is a wet granulation method, a dry granulation method or a direct compression method;
in the wet granulation, the adhesive drug release system in the oral mucosa adhesive agent prescription is added in two parts;
the wet granulation method comprises the steps of respectively crushing, sieving and mixing the pharmaceutical active ingredient, the first part of adhesive drug delivery system, the adhesive and the diluent according to the prescription amount, adding water for granulation, then adding the lubricant and the second part of adhesive drug delivery system, uniformly mixing and tabletting;
the adding amount of the first part of the adhesive drug release system is 85-95% of the prescription amount of the adhesive drug release system, and the rest is the second part of the adhesive drug release system;
the first part of the adhesive drug release system is hydroxypropyl methylcellulose and milk protein or chitosan or sodium alginate, and the second part of the adhesive drug release system is sodium dodecyl sulfate.
11. The method of claim 10, wherein the wet granulation comprises pulverizing the prescribed amount of the pharmaceutically active ingredient, the first part of the adhesive drug delivery system, the binder, and the diluent, respectively, sieving, mixing, adding water, granulating, adding the lubricant and the second part of the adhesive drug delivery system, mixing, and tabletting;
the adding amount of the first part of the adhesive drug release system is 89.1-91.7% of the prescription amount of the adhesive drug release system, and the rest is the second part of the adhesive drug release system.
12. An oral mucosa adhesive agent, which is characterized by comprising the following components:
25mg of lifoconazole;
HPMC15000 10.5mg；
17.5mg of chitosan;
3mg of sodium dodecyl sulfate;
26.7mg of starch;
lactose monohydrate 15 mg;
1mg of talcum powder; and
magnesium stearate 1.3 mg.
13. An oral mucosa adhesive agent, which is characterized by comprising the following components:
25mg of lifoconazole;
HPMC15000 10.5mg；
sodium alginate 17.5mg
3mg of sodium dodecyl sulfate;
26.7mg of starch;
lactose monohydrate 15 mg;
1mg of talcum powder; and
magnesium stearate 1.3 mg.
14. An oral mucosa adhesive agent, which is characterized by comprising the following components:
50mg of lifoconazole;
HPMC15000 20.5mg；
milk protein 27.5 mg;
5mg of sodium dodecyl sulfate;
8.7mg of starch;
lactose monohydrate 1 mg;
1mg of talcum powder;
magnesium stearate 1.3 mg.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101108172A (en) * | 2006-07-17 | 2008-01-23 | 天津药物研究院 | Oral sticking tablet and method of preparing the same |
| CN101437546A (en) * | 2006-05-02 | 2009-05-20 | 万能药生物有限公司 | Transmucosal composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101437546A (en) * | 2006-05-02 | 2009-05-20 | 万能药生物有限公司 | Transmucosal composition |
| CN101108172A (en) * | 2006-07-17 | 2008-01-23 | 天津药物研究院 | Oral sticking tablet and method of preparing the same |
Non-Patent Citations (1)
| Title |
|---|
| Efficacy of ravuconazole in treatment of mucosal candidosis in SCID mice;KARL V. CLEMONS，et al.;《ANTIMICROBIAL AGENTS AND CHEMOTHERAPY》;20011231;第45卷(第12期);3433-3436 * |
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