Apixaban oral soluble film and preparation method thereof

Abstract

The invention provides an apixaban oral soluble film and a preparation method thereof, and belongs to the field of apixaban preparations. The apixaban oral soluble film is prepared from apixaban, copovidone, polyoxyethylene, polyethylene glycol and sucralose. The preparation method comprises the following steps: weighing raw materials according to a formula ratio, and sieving to obtain a sieved material; uniformly mixing the sieved material to obtain a mixture; and preparing the apixaban oral soluble film from the mixture in a hot melt extrusion manner. Compared with the prior art, the apixaban injection can meet the requirements of postoperative patients with poor health and dysphagia or patients needing to be deprived of water on apixaban administration; the apixaban oral soluble film prepared according to the formula and the preparation method disclosed by the invention is good in film-forming property, smooth in surface, uniform in color and luster and high in disintegration speed; under different dissolution conditions, the apixaban oral soluble film shows the same dissolution amount, and it can be ensured that the product has the same treatment effect in different crowds.

Description

Technical Field

[0001] The invention belongs to the field of apixaban preparations and relates to an apixaban orosoluble film and a preparation method thereof. Background Art

[0002] Apixaban is indicated for the prevention of venous thromboembolic events (VTE) in adult patients undergoing elective hip or knee replacement surgery. Patients who undergo elective hip or knee replacement surgery are usually weaker after surgery and may not be able to swallow a whole tablet. For patients who cannot swallow a whole tablet, the Apixaban tablets need to be crushed and suspended in water or 5% glucose solution, or apple juice, or mixed with applesauce and taken orally in time. Alternatively, suspend the Apixaban tablets in 60 ml of water or 5% glucose solution and administer it in time through a nasogastric tube (Apixaban instructions; Shanghai Bristol-Myers Squibb Pharmaceuticals Co., Ltd.). This complex method of administration is a certain burden for patients or their caregivers.

[0003] Orodispersible film is a special drug carrier that can dissolve directly in the mouth and then enter the blood circulation through the oral mucosa to achieve rapid absorption of the drug. Its main advantages include rapid absorption, efficient release, accurate dosage, and easy use. As a new drug delivery system, it has flexible dosage and is suitable for children, the elderly, and patients with dysphagia. Therefore, it is very necessary to provide an orodispersible film product of apixaban.

[0004] The invention of CN116650448A provides an oral film containing Lebrexan and a preparation method thereof, wherein the film is prepared by adding an appropriate amount of carrier materials, plasticizers and other auxiliary materials. The invention is the first to develop Lebrexan into an oral film, which has a significantly faster dissolution rate than the original tablets, a smaller volume than tablets, more convenient administration, less dietary influence, and is not easy to lose. However, due to the difference in effective components, its preparation method and auxiliary material components are difficult to be directly applied to Apixaban.

[0005] CN104736142B provides a kind of apixaban liquid preparation, and provides the administration method of apixaban liquid preparation. To provide a kind of treatment that can be applied to the pediatric population and adult-related diseases that cannot swallow solid dosage forms, however, due to the poor water solubility of apixaban, a large amount of solubilizing agents are added in the patent, although the patent points out that it is adjusted in dosage according to the regulatory guidelines (regulatory guidelines) and the acceptable daily adjuvant intake of adjuvant safety literature, but in order to further improve the safety of children's medication, it is very necessary to provide an additive that is safer and has a simpler preparation process for apixaban.

[0006] At the same time, there is a significant difference in the drug release rate of the original apixaban tablets at 50rpm and 75rpm. The dissolution condition of 50rpm is closer to the gastrointestinal motility of postoperative patients. This difference in the release of the original tablets under different conditions may lead to a pharmacokinetic gap between normal subjects and patients, making the drug have different therapeutic effects in different populations; how to ensure that the apixaban preparation products have the same therapeutic effect in different populations and reduce the difference in therapeutic effects between different populations is also a problem that the original apixaban drug needs to overcome.

[0007] Therefore, how to provide an apixaban oral film-soluble preparation with safe excipients, simple preparation process and the ability to maintain the release consistency of apixaban under different conditions is one of the issues being studied in this field. Summary of the invention

[0008] The present invention aims at the problem that the prior art lacks an apixaban oral film preparation with safe auxiliary materials, concise preparation process and the ability to maintain the consistency of apixaban release under different conditions, provides an apixaban oral film and a preparation method thereof, and provides an applicable apixaban oral film preparation for postoperative patients with weak body and dysphagia or patients who need to abstain from water. The apixaban oral film does not require drinking water and swallowing, and the drug can enter the gastrointestinal tract with saliva, which can improve the compliance of the aforementioned patients.

[0009] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0010] An apixaban orosoluble film is composed of the following components:

[0011] Apixaban, copovidone, polyoxyethylene, polyethylene glycol, and sucralose.

[0012] Preferably, the apixaban orosoluble film is composed of the following components in percentage by mass:

[0013] Apixaban 5-15%, copovidone 7.8-81.0%, polyoxyethylene 7.8-81.0%, polyethylene glycol 3-7% and sucralose 0.5-2%.

[0014] Further preferably, the apixaban orosoluble film is composed of the following components in percentage by mass:

[0015] Apixaban 5-15%, copovidone 28-55%, polyoxyethylene 29.0-58.5%, polyethylene glycol 3-7% and sucralose 0.5-2%.

[0016] More preferably, the apixaban orosoluble film is composed of the following components in percentage by mass:

[0017] Apixaban 10%, copovidone 28-55%, polyoxyethylene 29.0-58.5%, polyethylene glycol 3-7% and sucralose 0.5-2%.

[0018] Most preferably, the apixaban orosoluble film is composed of the following components in percentage by mass:

[0019] Apixaban 10%, copovidone 33.6%, polyoxyethylene 50.4%, polyethylene glycol 5%, and sucralose 1%.

[0020] The present invention also provides a method for preparing the above-mentioned apixaban orosoluble film, comprising the following steps:

[0021] (1) weighing formula amounts of apixaban, copovidone, polyoxyethylene, polyethylene glycol, and sucralose and sieving them to obtain a sieved material;

[0022] (2) mixing the sieved materials obtained in step (1) uniformly to obtain a mixed material;

[0023] (3) preparing the apixaban orosoluble film by hot-melt extrusion of the mixture obtained in step (2).

[0024] Preferably, the sieve used in step (1) is a 30-50 mesh sieve.

[0025] Further preferably, the sieve is a 40-mesh sieve.

[0026] Preferably, the mixing in step (2) is carried out using a universal mixer.

[0027] More preferably, the mixing speed is 5-30 rpm and the mixing time is 5-30 min.

[0028] Most preferably, the mixing speed is 15 rpm and the mixing time is 10 min.

[0029] Preferably, the temperature of the hot melt extrusion in step (3) is set to 135°C to 170°C.

[0030] The present invention also provides an apixaban orosoluble film prepared by the preparation method.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] 1. The present invention provides an orodispersible film formula suitable for apixaban, and provides an orodispersible film of apixaban prepared by hot melt extrusion, and provides a detailed preparation method, which can meet the needs of postoperative patients with weak body and dysphagia or patients who need to abstain from water for apixaban medication.

[0033] 2. The apixaban orodispersible film prepared according to the formula and preparation method of the present invention has good film-forming properties, a smooth surface, uniform color, and a fast disintegration rate; it adopts hot-melt extrusion film-drawing technology, has high yield and small amplification effect, and does not use solvents to meet environmental protection requirements.

[0034] 3. The apixaban orodispersible film provided by the present invention shows a consistent dissolution amount under the dissolution conditions of 50 rpm and 75 rpm, which can ensure that the product has the same therapeutic effect in different populations and reduce the difference in therapeutic effect between different populations. DETAILED DESCRIPTION

[0035] It is worth noting that the raw materials used in the present invention are all common commercially available products, and their sources are not specifically limited.

[0036] The following sources of raw materials are provided for illustrative purposes:

[0037] Apixaban was purchased from Nanjing Zhengda Tianqing Pharmaceutical Co., Ltd.

[0038] The production equipment and testing equipment used in the present invention are as follows:

[0039] Instrument Name Instrument Manufacturer Hot Melt Extruder Sanofi Pharmaceutical packaging performance tester Jinan Saicheng Electronic Technology Intelligent disintegration instrument Tianda Tianfa Dissolution tester Tianda Tianfa

[0040] Example 1-9: An apixaban orosoluble film and a method for preparing the same

[0041] The raw materials and dosage of the apixaban oral dissolving film used in Examples 1-9 are shown in Table 1

[0042] Table 1 Raw materials and dosage of apixaban oral dissolving film

[0043] Example 1 Example 2 Example 3 Example 4 Example 5 Apixaban 10 5 15 9 11 Copolyvidone 33.6 9 71.1 8.6 73.8 Polyoxyethylene 50.4 81 7.9 77.4 8.2 Polyethylene glycol 5 4 5 4 5 Sucralose 2 1 1 1 2

[0044] Example 6 Example 7 Example 8 Example 9 Apixaban 10 10 5 15 Copolyvidone 30.00 55.00 28.00 31.00 Polyoxyethylene 56.00 29.00 58.50 48.0 Polyethylene glycol 3.0 4.0 7.0 4.0 Sucralose 1.0 1.0 0.5 2.0

[0045] Note: The dosage of raw materials in the table is the percentage of dosage. The absolute dosage of apixaban in Example 1-9 is 2.5 mg

[0046] The preparation method of the orosoluble apixaban film described in Examples 1-4 is as follows:

[0047] 1. Weigh the raw materials in the formula according to the contents in Table 1, and mix the raw materials through a 40-mesh sieve three times;

[0048] 2. Transfer the raw materials to the universal mixer, set the speed to 15 rpm, and the time to 10 minutes;

[0049] 3. Prepare the film using a hot melt extruder, set the extrusion temperature to 80, 100, 120, 135, 135, 135, 135°C and the screw speed to 20 rpm to obtain the orosoluble apixaban film.

[0050] The preparation method of the orosoluble apixaban film described in Example 5 is as follows:

[0051] 1. Weigh the raw materials in the formula according to the contents in Table 1, and mix the raw materials through a 30-mesh sieve three times;

[0052] 2. Transfer the raw materials to the universal mixer, set the speed to 5 rpm, and the time to 30 minutes;

[0053] 3. Prepare films using a hot melt extruder, set the extrusion temperatures to 90, 110, 140, 170, 170, 170, 170°C and the screw speed to 50 rpm to obtain apixaban orosoluble films.

[0054] The preparation method of the orosoluble apixaban film described in Examples 6-9 is as follows:

[0055] 1. Weigh the raw materials in the formula according to the contents in Table 1, and mix the raw materials through a 40-mesh sieve three times;

[0056] 2. Transfer the raw materials to the universal mixer, set the speed to 30 rpm, and the time to 5 minutes;

[0057] 3. Prepare films using a hot melt extruder, set the extrusion temperatures to 80, 100, 130, 155, 155, 155, 155° C., and the screw speed to 100 rpm to obtain apixaban orosoluble films.

[0058] Comparative Example 1-3: An apixaban orosoluble film and a preparation method thereof

[0059] The difference between Comparative Examples 1-3 and Example 1 is that the raw materials and dosage of the oral apixaban film are different. Specifically, see Table 2

[0060] Table 2 Raw materials and dosage of apixaban oral dissolving film

[0061] Comparative Example 1 Comparative Example 2 Comparative Example 3 Apixaban 3 5 20 Copolyvidone 36.8 4 61.2 Polyoxyethylene 55.2 85 6.8 Polyethylene glycol 5 5 10 Sucralose 1 1 2

[0062] Note: The dosage of raw materials in the table is the percentage of dosage. The absolute dosage of apixaban in comparative example 1-3 is 2.5 mg

[0063] Comparative Example 4: An apixaban orosoluble film and a preparation method thereof

[0064] The difference between Comparative Example 4 and Example 1 is that the preparation method of the orosoluble apixaban film is different, specifically:

[0065] The preparation method of the apixaban orosoluble film described in Comparative Example 4 is as follows:

[0066] 1. Weigh the raw materials in the formula according to the contents in Table 1, and mix the raw materials through a 40-mesh sieve three times;

[0067] 2. Transfer the raw materials to the universal mixer, set the speed to 15 rpm, the mixing time to 10 min, and test the powder properties after mixing;

[0068] 3. Prepare the film using a hot melt extruder, set the extrusion temperature to 80, 110, 140, 160, 160, 160, 160°C and the screw speed to 20 rpm to obtain the apixaban orosoluble film.

[0069] Comparative Example 5: An apixaban orosoluble film and a preparation method thereof

[0070] The difference between Comparative Example 5 and Example 1 is that the preparation method of the orosoluble apixaban film is different, specifically:

[0071] The preparation method of the apixaban orosoluble film described in Comparative Example 5 is as follows:

[0072] 1. Weigh the raw materials in the formula according to the contents in Table 1, and mix the raw materials through a 40-mesh sieve three times;

[0073] 2. Transfer the raw materials to the universal mixer, set the speed to 15 rpm, the mixing time to 10 min, and test the powder properties after mixing;

[0074] 3. Prepare the film using a hot melt extruder, set the extrusion temperature to 60, 80, 110, 130, 130, 130, 130°C and the screw speed to 20 rpm to obtain the orosoluble apixaban film.

[0075] Comparative Example 6-7: A kind of apixaban orosoluble film and its preparation method (solvent method)

[0076] The raw materials and dosage of the apixaban oral dissolving film (solvent method) used in Comparative Examples 6-7 are shown in Table 3:

[0077] Table 3 Raw materials and dosage of apixaban oral dissolving film (solvent method)

[0078] Comparative Example 6 Comparative Example 7 Apixaban 10 10 Hydroxypropyl methylcellulose 80 65 Hydroxyethyl Cellulose 9 / Polyethylene glycol / 24 Dimethicone 0.1 / Sucralose 0.9 1

[0079] Note: The raw materials in the table are all in percentage. The absolute dosage of apixaban in comparative example 6-7 is 2.5 mg

[0080] The preparation method of the apixaban oral dissolving film (solvent method) described in Comparative Examples 6-7 is as follows:

[0081] Take the formulated amount of hydroxypropyl methylcellulose or hydroxyethyl cellulose and disperse it in 90°C hot water, stir and dissolve it, cool it to room temperature, add the formulated amount of polyethylene glycol or dimethicone, stir and dissolve it, then add the formulated amount of sucralose, stir and dissolve it, add apixaban, stir and disperse it evenly, remove bubbles by ultrasound, evenly coat the drug on the substrate, heat and dry it to form a film, cut it into a suitable shape and size, and obtain the apixaban orosoluble film.

[0082] Comparative Example 8: An apixaban orosoluble film and a preparation method thereof (hot melt extrusion method)

[0083] The raw materials and dosage of the apixaban oral dissolving film (hot melt extrusion method) used in Comparative Example 8 are shown in Table 4:

[0084] Table 4 Raw materials and dosage of apixaban oral dissolving film (solvent method)

[0085] Comparative Example 8 Apixaban 10.0％ Polyvinyl alcohol 84.0％ Polyethylene glycol 5.0％ Sucralose 1.0％

[0086] Note: The raw materials in the table are all in percentage. The absolute dosage of apixaban in comparative example 8 is 2.5 mg

[0087] The preparation method of the apixaban orosoluble film (hot melt extrusion method) described in Comparative Example 8 is as follows:

[0088] 1. Weigh the batch prescription amount of raw materials and mix the raw materials through a 40-mesh sieve three times;

[0089] 2. Transfer the raw materials to the universal mixer, set the speed to 15 rpm, the mixing time to 10 min, and test the powder properties after mixing;

[0090] 3. Prepare films using a hot melt extruder, set the extrusion temperatures to 110, 140, 180, 180, 180, 180, 180°C and the screw speed to 50 rpm to obtain apixaban orosoluble films.

[0091] Comparative study 1: Disintegration time of apixaban oral film

[0092] The disintegration time limit test method of Appendix 0921 of the 2020 edition of the Chinese Pharmacopoeia was used to measure the disintegration time limit of Examples 1-5 and Comparative Examples 1-5. The results are shown in Table 5:

[0093] Table 5 Disintegration time of Examples 1-5 and Comparative Examples 1-5

[0094] Example Thickness / mm Disintegration time / s Example 1 0.08 9 Example 2 0.08 10 Example 3 0.08 9 Example 4 0.08 9 Example 5 0.08 9 Example 6 0.08 9 Example 7 0.08 11 Example 8 0.08 10 Example 9 0.08 9 Comparative Example 1 0.08 19 Comparative Example 2 0.08 28 Comparative Example 3 0.08 25 Comparative Example 4 0.08 21 Comparative Example 5 0.08 36 Comparative Example 6 0.09 51 Comparative Example 7 0.11 45 Comparative Example 8 0.08 20

[0095] According to the data in Table 1, the apixaban orodispersible film provided by Examples 1-5 of the present invention has a shorter disintegration time (≤10s) during the disintegration time test, indicating that the apixaban provided by the present invention has good disintegration performance, can effectively promote the dissolution of the active ingredient, and reduce the foreign body sensation caused by the long disintegration time of the orodispersible film.

[0096] However, since the comparative examples 1-3 made unreasonable adjustments to the apixaban orosoluble film provided by the present invention, the disintegration rate of the apixaban orosoluble film prepared in the comparative examples 1-3 was greatly reduced, and the required disintegration time was extended by 1.1 (19s)-2.1 (28s) times compared with that in Example 1.

[0097] Comparative Examples 4 (disintegration time 21s) and 5 (disintegration time 36s) are adjustments to the preparation process (temperature) of the Apixaban oral disintegrating film. The results show that using too high or too low a temperature will lead to a decrease in the performance of the Apixaban oral disintegrating film and reduce the disintegration performance.

[0098] Comparative test 2: Dissolution results of apixaban oral film:

[0099] The dissolution method was carried out in accordance with the first method of dissolution and release determination method of Part IV 0931 General Rules, 2020 Edition; the solvent was: pH 6.8 phosphate solution; dissolution determination was carried out on Examples 1-3 and the original tablets (Accord Healthcare SLU).

[0100] The results are as follows:

[0101] Table 6 Dissolution effect of Examples 1-3 and original tablets

[0102]

[0103] Note: The speed of the dissolution apparatus is 50 rpm. The data result is the dissolution rate of the active ingredient of apixaban, in %.

[0104] As can be seen from the data in Table 6, the dissolution rates of the apixaban oral dissolving films provided in Examples 1-3 of the present invention were all greater than 98% in the 45-min dissolution effect test, while the dissolution rate of the original drug was only 72%;

[0105] In terms of the early disintegration rate, the orodispersible Apixaban films provided by the present invention achieved an Apixaban dissolution rate of more than 85% at 15 minutes, while the orodispersible Apixaban films provided in Example 1 completed the dissolution of most of the Apixaban (95%) within only 5 minutes, far exceeding the 28% of the original tablets.

[0106] Comparative test 3: Properties of apixaban orodissolving film

[0107] The properties of the apixaban orodispersible films of Examples 1-5 and Comparative Examples 1-8 were tested. Only the apixaban orodispersible film prepared in Comparative Example 8 had a mottled color problem. The orodispersible films of other Examples and Comparative Examples had good film-forming properties, smooth surfaces, and uniform color.

[0108] Comparative test 4: compatibility test of raw materials and excipients

[0109] The single and total impurity contents of apixaban raw materials and excipients were determined under different conditions, and the compatibility of apixaban and excipients was studied by the impurity content.

[0110] The results are as follows:

[0111] Table 7 Compatibility of apixaban with excipients (impurities)

[0112]

[0113]

[0114] Note: Excipients have a certain degree of hygroscopicity, so some high-humidity samples are "off-white powder and lumpy solids". The reason is that the powder absorbs moisture and clumps.

[0115] It can be seen from the data in the above table that the compatibility of the apixaban and its excipients used in the present invention is good. Under different excipients and different conditions, the single impurity and total impurity contents of the apixaban-excipients are within the range values ​​(refer to the "Draft for Publicity of Apixaban [to be included in the Pharmacopoeia]", which can be seen in the official website of the State Pharmacopoeia Committee - Information Disclosure - Standard Publicity).

[0116] Comparative experiment 5: Dissolution effect of apixaban oral dissolving film and original tablets at different pH and rotation speed

[0117] 1. Dissolution effect at different pH:

[0118] Embodiment 1:

[0119] Dissolution conditions: Paddle method 50rpm

[0120] The results are as follows:

[0121] Table 8 Dissolution effect of apixaban oral dissolving film at different pH values ​​in Example 1

[0122]

[0123] Generic 8mg tablet data (Company: Accord Healthcare SLU):

[0124] The data are extracted from EMA data (Procedure No.EMEA / H / C / 005358 / 0000).

[0125] Dissolution conditions: Paddle method 50rpm

[0126] The results are as follows:

[0127] Table 9 Dissolution effect of original apixaban tablets at different pH

[0128]

[0129] According to the data in Table 8 and Table 9, the dissolution of the apixaban tablets of Accord Healthcare SLU was consistent under various pH conditions, but did not reach more than 95%. The dissolution of the apixaban oral dissolving film provided by the present invention was also consistent under various pH conditions, and reached more than 95%.

[0130] 2. Dissolution results at different speeds:

[0131] Table 10 Dissolution effect of apixaban oral dissolving film and original tablets at different rotation speeds in Example 1

[0132]

[0133] Note: The dissolution medium is pH 6.8 phosphate, and the data results are the dissolution rate of the active ingredient of apixaban, in %.

[0134] According to the data in Table 10, under different dissolution conditions (rotation speed, which can be compared to different digestive environments), the dissolution rate of the apixaban oral dissolving film provided in Example 1 of the present invention is higher than 97% within 45 minutes; while the dissolution rates of the original tablets under the dissolution conditions of 50 rpm and 75 rpm are 72% and 95% within 45 minutes, respectively, with a difference of 23%, indicating that the dissolution rate of the active ingredient of the original tablets under different digestive environments is significantly different, and it is difficult to reduce the difference in therapeutic effect between different populations.

[0135] Test Example 6

[0136] Stability Results:

[0137] The apixaban orosoluble films obtained in Examples 1 and 8 of the present invention were placed in a rapid stabilization box (55°C, 75% RH) for 1 month, an accelerated stabilization box (40°C / 75% RH) for 3 months, and a long-term stabilization box (25°C / 60% RH) for 3 months, and the related substances were determined. The impurity results are as follows:

[0138]

[0139] The results showed that the total impurity content of the apixaban oral dissolving film provided by the present invention did not increase under the conditions of rapid, accelerated and long-term, and remained consistent with that on day 0, all at 0.08%. The product had good stability under various conditions.

[0140] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. An orosoluble apixaban film, characterized in that: It is composed of the following components: Apixaban, copovidone, polyoxyethylene, polyethylene glycol, and sucralose.

2. The orosoluble apixaban film according to claim 1, characterized in that: The components are as follows by mass percentage: Apixaban 5-15%, copovidone 7.8-81.0%, polyoxyethylene 7.8-81.0%, polyethylene glycol 3-7% and sucralose 0.5-2%.

3. The orosoluble apixaban film according to claim 2, characterized in that: The components are as follows by mass percentage: Apixaban 5-15%, copovidone 28-55%, polyoxyethylene 29-58.5%, polyethylene glycol 3-7% and sucralose 0.5-2%.

4. The orosoluble apixaban film according to claim 2, characterized in that: The components are as follows by mass percentage: Apixaban 10%, copovidone 28-55%, polyoxyethylene 29-58.5%, polyethylene glycol 3-7% and sucralose 0.5-2%.

5. The method for preparing the orosoluble apixaban film according to claim 1, characterized in that: The following steps are involved: (1) weighing formula amounts of apixaban, copovidone, polyoxyethylene, polyethylene glycol, and sucralose and sieving them to obtain a sieved material; (2) mixing the sieved materials obtained in step (1) uniformly to obtain a mixed material; (3) preparing the apixaban orosoluble film by hot-melt extrusion of the mixture obtained in step (2).

6. The preparation method according to claim 5, characterized in that: The sieve used in step (1) is a 30-50 mesh sieve.

7. The preparation method according to claim 5, characterized in that: The mixing in step (2) is carried out by using a universal mixer.

8. The preparation method according to claim 7, characterized in that: The mixing speed is 5-30 rpm and the mixing time is 5-30 min.

9. The preparation method according to claim 5, characterized in that: The temperature of the hot melt extrusion in step (3) is 135°C to 170°C.

10. The apixaban orosoluble film prepared according to the preparation method according to any one of claims 5 to 9.

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