KR20200077268A - Uses Of Solifenacin Tartrate As Oral Dispersant - Google Patents

Abstract

Disclosed is a pharmaceutical formulation for oral administration for treating irritable bladder containing solifenacin tartrate as an active component, which is suitable for manufacturing into a formulation that hides the bitter taste of solifenacin and disperses quickly in the oral cavity, and is easy for irritable bladder patients to consume the pharmaceutical formulation without water.

Description

Use of Solifenacin Tartrate as a Pharmaceutical Formulation for Oral Administration {Uses Of Solifenacin Tartrate As Oral Dispersant}

The present invention relates to a pharmaceutical preparation for oral administration containing solifenacin tartrate as a pharmaceutical preparation for oral administration of solifenacin tartrate, which can hide the taste of solifenacin.

Irritable bladder is a syndrome that shows symptoms such as urinary frequency and nocturia with urgency. It shows a tendency to increase with age, and it is observed that 3 out of 10 people aged 65 years or older show irritable bladder symptoms. Patients with irritable bladder are often accompanied by dysphagia due to old age, and thus, a formulation capable of providing patient convenience is required.

Drugs that primarily act as muscarinic receptor antagonists are used to treat overactive bladder. Commonly used muscarinic receptor antagonists are solifenacin, of which solifenacin succinate is mainly used.

Since patients with irritable bladder are difficult to control urination and need to limit water intake, it is desirable to take irritable bladder treatments without ingesting moisture, and it is necessary to prepare a formulation that is dispersed in the oral cavity so that it can be taken even if there is dysphagia. However, since solifenacin has a strong taste and is unpleasant when taken without water, the dosage form dispersed in the oral cavity is low.

All over-the-counter sensitizing bladder treatments, including solifenacin, are commercially available in the form of tablets that must be taken with water. There are no known studies on the form of salts that are suitable for taking without water, but that can conceal the taste of solifenacin.

Republic of Korea Publication 10-2014-0146044 (2014.12.24)

According to an embodiment of the present invention provides a pharmaceutical preparation for oral administration for irritable bladder treatment suitable for manufacturing a formulation in which the taste of solifenacin is concealed and rapidly dispersed in the oral cavity.

The pharmaceutical preparation for oral administration for irritable bladder treatment according to the embodiment of the present invention is concealed from the taste of solifenacin and is easy to consume without moisture.

In the pharmaceutical preparation for oral administration for irritable bladder according to an embodiment of the present invention, the taste of solifenacin can be sufficiently concealed without a separate sweetener or additive, and patients who have hypersensitivity to specific sweeteners or additives or whose sugar intake should be restricted May be suitable for

The pharmaceutical formulation for oral administration according to the embodiment of the present invention includes solifenacin tartrate as an active ingredient and is for the treatment of irritable bladder.

The solifenacin tartrate may have a water solubility of 200 μg/ml or less.

The solifenacin tartrate may have a wetting angle of 20 degrees or more.

The solifenacin tartrate may have a particle diameter of 75 μm or less.

The pharmaceutical preparation for oral administration may be formulated as a formulation dissolved or dispersed in the oral cavity.

The formulation may be an oral dissolving film, fast-acting disintegrating tablet, oral disintegrating granules, or oral disintegrating granules.

Pharmaceutical formulations for oral administration for irritable bladder treatment according to an embodiment of the present invention may be suitable for manufacturing a formulation in which the taste of solifenacin is concealed and rapidly dispersed in the oral cavity.

The pharmaceutical preparation for oral administration for irritable bladder treatment according to an embodiment of the present invention may be easily ingested without moisture since the taste of solifenacin is concealed.

In the pharmaceutical preparation for oral administration for irritable bladder according to an embodiment of the present invention, the taste of solifenacin can be sufficiently concealed without a separate sweetener or additive, and patients who have hypersensitivity to specific sweeteners or additives or whose sugar intake should be restricted May be suitable for

1 is a comparison of the stability of each type of solifenacin salt. (p<0.05, ANOVA-Tukey)
Figure 2 shows the equilibrium water solubility of each type of solifenacin salt.
Figure 3 shows the contact angle for each type of solifenacin salt. (p<0.05, ANOVA-Tukey)
4 to 6 show the results of sensory evaluation of electrotongue by type of solifenacin salt.
Figure 7 shows the total score of the taste of each type of solifenacin salt.
Figure 8 shows the evaluation of bitter, sweet, sour, salty by type of solifenacin salt.
9 shows the evaluation of taste related to tactile sense for each type of solifenacin salt.

The pharmaceutical preparation for oral administration according to the embodiment of the present invention includes solifenacin tartaric acid salt as an active ingredient and is used for the treatment of irritable bladder.

The active ingredient refers to a component expected to exert a pharmacological function among raw materials used in the preparation of the preparation.

The chemical name of the solifenacin is (1R, 3'R)-3'-quinuclidinyl-1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate. The solifenacin has been reported to have excellent selective antagonism to the muscarinic M ₃ receptor and is useful as a therapeutic agent for neurogenic urinary tract, neurogenic bladder, enuresis, unstable bladder, bladder spasms, or chronic cystitis.

Irritable bladder occurs predominantly in high-age groups over the age of 45. Patients with irritable bladder may need to limit fluid intake because of frequent urination and difficulty controlling urination. Therefore, the oral administration preparation for the treatment of irritable bladder can be taken without water, and it is preferable to disperse rapidly in the oral cavity. However, solifenacin succinate, which was mainly used in the past, was not suitable as a formulation with a strong taste and dispersed in the oral cavity, and there was a problem in that patient compliance was poor.

The present inventors paid attention to the fact that solefenacin tartrate can most effectively conceal the taste of solifenacin, and that it is suitable for use as a formulation for oral administration that is easy to take without ingesting water. Invented pharmaceutical formulation for oral administration for the treatment of irritable bladder containing.

The solifenacin tartrate may have a water solubility of 180 μg/ml or less, 150 μg/ml or less, 120 μg/ml or less, 100 μg/ml or less, 95 μg/ml or less, 90 μg/ml or less, or 85 μg/ml or less. When the water solubility is high, solifenacin stimulates taste buds, so that the taste can be felt more strongly, and the compliance with taking may be reduced.

The solifenacin tartrate has a water solubility of 50 to 200 μg/ml, 60 to 150 μg/ml, 65 to 100 μg/ml, 70 to 90 μg/ml, 75 to 90 μg/ml, 80 to 90 μg/ml, or 80 to 85 μg It can be /ml. When the water solubility is high, solifenacin stimulates taste buds, so that the taste can be felt more strongly, and the compliance with taking may be reduced.

The solifenacin tartrate may have a wetting angle of 20 degrees or more, 23 degrees or more, 24 degrees or more, 25 degrees or more, 26 degrees or more, 27 degrees or more, 28 degrees or more, or 29 degrees or more. If the wetting angle is too low, solifenacin stimulates taste buds, so that the taste can be felt more strongly, and the dose compliance may be lowered.

The solifenacin tartrate has a wet angle of 20 to 35 degrees, 23 degrees to 34 degrees, 24 degrees to 33 degrees, 25 degrees to 32 degrees, 26 degrees to 31 degrees, 27 degrees to 30 degrees, 28 degrees to 30 degrees , Or 29 degrees to 30 degrees. If the wetting angle is too low, solifenacin stimulates taste buds, so that the taste can be felt more strongly, and the dose compliance may be lowered.

The solifenacin tartrate has a particle diameter of 100 μm or less, 95 μm or less, 90 μm or less, 85 μm or less, 80 μm or less, 75 μm or less, 70 μm or less, 65 μm or less, 60 μm or less, 55 μm or less, 50 μm or less, 45 μm or less , Or 40 μm or less. If the particle diameter of the solifenacin tartrate is too large, the foreign body feeling may be strong, the taste may be stronger, and dispersion may not be smooth in the oral cavity. If the particle diameter of the solifenacin tartrate is too small, the time remaining in the oral cavity may be long and the duration of feeling the taste of solifenacin may be long.

The solifenacin tartrate has a particle diameter of 40 to 100 μm, 45 to 100 μm, 50 to 100 μm, 55 to 100 μm, 60 to 100 μm, 65 to 100 μm, 70 to 100 μm, 75 to 100 μm , 80 to 100 μm, 40 to 90 μm, 45 to 90 μm, 50 to 90 μm, 55 to 90 μm, 60 to 90 μm, 65 to 90 μm, 70 to 90 μm, 75 to 90 μm, 80 to 90 μm , 40 to 85 μm, 45 to 85 μm, 50 to 85 μm, 55 to 85 μm, 60 to 85 μm, 65 to 85 μm, 70 to 85 μm, 75 to 85 μm, 80 to 85 μm, 40 to 80 μm , 45 to 80 μm, 50 to 80 μm, 55 to 80 μm, 60 to 80 μm, 65 to 80 μm, 70 to 80 μm, 75 to 80 μm, 40 to 75 μm, 45 to 75 μm, 50 to 75 μm , 55 to 75 μm, 60 to 75 μm, 65 to 75 μm, 70 to 75 μm, 40 to 70 μm, 45 to 70 μm, 50 to 70 μm, 55 to 70 μm, 60 to 70 μm, 65 to 70 μm , 40 to 65 μm, 45 to 65 μm, 50 to 65 μm, 55 to 65 μm, 60 to 65 μm, 40 to 60 μm, 45 to 60 μm, 50 to 60 μm, 55 to 60 μm, 40 to 55 μm , 45 to 55 μm, 50 to 55 μm, 40 to 50 μm, 45 to 50 μm, or 50 to 50 μm. If the particle diameter of the solifenacin tartrate is too large, the foreign body feeling may be strong, the taste may be stronger, and dispersion may not be smooth in the oral cavity. If the particle diameter of the solifenacin tartrate is too small, the time remaining in the oral cavity may be long and the duration of feeling the taste of solifenacin may be long.

The pharmaceutical preparation for oral administration may be formulated as a formulation dissolved or dispersed in the oral cavity. A significant proportion of hypersensitivity bladder patients over the age of 45 have dysphagia, and when taking tablets, tablets may have pain and sensation due to delayed passage in the esophagus. Therefore, the formulation of the overactive bladder treatment may be consumed without ingesting water, and a formulation dissolved or dispersed in the oral cavity may be preferable.

The pharmaceutical formulation for oral administration may further include a pharmaceutically acceptable carrier that can be added to a pharmaceutical formulation. The pharmaceutically acceptable carrier includes additives such as excipients, disintegrants, binders, lubricants, emulsifiers, suspending agents, stabilizers, etc., which are commonly used in the pharmaceutical field, and sweeteners, flavorings and/or coloring agents, etc., if necessary. It may be added.

The pharmaceutical preparations for oral administration include, for example, tablets, films, suspensions, granules, gels, pills, tinctures, decoctions, and agglutinations ( in various forms such as infusion, spirit, fluidxtract, elixir, extract, syrup, powder, or aromatic water Can be formulated. In addition, the tablet (tablet), for example, orally disintegrating tablets (orally disintegrating tablet), adhered tablets (mucoadhesive tablet), dispersible tablets (dispersible tablet), sublingual tablets (sublingual tablet), bacal tablets (buccal tablet), chewing tablets ( It can be formulated in various forms such as chewable tablet, dispensing tablet, mulitilayered tablet, press-coated tablet, effervescent tablet, solution tablet, etc. Can. In addition, a person skilled in the art can use various tablets in various modifications as necessary. More preferably, a formulation that immediately feels the taste of solifenacin upon oral administration, such as a liquid form or a formulation that disintegrates in the oral cavity (i.e., disintegrating in the oral cavity), such as an oral dispersible formulation, such as an oral dissolving film, oral cavity Disintegrating tablets, suspensions, suspension tablets, fast-acting disintegrating tablets, oral disintegrating granules, oral disintegrating troches, sublingual tablets, powders and / or chewable tablets.

In particular, when taking into consideration the situation in which the patient with dysphagia is to be taken and the situation to be taken without water, the pharmaceutical formulation according to the present invention is an oral dissolving film formulation, a fast-acting disintegrating tablet formulation, an oral disintegrating granule, or an oral disintegrating granule formulation It may be desirable.

The pharmaceutical preparation for oral administration may be used for taking without ingesting moisture.

The solifenacin tartrate may cover the taste of solifenacin, so it may be suitable to be produced in the form of a fast-acting disintegrating tablet, oral disintegrating granule, or oral disintegrating granule that is rapidly dispersed in the oral cavity. Since the solifenacin tartrate is highly concealed and has high patient compliance, it is produced in the form of a fast-acting disintegrating tablet, oral disintegrating granule, or oral disintegrating granule, and administered, thereby ingesting water from irritable bladder patients who have difficulty controlling urination. It can be easily restricted, and patients with dysphagia can be easily administered.

It will be described in more detail through the embodiments of the present invention. However, these examples are for illustrative purposes only, and the present invention is not limited to the following examples.

<Example 1: Solifenacin tartrate solution preparation>

Solifenacin tartrate was sized to be 75 μm or less in size using a No. 200 sieve (75 μm pore).

The formulated solifenacin tartrate was weighed with 2 mg, and mixed with 200 ml deionized water and stirred.

The stirred solution of solifenacin tartrate was filtered with a 0.45 μm PVDF w/GMF syringe filter, respectively, to prepare a solution of solifenacin tartaric acid at 0.01 mg/mL.

20 mg, 200 mg, 500 mg, and 1000 mg of solifenacin tartrate were weighed in the same manner as the above method, and mixed with 200 ml deionized water to 0.1 mg/mL, 1.0 mg/mL, 2.5 mg/mL, and 5.0 mg/mL, respectively. A solution of solifenacin tartrate was prepared.

<Comparative Example 1: Preparation of solifenacin succinate solution>

Solifenacin succinate was established using a No. 200 sieve (pore 75 μm) so that the particle size was 75 μm or less.

The formulated solifenacin succinate was weighed into 2 mg, and mixed with 200 ml deionized water and stirred.

The stirred solifenacin succinate solution was filtered with a 0.45 μm PVDF w/GMF syringe filter, respectively, to prepare a solifenacin succinate solution of 0.01 mg/mL.

20 mg, 200 mg, 500 mg, and 1000 mg of solifenacin succinate were weighed in the same manner as the above method, and mixed with 200 ml deionized water, respectively, 0.1 mg/mL, 1.0 mg/mL, 2.5 mg/mL, 5.0 mg/mL A solution of solifenacin succinate was prepared.

<Comparative Example 2: Preparation of solifenacin fumarate solution>

Solifenacin fumarate was sized so that the particle size was 75 μm or less using a No. 200 sieve (75 μm pore).

The formulated solifenacin fumarate was weighed with 2 mg, and mixed with 200 ml deionized water and stirred.

The stirred solifenacin fumarate solution was filtered with a 0.45 μm PVDF w/GMF syringe filter, respectively, to prepare a solution of solifenacin fumarate at 0.01 mg/mL.

20mg, 200mg, 500mg, and 1000mg of solifenacin fumarate were weighed in the same manner as the above method, and mixed with 200ml deionized water, respectively, 0.1mg/mL, 1.0mg/mL, 2.5mg/mL, 5.0mg/mL A solution of solifenacin fumarate was prepared.

Solutions prepared through the above Examples and Comparative Examples are shown in Table 1 below.

Concentration (mg/mL) Salt form Example 1-1 0.01 Solifenacin Tartrate Example 1-2 0.1 Example 1-3 1.0 Example 1-4 2.5 Example 1-5 5.0 Comparative Example 1-1 0.01 Solifenacin succinate Comparative Example 1-2 0.1 Comparative Example 1-3 1.0 Comparative Example 1-4 2.5 Comparative Example 1-5 5.0 Comparative Example 2-1 0.01 Solifenacin Fumarate Comparative Example 2-2 0.1 Comparative Example 2-3 1.0 Comparative Example 2-4 2.5 Comparative Example 2-5 5.0

<Experimental Example 1: Evaluation of stability by type of solifenacin salt>

Example 1, Comparative Example 1, and Comparative Example 2 were accurately weighed in 10 mg increments to open a 15 mL conical tube and stored for 15 days at a temperature of 60° C. and a relative humidity of 80%. The drug before storage, the drug 4 days after storage, the drug 8 days after storage, and the drug 15 days after storage were taken as samples, and 3 samples were prepared for each sample. The sample was prepared by the following method and analyzed under the following HPLC analysis conditions.

One. Solifenacin Test Solution Preparation

The sample was dissolved in 10 mL of the mobile phase for 30 minutes by ultrasonic shaking, cooled to room temperature, and filtered through a membrane filter having 0.45 μm pores to prepare a sample solution.

2. Preparation of standard solution of solifenacin

10 mg of solifenacin standard was weighed and placed in a 100 mL volumetric flask. After 50 mL of methanol was added and dissolved completely by ultrasonic shaking for 20 minutes, the mixture was cooled to room temperature, and 50 mL of methanol was added to make 100 mL. This was diluted with an appropriate amount of mobile phase to prepare a 100 μg/mL standard solution.

3. Solifenacin HPLC analysis conditions

-Mobile phase: A 6:4 (v/v) mixture of pH 3 buffer prepared by adding 0.1% (v/v) triethylamine to acetonitrile and 10 mM potassium dihydrogen phosphate was used.

-Column: Kinetex™ C8 5μm 100A (Angstrom) 250 x 4.6 mm or similar column

-Column temperature: 30 °C

-Detector: UV 210 nm

-Flow rate: 1.0 mL/min

-Injection volume: 20 μL

Referring to FIG. 1, it was confirmed that the initial stability of Example 1, Comparative Example 1, and Comparative Example 2 was similar. However, the stability difference between Example 1 and Comparative Example 1 was found to be statistically significant in the drug 15 days after storage. Therefore, it was confirmed that both of Example 1, Comparative Example 1, and Comparative Example 2 were stable, and Example 1 was more stable than Comparative Example 1.

<Experimental Example 2: Equilibrium solubility of each salt form of solifenacin>

The equilibrium solubility of Example 1, Comparative Example 2, and Comparative Example 3 was measured using a Sirius T3 apparatus (Sirius Analytical Instruments Ltd., East Sussex, UK). A curve-fitting method used for compounds with high solubility and rapid precipitation was used. Precipitation occurred in the dissolved material and titrated with acid or base until equilibrium was established. The resulting Bjerrum curve was used to determine the shift between the theoretical pKa titration curve and the experimental precipitation titration curve. Because the distance of the curve depends on the amount and solubility of the compound, solubility values can be calculated.

2, Comparative Example 1 is 9390 μg/mL, Comparative Example 2 is 87.52 μg/mL, Example 1 is 82.81 μg/mL, and Comparative Example 1 is 100 times higher than Comparative Example 2 and Example 1 It was confirmed to have a chart chart value. Since the drug must be in an aqueous solution state to act on taste buds, the difference in water solubility indicates a difference in the likelihood of being in solution. Therefore, in Comparative Example 1, it was judged that there was a possibility that the taste of the drug was stronger because the water solubility was relatively high.

<Experimental Example 3: Contact angle to confirm the wettability of each type of solifenacin salt>

The wettability and contact angle of Comparative Example 1, Comparative Example 2, and Example 1 were confirmed. The contact angle was measured using a contact angle analyzer (Phoenix 300-Touch, Seo Co., Suwon, Republic of Korea). After accurately weighing 100 mg of Comparative Example 1, Comparative Example 2, and Example 1, a specimen having a surface of 8.65 mm ² was prepared by processing a 15 mm circle with a weight of ¹ ton using a hydraulic tablet press. 25°C of deionized water was added dropwise to each sample surface. The droplet had a volume of 1.29 μL and was dropped at a height of 0.37 mm from the sample. The contact angle was measured 100 ms after dripping. Each sample was identified three times.

Referring to FIG. 3, the contact angle was measured to be 13.77° in Comparative Example 1, 23.76° in Comparative Example 2, and 29.61° in Example 1. Therefore, the wettability was the highest in Comparative Example 1 and the lowest in Example 1. This confirmed that the drug of Comparative Example 1, like the Experimental Example 2, is in an aqueous solution state and is likely to act on taste buds.

<Experimental Example 4: Electro-tongue sensory evaluation>

The taste difference was evaluated using an electro-tongue device (Astree e-tongue equipped with Alpha M.O.S. sensor set #2). Electro-tongue is a device that measures specific ions in a sample in a solution state with 7 nodes (ZZ, AB, BA, BB, CA, DA, and JE) to show the relative difference in taste in a PCA map. The PCA map is data that displays the relative difference of taste in coordinates on a two-dimensional map, and the X-axis is the point that shows the largest difference in taste. In Experimental Example 4, the difference in taste of about 95% was shown on the X-axis, so the coordinates of the X-axis were plotted on the graphs below. Each sample measurement was repeated 5 times, and was washed with deionized water between sample measurements.

4 to 6, Comparative Example 1 (1-1, 1-2, 1-3, 1-4, 1-5) did not have a large difference in taste according to concentration. However, Comparative Example 2 (2-1, 2-2, 2-3, 2-4, 2-5) and Example 1 (3-1, 3-2, 3-3, 3-4, 3-5) It was confirmed that the difference in taste according to the silver concentration was large. In addition, Comparative Example 1 showed a negative value during measurement, and Comparative Example 2 and Example 1 showed a positive value, confirming that the difference for a specific taste was large. (Specifically, what taste difference was confirmed by the panel sensory evaluation of Experimental Example 5 below.)

Although not clearly identified, Comparative Example 2 and Example 1 are thought to increase the difference in taste with increasing specific ions. In addition, when considering the amount of saliva in the oral cavity, an interval of 1.0 to 5.0 mg/mL (Comparative Examples 1-3 to 1-5, Comparative Examples 2-3 to 2-5, and Examples 1-3 to 1-5) It is thought to be similar to the real oral environment. Therefore, it was expected that the difference in taste of Comparative Example 1, Comparative Example 2, and Example 1 in the actual oral cavity would be large.

<Experimental Example 5: Panel sensory evaluation>

The panel sensory evaluation of Comparative Example 1, Comparative Example 2, and Example 1 was carried out according to the Ethics Code of the Helsinki Declaration. Fourteen healthy volunteers (20 to 35 years old) who had informed consent for the evaluation were selected. All applicants were trained prior to evaluation. Comparative Example 1, Comparative Example 2, and Example 1 were each weighed exactly 5 mg and used as a sample. Volunteers spit out the sample after 10 seconds in the oral cavity. The evaluation was conducted blindly, and the volunteers were divided into three groups. The evaluation interval for each sample was at least 1 hour, and 5 minutes before evaluation, the applicant's mouth was washed with 100 mL of drinking water.

The total score of taste (preference of taste), four basic taste (bitter taste, sweet taste, sour taste, salty taste), and other three senses related to tactile sense (slight taste, numbness, foreign body sensation) were evaluated. . The total score of the taste was evaluated from 1 to 9 points (1 = very bad taste, 5 = medium, 9 = very good taste), and the senses related to the four tastes and touches ranged from 1 to 5 points ( 1 = none, 3 = moderate, 5 = very strong). The arin taste is distinguished from the bitter taste, and the astringent taste and the spicy taste are felt in a complex manner, which means a sense related to tactile sense.

Referring to FIG. 7, Example 1 had a higher total score of one point than Comparative Example 1 and Comparative Example 2. 8 and 9, it is determined that the reason why the total score of the first embodiment is relatively high is that high sourness (FIG. 8) and low aridity (FIG. 9) have an effect. Referring to the results of Experimental Example 2 (solubility) and Experimental Example 3 (wetting angle), it is considered that the reason for the high arin taste of Comparative Example 1 (solifenacin succinate) is because of its high solubility and wettability. Comparative Example 1 (solifenacin succinate) is highly water-soluble, so it is easy to stimulate taste buds and nerves, and is thought to be difficult to mask or conceal the arin taste of solifenacin.

Also, referring to FIG. 8, it was confirmed that in Comparative Example 1, Comparative Example 2, and Example 1, the degree of feeling sourness was proportional to the acid value of the salt. Referring to this, in the electro-tongue sensory evaluation of Experimental Example 4, a specific ion causing a difference in taste is expected to be an acid, and it is believed that the sour taste, which is a unique taste of solifenacin, can be masked as acidity increases.

Therefore, considering the sensory evaluation and stability evaluation, it was confirmed that the salt form of solifenacin tartrate is the most suitable salt for oral dispersion solid preparations such as granules and fast disintegrating tablets.

Claims (6)

A pharmaceutical preparation for oral administration for the treatment of irritable bladder comprising solifenacin tartrate as an active ingredient.
According to claim 1,
The solifenacin tartrate has a water solubility of 200 μg/ml or less,
Pharmaceutical preparation for oral administration.
According to claim 1,
The solifenacin tartrate has a wetting angle of 20 degrees or more,
Pharmaceutical preparation for oral administration.
According to claim 1,
The solifenacin tartrate has a particle diameter of 75 μm or less,
Pharmaceutical preparation for oral administration.
According to claim 1,
The pharmaceutical formulation for oral administration is formulated into a formulation that is dissolved or dispersed in the oral cavity,
Pharmaceutical preparation for oral administration.
The method of claim 5,
The formulation is an oral dissolving film, oral disintegrating tablet, suspension, suspension tablet, fast-acting disintegrating tablet, oral disintegrating granule, oral disintegrating troche, sublingual tablet, powder or chewable tablet,
Pharmaceutical preparation for oral administration.

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