HU197204B - Process for production of inhalation-composition with increased practical endurance and without by-effect - Google Patents

Abstract

The present invention relates to a process for the preparation of a side-effect inhalation composition with increased lifetime, characterized in that the carrier is cellulose acetate and / or the polymeric material of formula (I) n is 0-8, m is from 5 to 90, the carbon number of R and R1 is 1- -10, with a molecular weight of between 2500 and 50000, and a) modifying the surface structure of any of said carriers by 0.1 to 25% by weight of poly (ethylene glycol) of from about 400 to about 4000% by weight of the known active ingredient. and / or from 0.1 to 25% by weight of methylphenyl silicone having a molecular weight of from 500 to 10000 moles - methyl to phenyl ratios of 1:10 to 10: 1 and / or 0.1 to 25% triacetin and / or diglycerol as plasticizer tetraacetate is dissolved in the active ingredient mixture and applied to the support, or b) 1-25% by weight of the 40-200 polymerization, 75-250 substitution weight per cellulose acetate carrier cellulose acetate having a molecular weight of 7000-45000, is dissolved in the active ingredient mixture and applied to the support, wetting the carrier, if desired, before or after the above steps with 0.05 to 25% by weight of camomile oil or camomile extract. 197204 -1-

Description

The present invention relates to a process for the preparation of an inhalation composition having an increased useful life, without side effects.

The use of passive inhalers is known to be a common device or method for the elimination of nasal obstruction, which is not of organic origin. In doing so, various compounds, known per se, are delivered to the inhaled air, which compounds are useful in removing nasal congestion and soothing swollen mucous membranes. Such compounds include menthol, camphor, methyl salicylate, adrenaline, ephedrine, amphetamine sulfate, eucalyptus oil (a mixture of several compounds), methyl amphetamine, propylhexedrine, and the like.

The object of the invention is the above-mentioned device for use, i.e. the passive inhaler

- a refinement process that substantially extends the life of the device; or, when used too frequently, it is also possible to avoid the adverse side effects of the most effective compositions characterized by high camphor and menthol content, thus preventing inflammation of the epithelium of the nasal mucosa.

The manufacture of passive inhalers has a very long history. The principle of the device is as follows: one tube can be locked - approx. 50-70 mm, diameter 10-15 mm - small at both ends - approx. There is an opening (s) of 1-1.5 mm in diameter and a mixture of known compounds capable of preventing nasal congestion, i.e. the active ingredient, is applied on the inside of the tube between the two apertures (or apertures) known per se. When the tube is removed from the protective pump and inserted through the nostril, most of the air flows through the carrier and, due to the relatively high linear velocity therein, the active ingredient in the carrier is aerosolized into the inhaled air. Getting to the nose

- collision - the aerosol condenses, exerting its targeted effect.

The knowledge about carriers can be divided into two parts. In one of the less common cases of formulation, the active ingredient is applied to an inorganic carrier of amikol [P.J. Au sitin, O. Grady: Inhalant preperations (Australia, June 14, 141410/1951) CA. P-48-6656 f.]. However, the inorganic-based carriers, due to the difficulties of the manufacturing technology, could not spread well enough. The preparation of the carrier is difficult to incorporate into continuous technology and the addition of the active ingredient and its proper homogeneity on the carrier are also difficult to achieve.

Other known - and at the same time their primary - role is in the field of organic fibrous materials for carriers, among which cellulose acetate-based ones are outstanding. Among the reasons for the increased importance of cellulose acetate is that this carrier fibrous material is inexpensive, readily available, and highly automated in its production.

In order to clarify the circumstances outlined above, one of the most important raw materials for the manufacture of cigarette filters is cellulose acetate fiber. (H.Sawada,

H.Kawamoto, Cellulose acetate tobaco filter, Japan 76.15.1220, C.A. 85 P 106800 f.), (H. Sawada, J. Kawamoto, Cigaret filter, USA. 3890983, C.A. 83 P 175684 s).

Due to other restrictions (poison lists, so-called drug lists), the range of active agents that can be applied to the carrier is, in fact, quite narrow when it comes to distributing and selling a passive inhaler on a larger scale. The following compounds known per se include menthol, camphor, methyl salicylate, boronyl acetate and the like. As is apparent from the list, there are sublimating (camphor) and relatively volatile compounds such as methyl salicylate and boronyl acetate. As a result, the problem is that the active ingredient, when applied to a carrier known per se, can remain on the carrier for a limited period of time because it sublimates or evaporates over time. Therefore, the object of the present invention is to increase the shelf life of passive inhalers.

Secondly, it is noteworthy that the most important constituents of the active ingredient, camphor and menthol, damage the nasal mucosa frequently, resulting in inflammation and wound formation. Therefore, it is a further object of the present invention to provide a composition which does not have the above-mentioned adverse side effects.

With respect to storage, the object of the present invention may be achieved in the following manner.

It has been found that the sorption characteristics of a cellulose acetate carrier known per se can be varied by wetting it with relatively high molecular weight polymers prior to or concurrently with the drug application. The polymers used are, for example, cellulose acetate and / or polyethylene glycol and / or methylphenylsilicone known per se.

Further, according to the present invention, in addition to or in addition to the known cellulose acetate fiber material, an organic polymer is used which has a greater structural similarity to the constituents of the active ingredient and due to the increased adsorptive binding of the active ingredient to the carrier. . This polymer has the structural formula (I) wherein n is from 0 to 8, m is from 5 to 90, represents an alkyl group of R 1 and R 1, and combinations of the above are allowed where the molecular weight of the polymer compound is 2500 -50000. For other applications of the polymeric compound of formula I in E: G.S. Runelberg, W.R. 5

Johnson and H.J. Grubbs reported facts (Menthol releasing additives for tobaco, Ger. Offen. 2436472, C.A. 83. P 175680 n).

According to the process of the invention, the cellulose acetate fiber carrier known per se is preferably softened, preferably with or without triacetin and / or diglycerol tetraacetate. In the latter case, together with the plasticizer, which dissolves to a limited extent in the carrier known per se, the active ingredient can be almost incorporated into the wind structure, whereby the life of the inhaler can be significantly increased.

Chamomile extract and / or camomile oil are used to prevent inflammation of the nasal mucosa as a side effect of the active ingredient,

0.05 to 25% by weight.

In describing the storage improvement measures of the present invention, it is outlined that the order of operations also plays an important role. In fact, the process has elements that are known per se, but can result in significant improvements in storage and effects as a result of one or more specific sequences and operational combinations. In particular, when applied in parallel with the plasticizer and / or the polymer solution known per se, the binding of the active ingredient to the carrier can be enhanced, since it is believed that not a simple adsorption interaction is to be expected but a shock absorbing layer.

With regard to the shelf life of the passive inhaler, both static and dynamic tests of the present invention have shown that 45 known active compounds alone, a combination of different compounds, have not been used as a carrier for passive inhalers on the , but which, on the basis of the cellulose acetate modified by the process according to the invention, is better stored than the prior art, retains its advantageous properties and effectiveness for a longer period of time.

The static assay we employed consisted of wetting the same volume, spatially expanded carriers with the same mixture of active ingredients. They were then kept at 50 ° C in an open inhalation body and plotted against the weight / weight loss time function. For ease of comparison, the resulting weight loss was always compared to the data obtained with an untreated cellulose acetate carrier, the weight loss obtained being considered as one unit.

For the dynamic method, the preparation of test samples is essentially the same as the static method. During the examination, air of a volume and velocity measured through the open inhalation body was passed. Here, care was taken to ensure that the linear velocity of the air passing through corresponds to the linear velocity at the time of intended use. The air loss function as a function of the loss of air was taken. The data were compared to a data set obtained with an untreated medium known per se, as described in the static method.

Results of .Storage Model Experiments

c. Table 3 summarizes the data that support the correctness of our expectations in our experimental hypothesis.

It turned out that

1.) It is particularly advantageous to modify the sorption characteristics of the cellulose acetate carrier known per se, for example by adding polyethylene glycol as described in claim 1. or methylphenylsilicone such as

No. 4 sample showed;

2.) Storage losses can be reduced if softener application is performed with the active ingredients as described in FIGS. s. sample data show;

3.) When a film-forming agent is applied to the surface of the carrier together with the active ingredients, a more soluble type of fibrous material is used, as shown in FIG. sample showed that we could achieve the most significant improvement;

4.) The polymer of formula (I) has a very advantageous addition to the cellulose acetate carrier known per se, as shown in Figs. s. sample data.

It is important to emphasize that the usability of the inhaler 50 has not been impaired by the change in carrier characteristics, that is, by the fact that the amount of active ingredient that can be removed by air is actually reduced. The reason for this will be explained below.

RESULTS OF STORAGE MODEL EXPERIMENTS

Number of samples: First Second Third 4th 5th 6th ranging (gram) Cellulose acetate 2. Formula (I) 0:25 0:25 0:20 0125 0125 polymer 0125 0125 0:25 3. Methylphenylsilicone 0.1 0:05 4. Poly (ethylene glycol) 5. Cellulose acetate 0.1 0.1 0:02 0.1 0:05 6. Triacetin 0025 0025 0:02 0:02 7. Diglycerol tetraacetate 0005 relative metrics Static test (tömegves zteségek) Average of 0.5-3 experimental hours 0.75 0.80 0.65 0.72 0.66 0.69 Average of 6-12 experimental hours 0.73 0.78 0.63 0.75 0.71 0.72 Dynamic test 50-250 dm ³ after average air flowed 500-1000 dm ³ air flowed 0.68 0.74 0.62 0.70 0.70 0.78 post average 0.69 0.71 0.66 0.67 0.74 0.75

The experimental results were compared with the data obtained with untreated 0.25 grams of cellulose acetate.

The active ingredient mixture used was 0.2 g menthol, 0.2 g camphor, 0.1 g methyl salicylate, 0.05 g boronyl acetate and 0.1 g camomile oil.

3-7. In Experiment No. 2, materials for modifying the surface of the carrier were applied to the carrier together with the active compound mixtures. Exception 2 experiment where the drug mixture was applied 6 hours after the surface modifiers. Table 1-5. Explanatory Notes to Substances Nos.

1. Cellulose acetate having a degree of polymerisation of 250 with a degree of substitution of 300 and a molecular weight of 68 000

2. A compound of the formula I wherein n = 4, m = 60 and R, R 1 = 5 (molecular weight 25,000).

3. Molecular weight = 4000, Methylphenyl ratio = 1: 2

4 mole weight = 1000

Degree of polymerization 5 = 75, substitution value = 150 (molecular weight: 15,500).

Chamomile oil and / or chamomile extract also had an unexpected effect. Our original goal was to treat the inflammatory condition that occurs when the inhaler is used too frequently. It has been found that the regular use of the inhaler of the present invention did not result in an inflammatory condition of the nasal mucosa, despite the need for high concentrations of needles in the preparation of inflammatory camphor. Instead of the expected causal treatment, we could, much more advantageously, eliminate the cause, the onset of inflammation.

Therefore, we wanted to clarify whether chamomile oil and / or chamomile extract 45 made the nasal mucosa more resistant or altered the mechanism of action of the inhaler at a point not previously studied.

It was a matter of course that The inhaler described in Application Example 50 was prepared with 15% chamomile oil without chamomile oil and based on the active ingredient. Both inhalers were then placed in a sealed experimental apparatus used for dynamic shelf life assays and, during normal use, air was passed through the inhalers at normal linear velocity, and the air was drawn into a 10 µm microscope slide perpendicular to the air movement. The labyrinth was scaled so that the linear velocity of air there was 1/5 of that measured in the inhaler. The slides were examined under light microscope at different flow rates (50, 150, 250, 500, 1000 dm ³ ).

The observations were summarized as follows:

a) In the samples without chamomile oil / chamomile extract small crystalline formations were observed already at 250 dm ³ air flow, and this recrystallization was more pronounced in the 500 dm ³ samples. So its effect on a specific target area

which may be a blocked nasal mucosa

- the active substance is precipitated at a non-homogeneous concentration, which can obviously result in an overdose of the active substance locally, where the anti-inflammatory effect begins to dominate its positive effects. Practical tests also support this fact.

b) In the case of samples containing chamomile oil / chamomile extract, the microscope slides were completely different, and of course the most important thing is that even when used, the inflammatory symptoms which are characteristic of the past are not present. Crystallization did not occur even at the last measurement time. It should be emphasized that the amounts of active compound dissolved on the slide were in accordance with the experiments described in (a).

This meant that after the addition of chamomile oil / chamomile extract, there would be no overdose of the local active ingredient due to recrystallization. The additive can inhibit crystallization, which is presumably - and this is reiterated because it has been well supported by practical tests - the primary cause of the inflammatory state. Of course, in some cases there may be organic causes of inflammation - colds, etc. - but this has been eliminated in practice tests as a distraction.

The composition and method of preparation of the present invention are exemplified without limiting the scope thereof.

Example 1

0.25 grams of cellulose acetate fiber

- degree of polymerization 250, displacement value 300, molecular weight: 68000 - 6 mm diameter, 30 mm long bed. It is covered with a sheet of paper having a specific weight of 40 g / m 2 about its longitudinal axis, and the wrapping paper is glued. 0.2 grams of menthol, 0.2 grams of camphor, 0.1 grams methyl salicylate, 0.05 grams boronyl acetate, and 0.05 grams methylphenylsilicone (MW 4,000; ratio of methylphenyl groups 1) : 2) we mix,

- After 3 hours, add 0.0825 grams of chamomile oil. The mixture thus obtained is passed through a capillary onto the carrier bed and the carrier moistened with the active ingredient is placed in a plastic body of the passive inhaler and sealed.

Example 2

0.05 grams of the polymer of formula I are n = 3, m = 50, R, 'R' carbon pattern: 8, molar weight: 25000, and 0.2 grams of cellulose acetate fiber having a degree of polymerization of 280 and 280. Formulated into a carrier of the size and embodiment described in Example 1. The active compound mixture of Example 1 was prepared and 0.1 grams of polyethylene glycol (1000 molar weight) was added to the resulting bed.

Example 3

0.2 grams of cellulose acetate having a degree of polymerization of 250, 280 substitutions, and 66000 molar masses are prepared in the same size and design as the carrier. 0.25 grams of menthol, 0.15 grams of camphor, 0.15 grams of methyl salicylate and 0.05 grams of boronyl acetate are added. After 3 hours, a clear solution was obtained by dissolving 0.03 grams of 75% cellulose acetate of 15500 molar weight in a 75% degree of polymerization solution of the active ingredient, followed by the addition of 0.1 grams of chamomile oil and proceeding as described in Example 1. in the following.

Example 4

0.25 grams of a 300 cellulose acetate fiber having a degree of polymerization of 250 substitutions and a molecular weight of 75,000 was prepared in the size and design described in Example 1. Following the waiting time of 3 hours, 0.05 grams of triacetin and 0.05 grams of diglycerol tetraacetate are added to the active compound described in Example 3 and applied to the vehicle as described therein.

Example 5

0.125 grams of fiber of formula I - n = 4, m = 60, R and R 1 alkyl radicals having 5, molecular weight: 25000 - and 0.125 grams of cellulose acetate having a degree of polymerisation of 350, 250 using a fiber to form a carrier of the size and design described in Example 1. 200 grams of menthol, 200 grams of methyl salicylate, 100 grams of bornylacetate are mixed with 150 grams of dried camomile flowers and extracted at 50 ° C for 24 hours. It is then filtered and the chamomile flowers are squeezed. To this camomile extract was added 200 grams of camphor and 40 grams of methylphenylsilicone. The latter has a molecular weight of 4,000 and a methylphenyl group ratio of 1: 2. 0.6 grams of the resulting mixture is applied to the support as described in Example 1.

-511

Example 6

0.25 grams of the polymeric fiber of Formula I - n = 3, m = 50, R and R18 - C8 alkyl, 25,000 - are formed into a carrier of the size and design described in Example 1. The active compound mixture of Example 1 and 0.05 grams of methylphenylsilicone surface modifier were applied to the vehicle.

Claims (1)

Patent Claim Point A process for the preparation of an inhaled, inhaled, inhaled formulation having a cellulose acetate fibrous material known per se and / or a fibrous material of the polymer of formula (I), wherein n is from 0 to 8, m is from 5 to 90, The number of carbon atoms of the R and R 1 alkyl groups may vary from 1 to 10, provided that combinations are used where the molecular weight is in the range of 2500 to 50,000, and (a) modifying the surface structure of any of said substrates to: 0.1% to 25% by weight of 5 to 400% by weight of polyethylene glycol and / or 0.1 to 25% by weight of 500 to 10,000 molar weight of methyl-phenylsilicon, based on the ratio of methyl to phenyl groups of 10% by weight. - 10: 110 and / or 0.1-25% by weight of triacetin and / or diglycerol tetraacetate as a plasticizer are dissolved in said known active compound mixture and then applied to the carrier, or (b) cellulose acetate, which is known per se 1-25% by weight of cellulose acetate having a degree of polymerization of 40-200, a substitution of 75-250 molar mass, and a molecular weight of 7000-45000 are added to 15 carriers by dissolution in a mixture of active ingredients known per se. 20 and applied to the carrier, the moiety being moistened with up to about 0.05% to about 25% by weight of chamomile oil or camomile extract before or after step a) or b), if desired.