Basis for suppositories or ovules and suppository or ovule composition based thereon and use thereof in a production process
Patent Information
- Authority / Receiving Office
- EP · EP
- Patent Type
- Applications
- Current Assignee / Owner
- IOI OLEO GMBH
- Filing Date
- 2023-08-04
- Publication Date
- 2026-06-10
Smart Images
Figure IMGF000008_0001
Abstract
Description
Basis for suppositories or ovules and suppository or ovule mass based thereon and their use in a manufacturing process
[0001] A base for suppositories or ovules is presented, consisting almost exclusively of polyglycerol fatty acid esters, whose physicochemical properties are determined in a desirable manner by adjusting the content of polyglycerol fatty acid monoesters. This allows for the easy incorporation of both hydrophilic and lipophilic active ingredients, either directly or dissolved, emulsified, dispersed, or suspended in a carrier liquid, into a suppository or ovule mass. The suppository or ovule mass can be easily processed into suppositories or ovules.
[0002] In the production of suppositories or ovules, bases based on hard fats are standard. Hard fats offer advantages for these purposes, but also one disadvantage. Hard fats are saturated mono-, di-, or triglycerides, which are usually used as mixtures. Their versatility in combination with a wide variety of active ingredients is advantageous. For example, a low hydroxyl number of the glyceride mixture is advantageous if the drug to be incorporated can potentially interact with hydroxyl groups, such as hydrolysis-sensitive acetylsalicylic acid. Conversely, the undesirable sedimentation of insoluble solids, such as bisacodyl, in the not yet fully solidified suppository or ovule mass can be reduced by using hard fats with a high hydroxyl number due to the associated emulsifying effect.The incorporation of fat-soluble substances, in turn, can lower the melting point of the suppository or ovule mass to such an extent that the resulting suppositories or ovules would be too soft even at room temperature to be practically processed and packaged. Here, too, the diversity of hard fat properties can be advantageously utilized, for example, by adding a hard fat with a higher melting point in sufficient quantities. However, the disadvantage of mono-, di-, and triglycerides is their tendency to exhibit polymorphism.
[0003] Hard fats in general, such as glycerol tripalmitate or glycerol tristearate, exist in both a crystalline, unstable α-modification and a metastable β'-modification or a stable β-modification. The modifications can transition from one to the other. The modifications differ particularly in the thickness of lamellar-packed, crystalline subunits, which are also referred to as subcellular units. For the α-modification of For example, under certain conditions, glycerol tristearate exhibited a layering of an average of 6 lamellar structures per subcellular unit. After complete conversion to the ß-modification, a layering of an average of 10.5 lamellar structures per subcellular unit and an increase in crystal thickness of approximately 67% was observed. The fact that the theoretically expected increase of 75% was not achieved is presumably due to the fact that the individual lamellae of the ß-modification exhibit a denser lamellar packing due to a tilt compared to the ß-modification.Since the β-modification exhibits faster formation kinetics than the β'- and β-modifications, at least at the low temperatures used in the production of suppositories and ovules, the β-modification is initially present before hardening. However, this modification rearranges into the more stable β-modification during and after solidification, increasing in volume, which may even be accompanied by macroscopic breakage. This phenomenon is known as post-hardening in the production of suppositories and ovules and is accompanied by a rise in the melting point that must be taken into account. The variety of options available in the development of active ingredient-containing suppository or ovule masses is also a disadvantage, since, at least for industrial-scale production regulations, a large number of possible formulations must be tested for each active ingredient, thus lengthening development time and increasing costs.
[0004] Hard fats are virtually insoluble in water. The active ingredient(s) are released when the suppositories made from them melt in the intestine, or ovules in the vagina. The melting temperature should therefore be approximately 1°C to 2°C below body temperature. The better the spreading of the molten dosage form, the larger the contact area with the respective mucous membrane, and the better the absorption of the active ingredient. The solubility of the active ingredient in the respective hard fat base influences the release. Rapid release is generally desired, as is rapid melting, so that the suppository does not migrate into the upper rectum, where absorption into the blood vessels leading to the liver can already be observed. This is accompanied by the first-pass effect, which is undesirable for this form of administration and hardly occurs when absorption from the lower rectum into the vena cava leading to the peripheral circulation.In particular, the post-hardening of suppositories or ovules due to polymorphism during prolonged storage can lead to an undesirable reduction in the availability of the active ingredient due to the resulting increase in melting point.
[0005] As an alternative to the use of hard fats in the preparation of suppository or ovule bases, the published patent application EP 1 023 895 A2 discloses A lipophilic, oily base, which may contain cocoa butter but also hard fats, along with polyethylene and additives such as polyglycerol fatty acid esters. The optimization of individual active ingredients through targeted selection of specific compositions appears rather difficult with this expanded mixture of components.
[0006] Patent JP 3 241 162 B2 also discloses the use of polyglycerol fatty acid esters in combination with a lipophilic, oily base, which also contains mono-, di-, and triglycerides, to enable the sustained release of pharmaceutically active ingredients from a suppository base composed in this way. Here, too, the usual hard fats are used and supplemented with additives intended to provide benefits. This disclosure also does not involve a simplification of the composition, and it also exhibits polymorphism.
[0007] The task therefore arises to provide an alternative basis for the production of suppositories and ovules, which retains the advantages of the commonly used hard fats, but no longer has the problem of increases in volume and melting point caused by polymorphism, reduces the number of properties to be taken into account and thus simplifies formulation development.
[0008] This challenge can be solved by the almost exclusive use of polyglycerol fatty acid esters, all of which are characterized by their free miscibility, as the basis for suppositories or ovules, since polyglycerol fatty acid esters exhibit no polymorphism. Surprisingly, it has been shown that the melting temperature, water absorption capacity, emulsification behavior, release of incorporated active ingredients, and breaking strength of the finished product can be easily adjusted by varying the content of polyglycerol fatty acid monoesters. Thus, the advantages of hard fats are retained while eliminating the complications associated with polymorphism.In general, such a polymorphism-free composition can be described as comprising, firstly, one or more polyglycerol fatty acid esters obtainable from a partial or complete esterification of a linear or branched polyglycerol having two to ten glyceryl units with one or more fatty acids each having from 6 to 22 carbon atoms, secondly, 4 to 15% by weight of the polyglycerol fatty acid esters are present as polyglycerol fatty acid monoesters, thirdly, it is free of mono-, di- and triglycerides and fourthly, it has a maximum of 2% by weight of further components resulting from the synthesis.
[0009] The use of polyglycerol fatty acid esters, which are obtained from the esterification of a linear or branched polyglycerol containing four to six glyceryl units with one or more fatty acids, each containing 12 to 18 carbon atoms, has proven particularly advantageous. Particularly good physcochemical properties, including the breaking strength of the base, alone or in combination with active ingredients, are achieved when polyglycerol fatty acid esters with four glyceryl units, which are partially or fully esterified with fatty acids containing 12 to 18 carbon atoms, are used as the first component. The polyglycerol fatty acid esters can also be mixed with one another postsynthetically, for example, a polyglycerol fatty acid partial ester with a polyglycerol fatty acid full ester.
[0010] The second component of the base, i.e. a corresponding polyglycerol fatty acid monoester, should make up 4 to 15 percent by weight of the base, but preferably 7 to 11 percent, particularly preferably 7 to 9 percent. The content of polyglycerol fatty acid monoesters can be adjusted via the synthesis conditions during esterification, in particular by the ratio of pressure to temperature and a precise weighing of the starting materials involved. The polyglycerol fatty acid monoester content of the base also determines its water absorption capacity, which is positively influenced by free hydroxyl groups, particularly on the same glyceryl backbone. It is advantageous, regardless of the exact location of the free hydroxyl groups, if the hydroxyl number of the base is in the range of 150 to 240.
[0011] The saponification number, as a measure of the free and bound fatty acids per gram, also indirectly provides information about the average chain length of the fatty acids used, assuming consistent synthesis quality. For the bases considered here for the production of suppositories or ovules, it is preferably in a range of 130 to 250, particularly preferably in a range of 150 to 190.
[0012] The melting point of the base should preferably be in a range of 35°C to 45°C. In particular, the use of the base in combination with aqueous active ingredient solutions can result in melting point depressions of up to 7°C, so that starting from a base that melts at 45°C, the combination with an aqueous active ingredient solution can result in a suppository or ovule mass with a melting point of 38°C, i.e., only 1°C above body temperature.
[0013] It has proven advantageous if the base, apart from common synthesis residues such as free polyglycerols or residual water, consists entirely of polyglycerol fatty acid esters with a polyglycerol fatty acid monoester content of 4 to 15 percent by weight and is therefore free of additional emulsifiers, whose influence on the physicochemical properties of the suppository or ovular mass to be produced using the base would undesirably require additional testing. Furthermore, the base is preferably free of components with controversial toxicity and potentially irritating mucous membranes, particularly polyethylene or polyethylene glycol, since suppositories are also frequently used in pediatrics.
[0014] The base offers the advantage that it can be combined with both hydrophilic and lipophilic pharmaceutical or cosmetic active ingredients to form a suppository or ovule mass. For this purpose, it is also possible to incorporate suitable pharmaceutical or cosmetic active ingredients into the base, dissolved, emulsified, dispersed, or suspended in a hydrophilic carrier liquid, just as is possible with a lipophilic carrier liquid for suitable active ingredients. The term "carrier liquid" here also includes so-called semi-solid states, such as the state of petroleum jelly at room temperature. It is also possible to mix active ingredients bound to or associated with suitable carrier solids with the suppository or ovule mass.
[0015] Paracetamol and ibuprofen have proven particularly suitable active ingredients for direct incorporation into the base. Lactic acid in water as a hydrophilic carrier fluid is well suited as an aqueous solution for incorporation into the base and preparation of a suppository or ovule mass, as is urea. Hyaluronic acid, which is highly water-absorbent, can also be dispersed in water as sodium hyaluronate with the base to form a suppository or ovule mass. Lipophilic active ingredients such as hemp oil or cannabidiol oil can be incorporated into the base.
[0016] The production of active ingredient-containing suppositories or ovules is achieved by first melting the base, then mixing it in the molten state with at least one active ingredient or an active ingredient-carrier liquid combination to form a still-liquid suppository or ovule mass, and finally shaping and portioning it before, during, or after the suppository or ovule mass has solidified. As a rule, shaping and portioning takes place by pouring the still-liquid suppository mass. The suppository or ovule mass can be formed into appropriate molds, i.e., before solidification. It is also possible to shape the already solidified suppository or ovule mass, for example, using pressing tools, provided there is no risk of sedimentation of the active ingredient during solidification. Finally, the suppository or ovule mass that is in the process of solidification, i.e., already has a higher viscosity than the melt, can also be shaped and portioned using molding tools.
[0017] In the case of lactic acid, which is used in ovules to restore a physiological pH value in the vagina and in cases of vaginal dryness, ovules based on polyethylene glycols with an average relative molecular weight of 1500 and 6000, into which an aqueous lactic acid solution is incorporated, are used according to the state of the art. This is because hard fats are unsuitable as a base due to the physicochemical properties of lactic acid and the risk of phase separation. The release of lactic acid at the site of action occurs through dissolution of the ovule, which is made more difficult in cases of vaginal dryness due to the lack of moisture. However, when an aqueous lactic acid solution is incorporated into the polyglycerol fatty acid ester-based base presented here, the release advantageously occurs through melting of the ovule at body temperature.For this application, polyglycerol 4-myristate / palmitate has proven advantageous as a polyglycerol fatty acid ester. Polyglycerol 4-myristate / palmitate is obtained by esterifying a mixture of myristic and palmitic acid in a ratio of 70:30 mixed with tetraglycerol and is referred to below as polyglycerol 4-myristate / palmitate (70:30).
[0018] Compared to hard fat-based bases, the bases according to claim 1 exhibit a lower flexural strength. They are therefore more elastic and, in the molten state, significantly more viscous, thus exhibiting greater spreadability. This is particularly advantageous when applying corresponding ovules. The flexural strength measurements were carried out using a universal tensile test machine from Coesfeld. The test specimens used were cylindrical suppositories with a torpedo-shaped tip, each weighing 2.0 g, 31 mm long from tip to end, and a 16 mm measuring section, which is 10 mm from the tip and 5 mm from the end of the suppository, to which pressure is exerted using a pressure beam. In preparation, all test specimens were stored at 20°C for 24 hours and only removed and measured immediately before the pressure test.The basic settings of the applied measuring program were as follows: Measuring method: compression test; speed 300 mm / min.; pre-load 0.2 N; maximum force 300 N; delta force: 2 N. Test specimens were fixed during the measurement so that the test specimens remained motionless even under compressive load.
[0019] The following table shows the results of the flexural fracture measurements on corresponding suppositories without active ingredient and with active ingredient in the form of 20% by weight of an 80% lactic acid solution based on polyglycerol-4-myristate or polyglycerol-4-myristate-palmitate (70:30), indicating the percentages of the various degrees of esterification, the hydroxyl number (OHN), the saponification number (VN), the water content, the melting point determined by means of differential scanning calorimetry, and the fracture stress, together with comparison suppositories made from the common hard fats Witepsol H15 and Witepsol W45: Table 1
[0020] For further explanation, two examples of a composition for a suppository or ovule base according to claim 1 and for a suppository or ovule mass according to claim 9 are given below: Example 1 : Basis for suppositories or ovules: Polyglycerol-4-myristate / -palmitate (70:30) with hydroxyl number 183, saponification number 169 and melting point 41.0°C of which 8.2% by weight monoester, 22.5% by weight diester, 31.8% by weight triester, 36.5% by weight tetraester, 0.9 wt% free tetraglycerol, <0.1 wt% water. Example 2: Suppository or ovule mass: 2.00 g mixture of 1 ,60 g base according to Example 1 and 0.40 g of 80% aqueous lactic acid solution with a melting point of 35.2°C or a multiple thereof. Example 3: Basis for suppositories or ovules: Polyglycerol-4-myristate With hydroxyl number 172, saponification number 178 and melting point 38.1 °C of which 8.3 wt% monoester, 24.2 wt% diester, 33.4 wt% triester, 33.7 wt% tetraester, 0.2 wt% free polyglycerol, 0.2 wt% water. Example 4: Suppository or ovule mass: 2.00 g mixture of 1 ,70 g base according to Example 3 and 0.30 g of hemp oil with a melting point of 35.6°C or a multiple thereof.
Claims
CLAIMS 1. Base for suppositories or ovules, composed of several components, characterized in that the composition i) comprises one or more polyglycerol fatty acid esters obtainable from a partial or complete esterification of a linear or branched polyglycerol containing two to ten glyceryl units with one or more fatty acids each having from 6 to 22 carbon atoms ii) and 4 to 15% by weight of polyglycerol fatty acid monoester according to i), iii) is free from mono-, di- and triglycerides iv) and consists of at least 98% by weight of the components of i) and ii).
2. Base according to claim 1, characterized in that the composition comprises as component i) one or more polyglyceryl fatty acid esters having four to six glyceryl units which are partially or fully esterified with fatty acids having 12 to 18 carbon atoms.
3. Base according to claim 1 or 2, characterized in that the composition comprises as component ii) 7 to 9% by weight of polyglycerol fatty acid monoesters.
4. Base according to one of the preceding claims, characterized in that the composition is free from additional emulsifiers.
5. Base according to one of the preceding claims, characterized in that the composition is free from polyethylene and polyethylene glycol.
6. Base according to one of the preceding claims, characterized by a hydroxyl number in a range of 150 to 240.
7. Base according to one of the preceding claims, characterized by a saponification number in a range of 130 to 250.
8. Base according to one of the preceding claims, characterized by a melting point in a range of 35°C to 45°C.
9. Suppository or ovule composition characterized by the base according to one of the preceding claims in combination with one or more cosmetic or pharmaceutical active ingredients.
10. Suppository or ovule mass according to claim 9, characterized in that at least one active ingredient is dissolved, emulsified, dispersed or suspended in a hydrophilic carrier liquid.
11. Suppository or ovule mass according to claim 9 or 10, characterized in that at least one active ingredient is dissolved, emulsified, dispersed or suspended in a lipophilic carrier liquid.
12. Suppository or ovule mass according to one of claims 9 to 11, characterized in that at least one active ingredient is associated with or bound to a solid carrier.
13. Suppository or ovule mass according to one of claims 9 to 12, characterized in that at least one active ingredient comes from the following group: Lactic acid, hyaluronic acid, paracetamol, ibuprofen, urea and their derivatives, hemp oil, cannabidiol oil.
4. A process for the production of suppositories or ovules, characterized by the following steps: i) melting the base according to one of claims 1 to 8, ii) mixing at least one active ingredient or an active ingredient-carrier liquid combination with the melted base to form a suppository or ovule mass according to one of claims 8 to 11, iii) shaping and portioning the suppository or ovule mass before, during or after the suppository or ovule mass has solidified.