阅读说明：本技术 双醋瑞因和健脾利湿药在制备治疗骨关节炎的药物中的应用 (Application of diacerein and spleen-tonifying and dampness-removing medicine in preparation of medicine for treating osteoarthritis ) 是由 王蓉 于 2021-08-05 设计创作，主要内容包括：本发明提供了一种双醋瑞因和健脾利湿药在制备治疗骨关节炎的药物中的应用,研究发现茯苓、白扁豆、薏苡仁、茯苓提取物、白扁豆提取物和薏苡仁提取物等健脾利湿药中含有大量多糖在肠道中能与双醋瑞因代谢产生的大黄酸结合,从而阻止大黄酸向大黄酸蒽酮的转化,显著降低大黄酸蒽酮对肠道的刺激,降低腹泻的发生率,这些物质还能与双醋瑞因胶囊发挥协同作用,显著提升治疗骨关节炎的效果。(The invention provides application of diacerein and spleen-tonifying and dampness-removing medicine in preparation of a medicine for treating osteoarthritis, researches show that poria cocos, white hyacinth beans, coix seeds, poria cocos extracts, white hyacinth bean extracts, coix seed extracts and other spleen-tonifying and dampness-removing medicines contain a large amount of polysaccharides which can be combined with rhein generated by diacerein metabolism in an intestinal tract, so that rhein is prevented from being converted into rhein anthrone, stimulation of rhein anthrone to the intestinal tract is remarkably reduced, and the occurrence rate of diarrhea is reduced.)

1. Use of diacerein and spleen invigorating and dampness removing medicine in preparation of medicine for treating osteoarthritis is provided.

2. The use according to claim 1, characterized in that the ratio of the mass of the spleen-invigorating and dampness-excreting drug to the mass of diacerein is greater than 0 and equal to or less than 3; preferably 1.2-2.4.

3. The use of claim 1 or 2, wherein the spleen-invigorating and dampness-draining drug is at least one selected from the group consisting of poria cocos, poria cocos extract, lablab album extract, coix seed extract, atractylodes macrocephala and atractylodis macrocephala extract.

4. The use of claim 3, wherein the spleen-invigorating and dampness-draining drug is selected from the group consisting of a combination of Poria cocos powder and Coix lacryma-jobi seed powder or a combination of a Poria cocos extract and Coix lacryma-jobi seed extract.

5. The use as claimed in claim 4, wherein the weight ratio of Poria cocos powder to Coix lacryma-jobi seed powder is 1: 2; or the mass ratio of the poria cocos extract to the coix seed extract is 1: 5.

6. A diacerein pharmaceutical composition is characterized by comprising diacerein and a spleen-invigorating and dampness-removing medicine.

7. The pharmaceutical composition according to claim 6, wherein the ratio of the mass of the spleen-invigorating and dampness-excreting drug to the mass of diacerein is greater than 0 and equal to or less than 3; preferably 1.2-2.4.

8. The pharmaceutical composition of claim 6 or 7, wherein the spleen-invigorating and dampness-draining drug is at least one selected from the group consisting of Poria cocos, Poria cocos extract, Dolichos lablab seed extract, Coix seed extract, Atractylodes macrocephala and Atractylodes macrocephala extract; preferably, the spleen-invigorating and dampness-removing medicine is selected from a composition of tuckahoe powder and coix seed powder or a composition of tuckahoe extract and coix seed extract.

9. A pharmaceutical formulation of diacerein, comprising a pharmaceutical composition according to any one of claims 6 to 8, further comprising pharmaceutically acceptable excipients;

preferably, the pharmaceutical preparation comprises, in parts by weight: 50 parts of diacerein; 60-300 parts of spleen-invigorating and dampness-eliminating medicine; 0-200 parts of a filler; 10-30 parts of an adhesive; 0-5 parts of a glidant.

10. The pharmaceutical formulation according to claim 9, comprising, in parts by weight: 50 parts of diacerein and 60 parts of spleen-tonifying and dampness-removing medicine; 173 parts of a filler; 15 parts of an adhesive; and 2 parts of a flow aid.

Technical Field

The invention relates to the technical field of medicines, in particular to application of diacerein and a spleen-tonifying and dampness-removing medicine in preparation of a medicine for treating osteoarthritis.

Background

Diarrhea is a common adverse effect associated with diacerein treatment, is one of drug-induced diarrhea, may occur without any warning, and is escalated to severe diarrhea within hours. Even mild to moderate diarrhea can be life threatening when combined with vomiting, dehydration or neutropenia.

Although broad spectrum antibiotics have been used to eliminate intestinal bacteria from the gastrointestinal tract prior to chemotherapy treatment to reduce reactivation, this approach has some drawbacks. On the one hand, intestinal bacteria play a crucial role in carbohydrate metabolism, vitamin production and processing of bile acids, sterols and xenobiotics. These broad-spectrum antibiotics are not ideal for removing intestinal bacteria and result in poor therapeutic effect for diarrhea. On the other hand, bacterial resistance to antibiotics is a crisis to human health, and unnecessary use of antibiotics is a significant factor contributing to this crisis.

The traditional Chinese medicine therapy is adopted to relieve diarrhea caused by the double vinegar residue treatment, and the traditional Chinese medicine therapy is researched as a brand new treatment method. However, the traditional Chinese medicine compound is usually prepared by mutually matching a plurality of different medicinal materials to achieve the effect of relieving diarrhea, and has the problems of various medicinal flavors, low treatment effect, high cost and poor patient adaptability.

Therefore, a traditional Chinese medicine with less medicinal ingredients, good treatment effect and low cost for relieving the diarrhea caused by the double vinegar residue treatment is needed.

Disclosure of Invention

Therefore, the invention aims to provide the traditional Chinese medicine for relieving diarrhea caused by the double vinegar residue treatment with less medicinal flavor, good treatment effect and low cost and the application thereof in preparing the medicine for treating osteoarthritis.

Therefore, the invention provides the application of diacerein and a spleen-tonifying and dampness-removing medicine in preparing a medicine for treating osteoarthritis.

Further, the ratio of the mass of the spleen-invigorating and dampness-draining medicine to the mass of diacerein is more than 0 and less than or equal to 3; preferably 1.2-2.4.

Further, the spleen-invigorating and dampness-removing medicine is at least one selected from poria cocos, poria cocos extract, white hyacinth bean extract, coix seed extract, bighead atractylodes rhizome and bighead atractylodes rhizome extract.

Further, the spleen-invigorating and dampness-removing medicine is selected from a composition of tuckahoe powder and coix seed powder or a composition of tuckahoe extract and coix seed extract.

Furthermore, the mass ratio of the tuckahoe powder to the coix seed powder is 1: 2; or the mass ratio of the poria cocos extract to the coix seed extract is 1: 5.

The invention also provides a diacerein pharmaceutical composition, which comprises diacerein and a spleen-tonifying and dampness-removing medicine.

Further, the ratio of the mass of the spleen-invigorating and dampness-draining medicine to the mass of diacerein is more than 0 and less than or equal to 3; preferably 1.2-2.4.

Further, the spleen-invigorating and dampness-removing medicine is at least one selected from poria cocos, poria cocos extract, white hyacinth bean extract, coix seed extract, bighead atractylodes rhizome and bighead atractylodes rhizome extract; preferably, the spleen-invigorating and dampness-removing medicine is selected from a composition of tuckahoe powder and coix seed powder or a composition of tuckahoe extract and coix seed extract.

The invention also provides a diacerein pharmaceutical preparation which is characterized by comprising any one of the pharmaceutical compositions and pharmaceutically acceptable auxiliary materials.

The pharmaceutically acceptable auxiliary materials are selected from conventional auxiliary materials such as a filling agent, a bonding agent, a glidant and the like.

Preferably, the pharmaceutical preparation comprises, in parts by weight: 50 parts of diacerein; 60-120 parts of spleen-invigorating and dampness-eliminating medicine; 0-200 parts of a filler; 10-30 parts of an adhesive; 0-5 parts of a glidant.

Further, the coating comprises the following components in parts by weight: 50 parts of diacerein and 60 parts of spleen-tonifying and dampness-removing medicine; 173 parts of a filler; 15 parts of an adhesive; and 2 parts of a flow aid.

For example, lactose, microcrystalline cellulose, starch, or the like can be used as the filler.

The binder can be hypromellose, croscarmellose sodium, etc.

Glidants such as magnesium stearate, silicon dioxide and the like can be used.

The pharmaceutical preparation can be capsules, tablets, granules, powder and other preparations.

The technical scheme of the invention has the following advantages:

the application of diacerein and spleen-tonifying and dampness-removing medicine provided by the invention in preparation of a medicine for treating osteoarthritis is characterized in that the spleen-tonifying and dampness-removing medicines such as poria cocos, white hyacinth bean, coix seed, poria cocos extract, white hyacinth bean extract and coix seed extract contain a large amount of polysaccharide which can be combined with rhein generated by diacerein metabolism in intestinal tracts, so that conversion of rhein to rhein anthrone is prevented, stimulation of rhein anthrone to the intestinal tracts is remarkably reduced, the occurrence rate of diarrhea is reduced, the diarrhea occurrence rate is remarkably different compared with a model group, and researches also find that the substances can play a synergistic effect with diacerein capsules, and the effect of treating osteoarthritis is remarkably improved.

Detailed Description

The following examples are provided to further understand the present invention, not to limit the scope of the present invention, but to provide the best mode, not to limit the content and the protection scope of the present invention, and any product similar or similar to the present invention, which is obtained by combining the present invention with other prior art features, falls within the protection scope of the present invention.

The examples do not show the specific experimental steps or conditions, and can be performed according to the conventional experimental steps described in the literature in the field. The reagents or instruments used are not indicated by manufacturers, and are all conventional reagent products which can be obtained commercially. Wherein the Poria extract, semen lablab album extract, Coicis semen extract, and Atractylodis rhizoma extract are obtained by soaking, pulverizing, pulping, collecting precipitate, and drying.

In the invention, the tuckahoe extract is obtained by taking tuckahoe, soaking for 12 hours, crushing and grinding into slurry, washing with clear water, collecting precipitate, dehydrating and drying. The white hyacinth bean extract is prepared by soaking white hyacinth bean for 8 hours, crushing and grinding, washing with clear water, collecting precipitate, dehydrating and drying. The Coicis semen extract is prepared by soaking Coicis semen for 16 hr, pulverizing, grinding into slurry, washing with clear water, collecting precipitate, dehydrating, and drying. The Atractylodis rhizoma extract is prepared by soaking Atractylodis rhizoma for 8 hr, pulverizing, grinding into slurry, washing with clear water, collecting precipitate, dehydrating, and drying.

The Poria powder, semen lablab album powder, Coicis semen powder, and Atractylodis rhizoma powder are prepared by pulverizing Poria, semen lablab album, Coicis semen, and Atractylodis rhizoma, and sieving (for example, 60 mesh sieve). Lactose, croscarmellose sodium and magnesium stearate all conform to the regulations of the 2020 edition of Chinese pharmacopoeia. Before use, diacerein is sieved by a 60-mesh sieve, croscarmellose sodium is sieved by a 24-mesh sieve, magnesium stearate is sieved by a 40-mesh sieve, and the lactose is 60-mesh lactose. Sieving Poria powder, semen lablab album powder, Coicis semen powder, Atractylodis rhizoma powder, Poria extract, semen lablab album extract, Coicis semen extract, and Atractylodis rhizoma extract with 60 mesh sieve.

Example 1

This example provides a pharmaceutical composition comprising 50g diacerein and 60g poria extract.

The embodiment also provides a capsule, which comprises the pharmaceutical composition, 173g of lactose (60 meshes), 15g of croscarmellose sodium and 2g of magnesium stearate.

The preparation method of the capsule comprises the following steps: the lactose 60 meshes, the tuckahoe extract, the diacerein and the croscarmellose sodium with the prescription amount are put into a V-shaped mixer for premixing for 10 minutes, then the magnesium stearate is added for mixing for 3 minutes, and a No. 1 hard capsule is filled by a capsule filling machine according to the specification of 0.3 g/capsule, and packaged: inspecting to remove the defective capsule, and polishing. And packaging the qualified capsules by using aluminum-plastic composite film bubble caps.

Example 2

The embodiment provides a pharmaceutical composition, which comprises 50g of diacerein and 60g of poria cocos powder.

The embodiment also provides a capsule, which comprises the pharmaceutical composition, 173g of lactose (60 meshes), 15g of croscarmellose sodium and 2g of magnesium stearate.

The preparation method of the capsule comprises the following steps: the lactose 60 meshes, the tuckahoe powder, the diacerein and the croscarmellose sodium with the prescription amount are put into a V-shaped mixer for premixing for 10 minutes, then the magnesium stearate is added for mixing for 3 minutes, and a No. 1 hard capsule is filled by a capsule filling machine according to the specification of 0.3 g/capsule, and is packaged: inspecting to remove the defective capsule, and polishing. And packaging the qualified capsules by using aluminum-plastic composite film bubble caps.

Example 3

This example provides a pharmaceutical composition comprising 50g diacerein and 90g of white hyacinth bean extract.

The embodiment also provides a capsule, which comprises the pharmaceutical composition, 143g of lactose (60 meshes), 15g of croscarmellose sodium and 2g of magnesium stearate.

The preparation method of the capsule comprises the following steps: the lactose 60 meshes, the white hyacinth bean extract, the diacerein and the croscarmellose sodium are added into a V-shaped mixer for premixing for 10 minutes, then the magnesium stearate is added for mixing for 3 minutes, and a No. 1 hard capsule is filled by a capsule filling machine according to the specification of 0.3 g/capsule, and packaged: inspecting to remove the defective capsule, and polishing. And packaging the qualified capsules by using aluminum-plastic composite film bubble caps.

Example 4

This example provides a pharmaceutical composition comprising 50g diacerein and 90g hyacinth bean flour.

The embodiment also provides a capsule, which comprises the pharmaceutical composition, 143g of lactose (60 meshes), 15g of croscarmellose sodium and 2g of magnesium stearate.

The preparation method of the capsule comprises the following steps: the lactose 60 meshes, the white hyacinth bean powder, the diacerein and the croscarmellose sodium are added into a V-shaped mixer for premixing for 12 minutes, then the magnesium stearate is added for mixing for 3 minutes, and a No. 1 hard capsule is filled by a capsule filling machine according to the specification of 0.3 g/capsule, and packaged: inspecting to remove the defective capsule, and polishing. And packaging the qualified capsules by using aluminum-plastic composite film bubble caps.

Example 5

The embodiment provides a pharmaceutical composition, which comprises 50g of diacerein and 120g of coix seed extract.

The embodiment also provides a capsule, which comprises the pharmaceutical composition, 143g of lactose (60 meshes), 15g of croscarmellose sodium and 2g of magnesium stearate.

The preparation method of the capsule comprises the following steps: the preparation method comprises the following steps of putting lactose 60 meshes, coix seed extract, diacerein and croscarmellose sodium into a V-shaped mixer, premixing for 12 minutes, adding magnesium stearate, mixing for 3 minutes, filling a No. 1 hard capsule by using a capsule filling machine according to the specification of 0.3 g/capsule, and packaging: inspecting to remove the defective capsule, and polishing. And packaging the qualified capsules by using aluminum-plastic composite film bubble caps.

Example 6

The embodiment provides a pharmaceutical composition, which comprises 50g of diacerein and 120g of coix seed powder.

The embodiment also provides a capsule, which comprises the pharmaceutical composition, 143g of lactose (60 meshes), 15g of croscarmellose sodium and 2g of magnesium stearate.

The preparation method of the capsule comprises the following steps: the lactose 60 meshes, the coix seed powder, the diacerein and the croscarmellose sodium are added into a V-shaped mixer for premixing for 10 minutes, then the magnesium stearate is added for mixing for 3 minutes, and a No. 1 hard capsule is filled by a capsule filling machine according to the specification of 0.3 g/capsule, and packaged: inspecting to remove the defective capsule, and polishing. And packaging the qualified capsules by using aluminum-plastic composite film bubble caps.

Example 7

The embodiment provides a pharmaceutical composition, which comprises 50g of diacerein, 10g of poria cocos extract and 50g of coix seed extract.

The embodiment also provides a capsule, which comprises the pharmaceutical composition, 173g of lactose (60 meshes), 15g of croscarmellose sodium and 2g of magnesium stearate.

The preparation method of the capsule comprises the following steps: adding lactose 60 mesh, Poria extract, Coicis semen extract, diacerein, and croscarmellose sodium into V-type mixer, premixing for 10 min, adding magnesium stearate, mixing for 3 min, filling No. 1 hard capsule with capsule filling machine according to specification of 0.3 g/capsule, and packaging: inspecting to remove the defective capsule, and polishing. And packaging the qualified capsules by using aluminum-plastic composite film bubble caps.

Example 8

The embodiment provides a pharmaceutical composition, which comprises 50g of diacerein, 20g of white hyacinth bean extract and 40g of coix seed extract.

The embodiment also provides a capsule, which comprises the pharmaceutical composition, 173g of lactose (60 meshes), 15g of croscarmellose sodium and 2g of magnesium stearate.

The preparation method of the capsule comprises the following steps: the prescription dose of lactose 60 meshes, white hyacinth bean extract, coix seed extract, diacerein and croscarmellose sodium are put into a V-shaped mixer for premixing for 10 minutes, magnesium stearate is added for mixing for 3 minutes, and a No. 1 hard capsule is filled by a capsule filling machine according to the specification of 0.3 g/capsule, and packaged: inspecting to remove the defective capsule, and polishing. And packaging the qualified capsules by using aluminum-plastic composite film bubble caps.

Example 9

The embodiment provides a pharmaceutical composition, which comprises 50g of diacerein, 20g of tuckahoe powder and 40g of coix seed powder.

The embodiment also provides a capsule, which comprises the pharmaceutical composition, 173g of lactose (60 meshes), 15g of croscarmellose sodium and 2g of magnesium stearate.

The preparation method of the capsule comprises the following steps: the lactose 60 meshes, the tuckahoe powder, the coix seed powder, the diacerein and the croscarmellose sodium with the prescription amount are put into a V-shaped mixer for premixing for 10 minutes, then the magnesium stearate is added for mixing for 3 minutes, and the No. 1 hard capsule is filled by a capsule filling machine according to the specification of 0.3 g/granule, and packaged: inspecting to remove the defective capsule, and polishing. And packaging the qualified capsules by using aluminum-plastic composite film bubble caps.

Example 10

The embodiment provides a pharmaceutical composition, which comprises 50g of diacerein, 50g of white hyacinth bean powder and 10g of coix seed powder.

The embodiment also provides a capsule, which comprises the pharmaceutical composition, 173g of lactose (60 meshes), 15g of croscarmellose sodium and 2g of magnesium stearate.

The preparation method of the capsule comprises the following steps: the lactose 60 meshes, the white hyacinth bean powder, the coix seed powder, the diacerein and the croscarmellose sodium are added into a V-shaped mixer for premixing for 10 minutes, then the magnesium stearate is added for mixing for 3 minutes, and the No. 1 hard capsule is filled by a capsule filling machine according to the specification of 0.3 g/granule, and packaged: inspecting to remove the defective capsule, and polishing. And packaging the qualified capsules by using aluminum-plastic composite film bubble caps.

Example 11

The embodiment provides a pharmaceutical composition, which comprises 50g of diacerein and 60g of bighead atractylodes rhizome powder.

The embodiment also provides a capsule, which comprises the pharmaceutical composition, 173g of lactose (60 meshes), 15g of croscarmellose sodium and 2g of magnesium stearate.

The preparation method of the capsule comprises the following steps: the lactose 60 meshes, the largehead atractylodes rhizome powder, the diacerein and the croscarmellose sodium are added into a V-shaped mixer according to the prescription amount, premixed for 10 minutes, then added with magnesium stearate, mixed for 3 minutes, filled by a capsule filling machine according to the specification of 0.3 g/capsule by a No. 1 hard capsule, and packaged: inspecting to remove the defective capsule, and polishing. And packaging the qualified capsules by using aluminum-plastic composite film bubble caps.

Example 12

This example provides a pharmaceutical composition comprising 50g diacerein and 60g atractylodes macrocephala extract.

The embodiment also provides a capsule, which comprises the pharmaceutical composition, 173g of lactose (60 meshes), 15g of croscarmellose sodium and 2g of magnesium stearate.

The preparation method of the capsule comprises the following steps: the lactose 60 meshes, the white atractylodes rhizome extract, the diacerein and the croscarmellose sodium are added into a V-shaped mixer for premixing for 10 minutes, then the magnesium stearate is added for mixing for 3 minutes, and a No. 1 hard capsule is filled by a capsule filling machine according to the specification of 0.3 g/capsule, and packaged: inspecting to remove the defective capsule, and polishing. And packaging the qualified capsules by using aluminum-plastic composite film bubble caps.

Comparative example 1

The embodiment also provides a capsule, which comprises 50g of diacerein, 233g of lactose (60 meshes), 15g of croscarmellose sodium and 2g of magnesium stearate.

The preparation method of the capsule comprises the following steps: the lactose 60 meshes, diacerein and croscarmellose sodium in the prescription amount are put into a V-shaped mixer for premixing for 10 minutes, then magnesium stearate is added for mixing for 3 minutes, and a No. 1 hard capsule is filled by a capsule filling machine according to the specification of 0.3 g/capsule, and packaged: inspecting to remove the defective capsule, and polishing. And packaging the qualified capsules by using aluminum-plastic composite film bubble caps.

Experimental example 1

280 clean-grade mice, half of each mouse, and 18-22 g of body weight. Groups were randomized into 14, blank A, comparative 1, examples 1-12, and 20 each. The groups of examples 1-12 and the group of comparative example 1 are respectively prepared by adding purified water into the capsule content of each example and comparative example to prepare 0.6g/ml suspension for administration, and performing intragastric administration at a dose of 0.1ml/10g each time, and performing 1 time respectively in the morning and at the evening. The blank control group was gavaged with saline of the same volume. The maximum is 10 days of continuous gavage, diarrhea is indicated when soft, thin stools or mucus appear, the number of days D of diarrhea is recorded, the mice complete the test and are not dosed any more subsequently. If no diarrhea was observed within 10 days, the score was 11.

Evaluation indexes are as follows: incidence of diarrhea ═ 11n-D₁-D₂-D₃-D₄-D₅-D₆…-D_n) And/n, note: n is the number of mice completing the test, and the mice falling off in the middle are eliminated.

The results are shown in Table 1.

TABLE 1 incidence of diarrhea/%)

As can be seen from the results, examples 1 to 12 significantly reduced the incidence of diarrhea compared to control 1. There was no significant difference in the incidence of diarrhea between examples 1, 3 and 5, with examples 7 and 9 being the best. Compared with the group of comparative example 1, the groups of examples 11 to 12 added with the powder or extract of white atractylodes rhizome, which had the general function of invigorating spleen and eliminating dampness, could improve the function of gastrointestinal tract and reduce the incidence of diarrhea. However, the polysaccharide component is less and cannot be fully combined with rhein generated by metabolism of diacerein, so the effect of reducing the conversion of rhein to rhein anthrone is not ideal, and the diarrhea incidence rate is obviously improved compared with the groups of examples 1-10.

Experimental example 2

Experimental animals: SPF grade SD rat, healthy, 6-8W, male, body weight 180-200 g.

Modeling osteoarthritis: SD rats are raised in SPF environment, are raised adaptively for 7 days, and are injected with 0.2ml of iodoacetic acid into joint cavities of the rats at a time. Osteoarthritis model rats were obtained 10 days later.

Osteoarthritis model rats 60, randomly divided into three groups: blank control group, diacerein + poria extract group. The diacerein group is prepared into 0.2g/ml suspension by adding purified water into commercially available diacerein capsule powder, and the suspension is subjected to intragastric administration at a dose of 0.1ml/10g each time, and is administered 1 time respectively in the morning and at night. The diacerein and poria extract group is prepared into 0.2g/ml suspension by using the capsule powder obtained in example 1 and adding purified water, and the suspension is subjected to intragastric administration for 1 time respectively in the morning and evening according to 0.1ml/10 g. The blank control group was gavaged with saline of the same volume. The gavage was continued for 5 days and TNF-. alpha.levels in rat serum were measured on day 6.

TABLE 2 TNF-alpha concentration assay results (ng/L) in rat serum

Group of	n	TNF-alpha concentration
			Blank control group	18	173.93±5.27
Comparative example 1 group	20	148.42±4.26
			EXAMPLE 1 group	19	131.27±3.31

The above results show that: diacerein has the effect of reducing the concentration of TNF-alpha in the serum of a rat with an osteoarthritis model, diacerein and a poria cocos extract further reduce the concentration of TNF-alpha in the serum of a rat with an osteoarthritis model, and the concentration of TNF-alpha is directly related to osteoarthritis, so that the poria cocos extract is used in a diacerein pharmaceutical composition and can play a synergistic effect and enhance the treatment effect of diacerein.

It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.